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Sample records for galactorrhea syndrome caused

  1. [Primary glucocorticoid resistance syndrome presenting as pseudo-precocious puberty and galactorrhea].

    PubMed

    Xiang, Shu-lin; He, Li-ping; Ran, Xing-wu; Tian, Hao-ming; Li, Xiu-jun; Liang, Jin-zhong

    2008-09-01

    Primary glucocorticoid resistance syndrome (PGRS) is a rare condition characterized by hypercortisolism without Cushing's syndrome. This report describes a 7-year-old boy of PGRS with pseudo-precocious puberty and galactorrhea as the main manifestation. His height was 135 cm and body weight was 31 kg. Pigmentation could be seen in the skin, mammary areola and penis. He had hirsutism, low hair line, coarse voice, Tanner stage 3 pubic hair, penis in adult form, accelerated linear growth, and advanced bone age (13 yr.), but normal (for age) testes. Furthermore, he had mammoplasia and galactorrhea. There were no features of glucocorticoid (GC) excess. Hepatic function was impaired (ALT 1426 IU/L, AST 611 IU/L) with no definite causes. Serum cortisol concentration was 1294 nmol/L, 777 nmol/L, 199.3 nmol/L at 8:00, 16:00 and 24:00 respectively. Plasma adrenocorticotropic hormone (ACTH) was normal or a little higher (43.9-80 ng/L). Urinary-free cortisol (UFC) was normal (55.5-62.4 microg/24 h). Serum estradiol (E2), progesterone (P), testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were normal. Serum dehydroepiandrosterone sulfate (DHEAS, 60 microg/dL) and serum prolactin (PRL, 58.7-183.9 ng/mL) level were high, urinary dehydroepiandrosterone (DHEA) level was also elevated (0.96-3.2 mg/mL). Gonadotrophin hormone-releasing hormone (GnRH) stimulation test was negative. Serum cortisol responded normally to insulin-induced hypoglycemia. However, serum cortisol and plasma ACTH concentration was suppressed to more than 50% by 0.5 mg dexamethasone (DEX). The diagnosis of PGRS was made. TREATMENT AND FOLLOW-UP: The patient received a treatment of 0.75-1.0 mg/d DEX. Because of galactorrhea, bromocriptine was given by 1.25-3.75 mg/d. After 24 months follow-up, the pigmentation was relieved and galactorrhea disappeared. No advanced development of the external genitalia and breast was found. The acceleration of the bone age was also slowed down. But

  2. A 33-Year-Old Man with Gynaecomastia and Galactorrhea as the First Symptoms of Graves Hyperthyroidism.

    PubMed

    Khoohaphatthanakul, Somdul; Sriwijitkamol, Apiradee

    2016-01-01

    Graves' hyperthyroidism has a various number of well-recognized manifestations. Galactorrhea is a rare manifestation in this disease. We describe a 33-year-old man who presented with the symptoms of hyperthyroidism, gynaecomastia, and galactorrhea for 2 months. Physical examination revealed goitre, gynaecomastia, and galactorrhea, bilaterally. Laboratory investigations demonstrated high free thyroxine with suppressed thyroid-stimulating hormone level together with elevated anti-TSH receptor; therefore, the diagnosis of Graves' disease was confirmed. Other investigations to elucidate the etiology of galactorrhea were normal, so the galactorrhea was hypothesized to be caused by Graves' disease. The gynaecomastia and galactorrhea resolved with the successful treatment of hyperthyroidism. Although the galactorrhea is extremely rare in thyrotoxicosis male patients, to the best of our knowledge, this is the third case which reported gynaecomastia and galactorrhea in male patient who presented with thyrotoxicosis.

  3. Galactorrhea

    MedlinePlus

    ... milky discharge. It is not related to milk production in breastfeeding. The breasts may leak only when ... some things you can do to help. Avoid stimulating your breasts. Avoid touching your nipples during sexual ...

  4. Euprolactinemic Gynecomastia and Galactorrhea with Risperidone-Fluvoxamine Combination

    PubMed Central

    P.J., Pratheesh; Praharaj, Samir Kumar; Srivastava, Ashish

    2011-01-01

    Risperidone is associated with hyperprolactinemia and its consequent symptoms such as gynnecomastia, galactorrhea and sexual dysfunction in adults, and less so in adolescents. Rarely, serotonin reuptake inhibitors are also associated with such adverse effects. We report a case of gynecomastia and galactorrhea in an adolescent male while on a combination of risperidone and fluvoxamine, although the serum prolactin was within normal range. PMID:22506441

  5. What Causes Rett Syndrome?

    MedlinePlus

    ... early-onset seizure variant of Rett syndrome. Human Molecular Genetics , Jul 15;14(14), 1935–1946. Retrieved June ... Dragich, J., & Schanen, C. (2003). Rett Syndrome: Clinical-Molecular Correlates. In G. Fisch (Ed.), Genetics and neurobehavioral disorders (pp. 391–418). Totowa, NJ: ...

  6. Acute compartment syndrome caused by uncontrolled hypothyroidism.

    PubMed

    Modi, Anar; Amin, Hari; Salzman, Matthew; Morgan, Farah

    2017-06-01

    Acute compartment syndrome is increased tissue pressure exceeding perfusion pressure in a closed compartment resulting in nerve and muscle ischemia. Common precipitating causes are crush injuries, burns, substance abuse, osseous or vascular limb trauma. This is a case of 42year old female with history of hypothyroidism who presented to emergency room with acute onset of severe pain and swelling in right lower extremity. Physical examination was concerning for acute compartment syndrome of right leg which was confirmed by demonstration of elevated compartmental pressures. No precipitating causes were readily identified. Further laboratory testing revealed uncontrolled hypothyroidism. Management included emergent fasciotomy and initiating thyroid hormone replacement. This case represents a rare association between acute compartment syndrome and uncontrolled hypothyroidism. We also discuss the pathogenesis of compartment syndrome in hypothyroid patients and emphasize the importance of evaluating for less common causes, particularly in setting of non-traumatic compartment syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. An uncommon cause of anaemia: Sheehan's syndrome.

    PubMed

    Melchardt, Thomas; Namberger, Konrad; Weiss, Lukas; Egle, Alexander; Faber, Viktoria; Greil, Richard

    2010-12-01

    Ischemic pituitary necrosis due to severe postpartum haemorrhage called Sheehan's syndrome is a rare cause of hypopituitarism in the western world, but much more common in developing countries. A 45-year-old female patient being a war refugee from Chechnya with severe anaemia and fatigue was diagnosed at our outpatient department with Sheehan's syndrome after severe postpartum haemorrhage and emergency hysterectomy 15 years ago. Panhypopituitarism was adequately treated with substitution of hydrocortisone, thyroxine and transdermal oestrogen which resulted in haemoglobin increase to nearly normal levels and symptoms improved immediately. Severe anaemia caused by panhypopituitarism shows the importance of the hormonal system for erythropoiesis. Clinical and basic scientific evidence indicates thyroidal hormones to be the main cause.

  8. Dysphagia caused by a lateral medullary infarction syndrome (Wallenberg's syndrome)

    PubMed Central

    El Mekkaoui, Amine; Irhoudane, Hanane; Ibrahimi, Adil; El Yousfi, Mounia

    2012-01-01

    A 68-year-old man was referred to our hospital for a dysphagia evolving for 10 days. Clinical examination had found neurological signs as contralateral Horner's syndrome, ipsilateral palatal paresis, gait ataxia and hoarseness. Video-fluoroscopy showed a lack of passage of contrast medium to the distal esophagus. Esogastroduodenoscopy was normal. The cranial MRI had shown an acute ischemic stroke in the left lateral medullar region and the diagnosis of Wallenberg syndrome (WS) was established. WS remains an unknown cause of dysphagia in the clinical practice of the gastroenterologist. PMID:23077713

  9. Infrasellar pituitary gangliocytoma causing Cushing's syndrome.

    PubMed

    Domingue, Marie-Eve; Marbaix, Etienne; Do Rego, Jean-Luc; Col, Vincent; Raftopoulos, Christian; Duprez, Thierry; Vaudry, Hubert; Maiter, Dominique

    2015-10-01

    Pituitary gangliocytomas are uncommon neuronal tumours that may present with endocrine disorders, the most frequent being acromegaly caused by growth hormone hypersecretion. Cushing's syndrome is very rarely seen with gangliocytomas. We report the unique case of a 62 year-old woman whose clinical picture and endocrine testing clearly demonstrated adrenocorticotropin (ACTH)-dependent Cushing's syndrome. Pituitary magnetic resonance imaging showed a 12-mm homogeneous, infra- and retrosellar mass first diagnosed as pituitary macroadenoma. Transsphenoidal surgery was performed and allowed complete resection of the tumour with sparing of normal anterior pituitary. Very low postoperative serum cortisol and ACTH levels were observed in the early postoperative period and the patient is still in remission 18 months after surgery, thus demonstrating that the resected lesion was entirely responsible for the clinical picture. Histological and immunocytochemical analyses demonstrated a benign tumour composed of mature neuronal cells suggestive of a gangliocytoma, expressing both ACTH and corticotropin-releasing hormone (CRH). The tumour was surrounded by a rim of pituitary tissue containing ACTH-producing endocrine cells. Careful analysis of the resected lesion did not reveal any pituitary microadenoma. We search literature for similar cases and retraced only nine cases of gangliocytomas associated with Cushing's syndrome. In most of them, the tumour was combined with either pituitary corticotroph adenoma or hyperplasia. Our case represents a unique case of an infrasellar pituitary gangliocytoma which was able to cause Cushing's syndrome by both direct ACTH production and CRH-induced stimulation of neighbour normal corticotroph cells.

  10. [Case of posterior reversible encephalopathy syndrome caused by Fisher syndrome].

    PubMed

    Yokoi, Katsunori; Ando, Tetsuo; Kawakami, Osamu

    2018-01-26

    This report presents a case of a 71-year-old woman with Fisher syndrome who had posterior reversible encephalopathy syndrome (PRES) before the initiation of intravenous immunoglobulin (IVIg) treatment. She had symptoms of common cold 2 weeks before the onset of PRES. On the day of the onset, she began to stagger while walking. On day 2, she developed hypertension, vision impairment, and limb weakness and was admitted to the hospital. On day 3, she was provided steroid pulse therapy. On day 4, she developed convulsions and right imperfection single paralysis and was transferred to the our hospital. During the transfer, the patient was conscious. Her blood pressure was high at 198/107 mmHg. She had mild weakness in her limbs and face, light perception in both eyes, dilation of both pupils, total external ophthalmoplegia, no tendon reflexes, and limb and trunk ataxia. We diagnosed PRES because of the high signal intensities observed on T 2 -weighted MRI on both sides of the parietal and occipital lobes. We also diagnosed Fisher syndrome because of a positive anti-GQ1b immunoglobulin G antibody test and albuminocytologic dissociation in the cerebrospinal fluid. PRES showed prompt improvement with antihypertensive therapy, whereas Fisher syndrome slowly improved over a course of 2 months. This case is the first report of PRES without IVIg suggesting that Fisher syndrome induces hypertension and causes PRES.

  11. Sudden infant death syndrome caused by poliomyelitis.

    PubMed

    Dunne, J W; Harper, C G; Hilton, J M

    1984-07-01

    Most seemingly well infants who die suddenly and unexpectedly have no adequate cause of death found on thorough postmortem examination. Respiratory and enteric viruses are often present, especially in the upper respiratory tract, but the infective process seems, of itself, insufficient to cause death. In the remainder of the cases, a variety of lesions will be discovered, including viral myocarditis, bronchiolitis, and sepsis. We report a case of sudden and unexpected death in a 5-week-old male infant due to acute anterior poliomyelitis. This case illustrates the importance of a thorough postmortem examination, including histologic studies of the brain stem and spinal cord in cases of sudden infant death syndrome.

  12. [Toxic shock syndrome caused by pyogenic bacteria].

    PubMed

    Gábor, Zsuzsa; Szekeres, Sándor; Gacs, Mária

    2003-01-12

    Case reports and review of the literature. Severe toxic shock syndrome caused by invasive infection with pyogenic bacteria Staphylococcus aureus or group A Streptococcus pyogenes, with high mortality rates in cases of the latter, remained one of the most problematic chapters of critical care medicine to date. To give an overview on the epidemiology, clinical manifestations, the complex therapeutical approaches of the syndrome and, on the role and mechanisms of action of bacterial superantigens in the pathophysiological processes as well. Literary data, and some illustrative selected cases demonstrate that, the incidence of TSS shows increasing tendency worldwide and, that otherwise healthy, younger people are the most frequently affected. As for prognosis: early diagnosis and treatment with sufficient radicality are of decisive importance.

  13. LRIG2 mutations cause urofacial syndrome.

    PubMed

    Stuart, Helen M; Roberts, Neil A; Burgu, Berk; Daly, Sarah B; Urquhart, Jill E; Bhaskar, Sanjeev; Dickerson, Jonathan E; Mermerkaya, Murat; Silay, Mesrur Selcuk; Lewis, Malcolm A; Olondriz, M Beatriz Orive; Gener, Blanca; Beetz, Christian; Varga, Rita E; Gülpınar, Omer; Süer, Evren; Soygür, Tarkan; Ozçakar, Zeynep B; Yalçınkaya, Fatoş; Kavaz, Aslı; Bulum, Burcu; Gücük, Adnan; Yue, Wyatt W; Erdogan, Firat; Berry, Andrew; Hanley, Neil A; McKenzie, Edward A; Hilton, Emma N; Woolf, Adrian S; Newman, William G

    2013-02-07

    Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease. We have previously shown that UFS is also caused by mutations in HPSE2, encoding heparanase-2. LRIG2 and heparanase-2 were immunodetected in nerve fascicles growing between muscle bundles within the human fetal bladder, directly implicating both molecules in neural development in the lower urinary tract. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  14. LRIG2 Mutations Cause Urofacial Syndrome

    PubMed Central

    Stuart, Helen M.; Roberts, Neil A.; Burgu, Berk; Daly, Sarah B.; Urquhart, Jill E.; Bhaskar, Sanjeev; Dickerson, Jonathan E.; Mermerkaya, Murat; Silay, Mesrur Selcuk; Lewis, Malcolm A.; Olondriz, M. Beatriz Orive; Gener, Blanca; Beetz, Christian; Varga, Rita E.; Gülpınar, Ömer; Süer, Evren; Soygür, Tarkan; Özçakar, Zeynep B.; Yalçınkaya, Fatoş; Kavaz, Aslı; Bulum, Burcu; Gücük, Adnan; Yue, Wyatt W.; Erdogan, Firat; Berry, Andrew; Hanley, Neil A.; McKenzie, Edward A.; Hilton, Emma N.; Woolf, Adrian S.; Newman, William G.

    2013-01-01

    Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease. We have previously shown that UFS is also caused by mutations in HPSE2, encoding heparanase-2. LRIG2 and heparanase-2 were immunodetected in nerve fascicles growing between muscle bundles within the human fetal bladder, directly implicating both molecules in neural development in the lower urinary tract. PMID:23313374

  15. Emerging Hyperprolactinemic Galactorrhea in Obsessive Compulsive Disorder with a Stable Dose of Fluoxetine.

    PubMed

    Chatterjee, Seshadri Sekhar; Mitra, Sayantanava; Mallik, Nitu

    2015-12-31

    While fluoxetine (FXT) is a frequently prescribed selective serotonin reuptake inhibitor (SSRI), with few major side-effects; altered serotonergic transmissions in hypothalamic pathways might lead to a distressing, and often embarrassing, manifestation of galactorrhea by altering prolactin release in those on FXT. We report here a case of FXT-induced hyperprolactinemic galactorrhea developing late into treatment on a stable regimen, who responded well to subsequent replacement with sertraline. Based on present finding, we suggest that while SSRIs may share similar mechanisms of action, there exist individual differences in their effects on prolactin secretion pathways.

  16. SKIV2L Mutations Cause Syndromic Diarrhea, or Trichohepatoenteric Syndrome

    PubMed Central

    Fabre, Alexandre; Charroux, Bernard; Martinez-Vinson, Christine; Roquelaure, Bertrand; Odul, Egritas; Sayar, Ersin; Smith, Hilary; Colomb, Virginie; Andre, Nicolas; Hugot, Jean-Pierre; Goulet, Olivier; Lacoste, Caroline; Sarles, Jacques; Royet, Julien; Levy, Nicolas; Badens, Catherine

    2012-01-01

    Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease. PMID:22444670

  17. Preterm labor: one syndrome, many causes.

    PubMed

    Romero, Roberto; Dey, Sudhansu K; Fisher, Susan J

    2014-08-15

    Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment. Copyright © 2014, American Association for the Advancement of Science.

  18. Break-dance: an unusual cause of hammer syndrome.

    PubMed

    Schneider, Frédéric; Milesi, Ilaria; Haesler, Erik; Wicky, Stephan; Schnyder, P; Denys, Alban

    2002-01-01

    We report the case of a young break-dancer presenting with hammer syndrome. This syndrome has been correlated with many professional and recreational activities but this is, to our knowledge, the first description of hammer syndrome caused by break-dancing. The etiology, diagnosis and treatment modalities of this rare syndrome are considered.

  19. Break-Dance: An Unusual Cause of Hammer Syndrome

    SciT

    Schneider, Frederic; Milesi, Ilaria; Haesler, Erik

    2002-08-15

    We report the case of a young break-dancer presenting with hammer syndrome. This syndrome has been correlated with many professional and recreational activities but this is, to our knowledge, the first description of hammer syndrome caused by break-dancing. The etiology, diagnosis and treatment modalities of this rare syndrome are considered.

  20. Piriformis syndrome: a cause of nondiscogenic sciatica.

    PubMed

    Cass, Shane P

    2015-01-01

    Piriformis syndrome is a nondiscogenic cause of sciatica from compression of the sciatic nerve through or around the piriformis muscle. Patients typically have sciatica, buttocks pain, and worse pain with sitting. They usually have normal neurological examination results and negative straight leg raising test results. Flexion, adduction, and internal rotation of the hip, Freiberg sign, Pace sign, and direct palpation of the piriformis cause pain and may reproduce symptoms. Imaging and neurodiagnostic studies are typically normal and are used to rule out other etiologies for sciatica. Conservative treatment, including medication and physiotherapy, is usually helpful for the majority of patients. For recalcitrant cases, corticosteroid and botulinum toxin injections may be attempted. Ultrasound and other imaging modalities likely improve accuracy of injections. Piriformis tenotomy and decompression of the sciatic nerve can be done for those who do not respond.

  1. Red man syndrome caused by vancomycin powder.

    PubMed

    Nagahama, Yasunori; VanBeek, Marta J; Greenlee, Jeremy D W

    2018-04-01

    Red man syndrome (RMS) is a well-known hypersensitivity reaction caused by intravenous administration of vancomycin, with symptoms ranging from flushing, erythematous rash, pruritus, mild to profound hypotension, and even cardiac arrest. RMS has not previously been described from local application of vancomycin powder in a surgical wound, a technique increasingly utilized for infection prophylaxis in many surgical disciplines including neurosurgery. We describe the first reported case of RMS as a result of local intra-wound application of vancomycin powder for infection prophylaxis. A 73-year-old male with a history of Parkinson's disease underwent 2-stage deep brain stimulation implantation surgeries. Vancomycin powder was applied locally in the surgical wounds for infection prophylaxis during both of the surgeries. The patient developed a well-demarcated, geometric erythematous pruritic rash following the second surgery that was clinically diagnosed as RMS and resolved without sequelae. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Hyperthyroidism caused by acquired immune deficiency syndrome.

    PubMed

    Wang, J-J; Zhou, J-J; Yuan, X-L; Li, C-Y; Sheng, H; Su, B; Sheng, C-J; Qu, S; Li, H

    2014-01-01

    Acquired immune deficiency syndrome (AIDS) is an immune deficiency disease. The etiology of hyperthyroidism, which can also be immune-related, is usually divided into six classical categories, including hypophyseal, hypothalamic, thyroid, neoplastic, autoimmune and inflammatory hyperthyroidism. Hyperthyroidism is a rare complication of highly active antimicrobial therapy (HAART) for human immunodeficiency virus (HIV). Hyperthyroidism caused directly by AIDS has not been previously reported. A 29-year-old man who complained of dyspnea and asthenia for 1 month, recurrent fever for more than 20 days, and breathlessness for 1 week was admitted to our hospital. The thyroid function test showed that the level of free thyroxine (FT4) was higher than normal and that the level of thyroid-stimulating hormone (TSH) was below normal. He was diagnosed with hyperthyroidism. Additional investigations revealed a low serum albumin level and chest infection, along with diffuse lung fibrosis. Within 1 month, he experienced significant weight loss, no hand tremors, intolerance of heat, and perspiration proneness. We recommended an HIV examination; subsequently, AIDS was diagnosed based on the laboratory parameters. This is the first reported case of hyperthyroidism caused by AIDS. AIDS may cause hyperthyroidism by immunization regulation with complex, atypical, and easily ignored symptoms. Although hyperthyroidism is rare in patients with AIDS, clinicians should be aware of this potential interaction and should carefully monitor thyroid function in HIV-positive patients.

  3. Sanfilippo syndrome: causes, consequences, and treatments

    PubMed Central

    Fedele, Anthony O

    2015-01-01

    Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, refers to one of five autosomal recessive, neurodegenerative lysosomal storage disorders (MPS IIIA to MPS IIIE) whose symptoms are caused by the deficiency of enzymes involved exclusively in heparan sulfate degradation. The primary characteristic of MPS III is the degeneration of the central nervous system, resulting in mental retardation and hyperactivity, typically commencing during childhood. The significance of the order of events leading from heparan sulfate accumulation through to downstream changes in the levels of biomolecules within the cell and ultimately the (predominantly neuropathological) clinical symptoms is not well understood. The genes whose deficiencies cause the MPS III subtypes have been identified, and their gene products, as well as a selection of disease-causing mutations, have been characterized to varying degrees with respect to both frequency and direct biochemical consequences. A number of genetic and biochemical diagnostic methods have been developed and adopted by diagnostic laboratories. However, there is no effective therapy available for any form of MPS III, with treatment currently limited to clinical management of neurological symptoms. The availability of animal models for all forms of MPS III, whether spontaneous or generated via gene targeting, has contributed to improved understanding of the MPS III subtypes, and has provided and will deliver invaluable tools to appraise emerging therapies. Indeed, clinical trials to evaluate intrathecally-delivered enzyme replacement therapy in MPS IIIA patients, and gene therapy for MPS IIIA and MPS IIIB patients are planned or underway. PMID:26648750

  4. Sjogren's Syndrome: Can It Cause Recurrent UTIs?

    MedlinePlus

    ... home/about-sjogrens/symptoms. Accessed Nov. 11, 2015. Fox R. Clinical manifestations of Sjogren's syndrome: Exocrine gland ... www.uptodate.com/home. Accessed Nov. 11, 2015. Fox R, et al. Clinical manifestations of Sjogren's syndrome: ...

  5. Ischemic syndromes causing dizziness and vertigo.

    PubMed

    Choi, K-D; Lee, H; Kim, J-S

    2016-01-01

    Dizziness/vertigo and imbalance are the most common symptoms of vertebrobasilar ischemia. Even though dizziness/vertigo usually accompanies other neurologic symptoms and signs in cerebrovascular disorders, a diagnosis of isolated vascular vertigo is increasing markedly by virtue of recent developments in clinical neurotology and neuroimaging. It is important to differentiate isolated vertigo of a vascular cause from more benign disorders involving the inner ear, since therapeutic strategies and prognosis differ between these two conditions. Over the last decade, we have achieved a marked development in the understanding and diagnosis of vascular dizziness/vertigo. Introduction of diffusion-weighted magnetic resonance imaging (MRI) has greatly enhanced detection of infarctions in patients with vascular dizziness/vertigo, especially in the posterior-circulation territories. However, well-organized bedside neurotologic evaluation is even more sensitive than MRI in detecting acute infarction as a cause of spontaneous prolonged vertigo. Furthermore, detailed evaluation of strategic infarctions has elucidated the function of various vestibular structures of the brainstem and cerebellum. In contrast, diagnosis of isolated labyrinthine infarction still remains a challenge. This diagnostic difficulty also applies to isolated transient dizziness/vertigo of vascular origin. Regarding the common nonlacunar mechanisms in the acute vestibular syndrome from small infarctions, individual strategies may be indicated to prevent recurrences of stroke in patients with vascular vertigo. © 2016 Elsevier B.V. All rights reserved.

  6. Neuroleptic malignant syndrome possibly caused by molindone hydrochloride.

    PubMed

    Gradon, J D

    1991-10-01

    The case of a patient who developed neuroleptic malignant syndrome (NMS) on three separate occasions is presented. Her third bout of this syndrome possibly was caused by molindone hydrochloride. This medication has been reported only once previously to cause NMS. The pharmacology of molindone is reviewed and a complicating factor in this case--the recent onset of hypothyroidism--is discussed together with its implication in the development of the clinical manifestations of this syndrome.

  7. Hantavirus pulmonary syndrome: encephalitis caused by virus Andes.

    PubMed

    Talamonti, Lionel; Padula, Paula J; Canteli, María Sol; Posner, Federico; Marczeski, Fanny Pires; Weller, Carlos

    2011-04-01

    Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS) are rodent-borne emerging diseases caused by members of the genus Hantavirus, family Bunyaviridae. Some species of hantavirus may cause encephalitis, but this is the first report in Andes virus associated to HPS.

  8. What Causes Prader-Willi Syndrome?

    MedlinePlus

    ... Browse AZTopics Browse A-Z Adrenal Gland Disorders Autism Spectrum Disorder (ASD) Down Syndrome Endometriosis Learning Disabilities Menstruation and ... NICHD Research Information Find a Study More Information Autism Spectrum Disorder (ASD) About NICHD Research Information Find a Study ...

  9. Triple X Syndrome: Symptoms and Causes

    MedlinePlus

    ... be more pronounced — possibly including developmental delays and learning disabilities. Treatment for triple X syndrome depends on which ... motor skills, such as sitting up and walking Learning disabilities, such as difficulty with reading (dyslexia), understanding or ...

  10. A rare cause of acute coronary syndrome: Kounis syndrome.

    PubMed

    Almeida, João; Ferreira, Sara; Malheiro, Joana; Fonseca, Paulo; Caeiro, Daniel; Dias, Adelaide; Ribeiro, José; Gama, Vasco

    2016-12-01

    Kounis syndrome is an acute coronary syndrome in the context of a hypersensitivity reaction. The main pathophysiological mechanism appears to be coronary vasospasm. We report the case of a patient with a history of allergy to quinolones, who was given ciprofloxacin before an elective surgical procedure and during drug administration developed symptoms and electrocardiographic changes suggestive of ST-segment elevation acute coronary syndrome. The drug was suspended and coronary angiography excluded epicardial coronary disease. Two hours after withdrawal of the drug the symptoms and ST elevation had resolved completely. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Polymyositis-like syndrome caused by hypothyroidism, presenting as camptocormia.

    PubMed

    Kim, Ji Min; Song, Eun Joo; Seo, Jae Seok; Nam, Eon Jeong; Kang, Young Mo

    2009-01-01

    Polymyositis-like syndrome characterized by proximal muscle weakness and elevation of muscle enzymes may be a presenting manifestation of hypothyroidism. Camptocormia, which can be caused by myopathy of the paraspinal muscles, is an involuntary truncal flexion of the thoracolumbar spine while standing or walking. Among various neuromuscular disorders, hypothyroidism has not been reported in the literature as a cause of camptocormia. This is the first report of polymyositis-like syndrome with camptocormia caused by hypothyroidism.

  12. Kindler syndrome causing severe cicatricial ectropion.

    PubMed

    Lelli, Gary J

    2010-01-01

    A 32-year-old female with Kindler syndrome presented with a 5-year history of lower eyelid malposition, corneal exposure, and recurrent erosions. Severe anterior lamellar cicatricial changes were noted bilaterally, with bilateral lower eyelid ectropion and retraction. Tarsal eversion was noted on the left lower eyelid. The patient had repeatedly failed conservative treatments for keratopathy and was treated surgically, with resolution of corneal disease and improved lower eyelid position. A review of Kindler syndrome is provided, geared toward the oculoplastic surgeon who may participate in the care of these patients.

  13. A Rare Cause of Hypothalamic Obesity, Rohhad Syndrome: 2 Cases.

    PubMed

    Şiraz, Ülkü Gül; Okdemir, Deniz; Direk, Gül; Akın, Leyla; Hatipoğlu, Nihal; Kendırcı, Mustafa; Kurtoğlu, Selim

    2018-03-19

    Rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) syndrome is a rare disease that is difficult to diagnosis and distinguish from genetic obesity syndromes. The underlying causes of the disease has not been fully explained. Hypothalamic dysfunction causes endocrine problems, respiratory dysfunction and autonomic alterations. There are around 80 reported patients due to lack of recognition. We present two female patient suspected of ROHHAD due to weight gain since early childhood. The presented symptoms, respiratory and circulatory dysfunction, hypothalamic hypernatremia, hypothalamo-pituitary hormonal disorders such as santral hypothyrodism, hyperprolactinemia and santral early puberty are completely matched the criteria of ROHHAD syndrome. ROHHAD syndrome should be considered in differential diagnosis since it is difficult to distinguish from causes of monogenic obesity. Early identification of the disease reduces morbidity of the syndrome and patients require regular follow-up by a multidisciplinary approach.

  14. Chronic Fatigue Syndrome: Searching for the Cause and Treatment.

    ERIC Educational Resources Information Center

    Eichner, Edward R.

    1989-01-01

    Chronic fatigue syndrome became known nationally in l985 with a pseudoepidemic in a Nevada resort community. Initially and erroneously linked to the Epstein-Barr virus, the cause of this puzzling syndrome and the mind-body connection are areas of controversy and research. (Author/SM)

  15. Locked-in syndrome caused by a solitary pontine abscess.

    PubMed Central

    Murphy, M J; Brenton, D W; Aschenbrener, C A; Van Gilder, J C

    1979-01-01

    The clinical and pathological findings in a patient with locked-in syndrome caused by a solitary pontine abscess are reported for the first time. Successful treatment of brainstem abscess rests on early and accurate diagnosis. Images PMID:501372

  16. Hoigne Syndrome Caused by Intralesional Meglumine Antimoniate

    PubMed Central

    Guarneri, Claudio; Tchernev, Georgi; Wollina, Uwe; Lotti, Torello

    2017-01-01

    Hoigne syndrome (HS) is the term coined to describe an acute, non-allergic, psychiatrically based reaction occurring with a wide list of medications, mainly antibiotics. Since its first description by Hoigne and Schoch in 1959, few cases have been reported in medical literature and, although antimicrobials are commonly used, very rarely in dermatology. The authors describe the first case occurred after intralesional administration of meglumine antimoniate and briefly discuss the pathogenetic hypotheses on this atypical adverse drug reaction. PMID:28785339

  17. [Hypogonadism caused by Gorlin-Goltz syndrome].

    PubMed

    Marín Romero, Olivia; Hernández Marín, Imelda; Ayala Ruiz, Aquiles R

    2006-09-01

    The Gorlin-Goltz syndrome is a dominant autosomic disorder characterized by cancerigenic predisposition and multiple development defects, apparently without reproductive compromise. The complex is characterized by four primary symptoms, which include nevoid basal cell epitheliomas malignantly prone, keratocystic jaw, skeletal abnormalities and intracranial calcifications. Apparently, reproductive problems reported had been rarely associated with this syndrome. We present the case of a patient with clinic stigmatae of Gorlin-Goltz syndrome, who had a characteristic progress as seen in the literature; he was the fifth product of a 43 year-old female (father was 48 years old); who at birth disclosed right eye microftalmy, bilateral cryptorchidism surgically treated at age of six. At puberty, an odontogenic cyst of the jaw was noted and enucleated. He also showed facial nevi in neck, thorax and abdomen. When he was admitted being 14 years old in our clinic, he had recurrent bilateral cryptorchidism, sexual immatturity and infertility. It is important to take into consideration Gorlin-Goltz stigmatae in cases of hypogonadism in order to recognize a further genetic influence.

  18. Ectopic ACTH syndrome caused by pulmonary carcinoid tumourlets.

    PubMed

    Povedano, S T; Pastor, C V; Seoane, C P; Reina, L J; Moreno, M A; Ortega, R P; López-Rubio, F; López, P B

    2001-06-01

    The differential diagnosis of Cushing's syndrome is a major challenge to clinical endocrinologists, especially those infrequent cases referred to as occult ectopic ACTH syndromes. Although bronchial carcinoids are well known to be a cause of Cushing's syndrome due to ectopic ACTH secretion, very few cases of carcinoid tumourlets causing an ACTH ectopic syndrome have been reported, and their origin remains controversial. For some authors, tumourlets and typical carcinoids represent distinct pathological entities, whilst others hold that tumourlets are merely microscopic carcinoid tumours. We report a patient with an aggressive Cushing's syndrome that required bilateral adrenalectomy, diagnosed 22 years before a 3-cm lung nodule became apparent on routine chest X-ray. The biopsy after lung surgery revealed a typical peripheral bronchial carcinoid surrounded by tumourlets. Both tumourlets and carcinoid tumour showed strongly positive ACTH immunostaining. Recently, Arioglu et al. (1998) reported a case of Cushing's syndrome caused by pulmonary carcinoid tumourlets, concluding that this entity should be considered in the differential diagnosis of occult ectopic ACTH syndrome. Furthermore, we consider that the carcinoid tumourlets found in our patient, were the initial source of ACTH, leading to Cushing's syndrome with a rapid onset, and that a loss of cell proliferation control in one of such tumourlets many years later, could have resulted in the development of a typical carcinoid tumour, reinforcing the theory of a common origin of these lesions.

  19. Guillain-Barré syndrome: causes, immunopathogenic mechanisms and treatment.

    PubMed

    Jasti, Anil K; Selmi, Carlo; Sarmiento-Monroy, Juan C; Vega, Daniel A; Anaya, Juan-Manuel; Gershwin, M Eric

    2016-11-01

    Guillain-Barré syndrome is a rare disease representing the most frequent cause of acute flaccid symmetrical weakness of the limbs and areflexia usually reaching its peak within a month. The etiology and pathogenesis remain largely enigmatic and the syndrome results in death or severe disability in 9-17% of cases despite immunotherapy. Areas covered: In terms of etiology, Guillain-Barré syndrome is linked to Campylobacter infection but less than 0.1% of infections result in the syndrome. In terms of pathogenesis, activated macrophages and T cells and serum antibodies against gangliosides are observed but their significance is unclear. Expert commentary: Guillain-Barré syndrome is a heterogeneous condition with numerous subtypes and recent data point towards the role of ganglioside epitopes by immunohistochemical methods. Ultimately, the syndrome results from a permissive genetic background on which environmental factors, including infections, vaccination and the influence of aging, lead to disease.

  20. [Multiple bladder diverticula caused by occipital horn syndrome].

    PubMed

    Legros, L; Revencu, N; Nassogne, M-C; Wese, F-X; Feyaerts, A

    2015-11-01

    We report on the case of a child who presented with recurrent, multiple, and voluminous bladder diverticula. Bladder diverticula are defined as a herniation of the mucosa through the bladder muscle or the detrusor. Causes are numerous and diverticula can be classified into primary congenital diverticula (para-ureteral - or Hutch diverticula - and posterolateral diverticula); secondary diverticula (resulting from chronic mechanical obstruction or from neurological disease; and diverticula secondary to connective tissue or muscle fragility. The latter is seen in disease entities such as prune belly syndrome, Ehlers-Danlos syndrome, cutis laxa syndrome, OHS (occipital horn syndrome), Menkes disease, and Williams-Beuren syndrome. In this patient, the cause of these diverticula was OHS, a genetic, recessive X-chromosome-linked syndrome, responsible for abnormal tissue caused by a disorder in copper metabolism. This case reminds us of the importance of pushing the diagnostic workup when presented with multiple and/or large bladder diverticula, and in particular to search for rare malformation syndromes after exclusion of an obstacle. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. Nakalanga Syndrome: Clinical Characteristics, Potential Causes, and Its Relationship with Recently Described Nodding Syndrome

    PubMed Central

    Föger, Kathrin; Gora-Stahlberg, Gina; Sejvar, James; Ovuga, Emilio; Jilek-Aall, Louise; Schmutzhard, Erich

    2017-01-01

    Nakalanga syndrome is a condition that was described in Uganda and various other African countries decades ago. Its features include growth retardation, physical deformities, endocrine dysfunction, mental impairment, and epilepsy, amongst others. Its cause remains obscure. Nodding syndrome is a neurological disorder with some features in common with Nakalanga syndrome, which has been described mainly in Uganda, South Sudan, and Tanzania. It has been considered an encephalopathy affecting children who, besides head nodding attacks, can also present with stunted growth, delayed puberty, and mental impairment, amongst other symptoms. Despite active research over the last years on the pathogenesis of Nodding syndrome, to date, no convincing single cause of Nodding syndrome has been reported. In this review, by means of a thorough literature search, we compare features of both disorders. We conclude that Nakalanga and Nodding syndromes are closely related and may represent the same condition. Our findings may provide new directions in research on the cause underlying this neurological disorder. PMID:28182652

  2. Genetic, chromosomal, and syndromic causes of neural tube defects.

    PubMed

    Seidahmed, Mohammed Z; Abdelbasit, Omer B; Shaheed, Meeralebbae M; Alhussein, Khalid A; Miqdad, Abeer M; Samadi, Abdulmohsen S; Khalil, Mohammed I; Al-Mardawi, Elham; Salih, Mustafa A

    2014-12-01

    To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions.

  3. Genetic, chromosomal, and syndromic causes of neural tube defects

    PubMed Central

    Seidahmed, Mohammed Z.; Abdelbasit, Omer B.; Shaheed, Meeralebbae M.; Alhussein, Khalid A.; Miqdad, Abeer M.; Samadi, Abdulmohsen S.; Khalil, Mohammed I.; Al-Mardawi, Elham; Salih, Mustafa A.

    2014-01-01

    Objective: To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. Methods: We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. Results: Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. Conclusions: There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions. PMID:25551112

  4. Mutations in HPSE2 Cause Urofacial Syndrome

    PubMed Central

    Daly, Sarah B.; Urquhart, Jill E.; Hilton, Emma; McKenzie, Edward A.; Kammerer, Richard A.; Lewis, Malcolm; Kerr, Bronwyn; Stuart, Helen; Donnai, Dian; Long, David A.; Burgu, Berk; Aydogdu, Ozgu; Derbent, Murat; Garcia-Minaur, Sixto; Reardon, Willie; Gener, Blanca; Shalev, Stavit; Smith, Rupert; Woolf, Adrian S.; Black, Graeme C.; Newman, William G.

    2010-01-01

    Urinary voiding dysfunction in childhood, manifesting as incontinence, dysuria, and urinary frequency, is a common condition. Urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by facial grimacing when attempting to smile and failure of the urinary bladder to void completely despite a lack of anatomical bladder outflow obstruction or overt neurological damage. UFS individuals often have reflux of infected urine from the bladder to the upper renal tract, with a risk of kidney damage and renal failure. Whole-genome SNP mapping in one affected individual defined an autozygous region of 16 Mb on chromosome 10q23-q24, within which a 10 kb deletion encompassing exons 8 and 9 of HPSE2 was identified. Homozygous exonic deletions, nonsense mutations, and frameshift mutations in five further unrelated families confirmed HPSE2 as the causative gene for UFS. Mutations were not identified in four additional UFS patients, indicating genetic heterogeneity. We show that HPSE2 is expressed in the fetal and adult central nervous system, where it might be implicated in controlling facial expression and urinary voiding, and also in bladder smooth muscle, consistent with a role in renal tract morphology and function. Our findings have broader implications for understanding the genetic basis of lower renal tract malformations and voiding dysfunction. PMID:20560210

  5. Mutations in HPSE2 cause urofacial syndrome.

    PubMed

    Daly, Sarah B; Urquhart, Jill E; Hilton, Emma; McKenzie, Edward A; Kammerer, Richard A; Lewis, Malcolm; Kerr, Bronwyn; Stuart, Helen; Donnai, Dian; Long, David A; Burgu, Berk; Aydogdu, Ozgu; Derbent, Murat; Garcia-Minaur, Sixto; Reardon, Willie; Gener, Blanca; Shalev, Stavit; Smith, Rupert; Woolf, Adrian S; Black, Graeme C; Newman, William G

    2010-06-11

    Urinary voiding dysfunction in childhood, manifesting as incontinence, dysuria, and urinary frequency, is a common condition. Urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by facial grimacing when attempting to smile and failure of the urinary bladder to void completely despite a lack of anatomical bladder outflow obstruction or overt neurological damage. UFS individuals often have reflux of infected urine from the bladder to the upper renal tract, with a risk of kidney damage and renal failure. Whole-genome SNP mapping in one affected individual defined an autozygous region of 16 Mb on chromosome 10q23-q24, within which a 10 kb deletion encompassing exons 8 and 9 of HPSE2 was identified. Homozygous exonic deletions, nonsense mutations, and frameshift mutations in five further unrelated families confirmed HPSE2 as the causative gene for UFS. Mutations were not identified in four additional UFS patients, indicating genetic heterogeneity. We show that HPSE2 is expressed in the fetal and adult central nervous system, where it might be implicated in controlling facial expression and urinary voiding, and also in bladder smooth muscle, consistent with a role in renal tract morphology and function. Our findings have broader implications for understanding the genetic basis of lower renal tract malformations and voiding dysfunction.

  6. Iatrogenic Cushing's syndrome caused by intranasal steroid use.

    PubMed

    Dursun, Fatma; Kirmizibekmez, Heves

    2017-01-01

    Cushing's syndrome (CS) is common after oral steroid use and has also been reported following topical or inhaled use, but it is extremely uncommon after intranasal administration. This is the case of a 6-year-old child who developed Cushing's syndrome after intranasal application of dexamethasone sodium phosphate for a period of 6 months. Pediatricians and other clinical practitioners should be aware that high-dose and long-term nasal steroid administration may cause iatrogenic Cushing's syndrome characterized by complications of glucocorticoid excess as well as serious and even life-threatening complications of adrenal insufficiency.

  7. Maternally inherited Leigh syndrome: an unusual cause of infantile apnea.

    PubMed

    Shuk-kuen Chau, Christy; Kwok, Ka-li; Ng, Daniel K; Lam, Ching-Wan; Tong, Sui-Fan; Chan, Yan-Wo; Siu, Wai-Kwan; Yuen, Yuet-Ping

    2010-06-01

    Leigh Syndrome is an uncommon cause of infantile apnea. We report a 5-month-old girl with sudden respiratory arrest followed by episodic hyper- and hypo-ventilation, encephalopathy, and persistent lactic acidosis. Computed tomography of the brain revealed symmetric low densities over the basal ganglia, internal capsule, thalami, and midbrain. Cardiac echocardiogram was suggestive of hypertrophic cardiomyopathy. Diagnosis of Leigh syndrome due to T8993G mutation was confirmed with polymerase chain reaction and direct DNA sequencing of mitochondrial genome. To our knowledge, this is the first report of proven maternally inherited Leigh syndrome in Hong Kong.

  8. Munchausen syndrome by proxy caused by ipecac poisoning.

    PubMed

    Carter, Kathryn Elizabeth; Izsak, Eugene; Marlow, James

    2006-09-01

    To present a case of Munchausen syndrome by proxy caused by ipecac poisoning to increase the awareness of their warning signs and symptoms so that they may be recognized and diagnosed earlier. Report of one case of a child who was determined to be a victim of Munchausen syndrome by proxy by ipecac poisoning who was hospitalized multiple times over a 4-year period at 2 different hospitals before an accurate diagnosis was made.

  9. Unilateral facial paralysis caused by Ramsay Hunt syndrome.

    PubMed

    Pereira, Flávia P; Guskuma, Marcos H; Luvizuto, Eloá R; Faco, Eduardo F S; Magro-Filho, Osvaldo; Hochuli-Vieira, Eduardo

    2011-09-01

    The Ramsay Hunt syndrome is a rare disease caused by an infection of the geniculate ganglion by the varicella-zoster virus. The main clinical features of the syndrome are as follows: Bell palsy unilateral or bilateral, vesicular eruptions on the ears, ear pain, dizziness, preauricular swelling, tingling, tearing, loss of taste sensation, and nystagmus. We describe a 23-year-old white woman, who presented with facial paralysis on the left side of the face, pain, fever, ear pain, and swelling in the neck and auricular region on the left side. She received appropriate treatment with acyclovir, vitamin B complex, and CMP nucleus. After 30 days after presentation, the patient did not show any signs or symptoms of the syndrome. At follow-up at 1 year, she showed no relapse of the syndrome.

  10. Causes of infertility in men with Down syndrome.

    PubMed

    Stefanidis, K; Belitsos, P; Fotinos, A; Makris, N; Loutradis, D; Antsaklis, A

    2011-10-01

    Men with Down syndrome are considered as infertile although the causes of infertility are not known in detail yet. Although this constitutes a general rule there are three confirmed cases of parenting by fathers with Down syndrome. Many investigators have addressed the causes of infertility and their studies indicate that the causes may be hormonal deficits, morphological alterations of the gonads, abnormal spermatogenesis, psychological and social factors related to the mental retardation. It is obvious that the extra chromosome 21 has a detrimental direct and indirect effect on the reproductive capacity of the affected male patient. But the definite cause of the insufficient and inadequate spermatogenesis remains to be discovered. © 2011 Blackwell Verlag GmbH.

  11. A Rare Cause of Obstructive Sleep Apnea Syndrome: Retropharyngeal Lipoma

    PubMed Central

    Dilek, Okan; Yilmaz, Cengiz; Gulek, Bozkurt; Akin, Mehmet Ali

    2017-01-01

    Lipoma is the most common benign mesenchymal neoplasm. About 16% of lipomas arise in the head and neck region, especially in the posterior neck. Large lipomas that originate from the retropharyngeal space may cause dyspnea, dysphagia, and snoring and occasionally may lead to obstructive sleep apnea syndrome (OSAS). Herein, we report a 45-year-old male patient with OSAS caused by a giant retropharyngeal lipoma with emphasis on CT findings. PMID:28912996

  12. Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus.

    PubMed

    Rasmuson, J; Andersson, C; Norrman, E; Haney, M; Evander, M; Ahlm, C

    2011-05-01

    Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.

  13. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome

    PubMed Central

    Boyden, Lynn M.; Kam, Chen Y.; Hernández-Martín, Angela; Zhou, Jing; Craiglow, Brittany G.; Sidbury, Robert; Mathes, Erin F.; Maguiness, Sheilagh M.; Crumrine, Debra A.; Williams, Mary L.; Hu, Ronghua; Lifton, Richard P.; Elias, Peter M.; Green, Kathleen J.; Choate, Keith A.

    2016-01-01

    Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin. PMID:26604139

  14. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.

    PubMed

    Boyden, Lynn M; Kam, Chen Y; Hernández-Martín, Angela; Zhou, Jing; Craiglow, Brittany G; Sidbury, Robert; Mathes, Erin F; Maguiness, Sheilagh M; Crumrine, Debra A; Williams, Mary L; Hu, Ronghua; Lifton, Richard P; Elias, Peter M; Green, Kathleen J; Choate, Keith A

    2016-01-15

    Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Lumbar vertebral hemangioma causing cauda equina syndrome: a case report.

    PubMed

    Ahn, Henry; Jhaveri, Subir; Yee, Albert; Finkelstein, Joel

    2005-11-01

    Case report. To report a case of lumbar hemangioma causing neurogenic claudication and early cauda equina, managed with hemostatic vertebroplasty and posterior decompression. This is the first report to our knowledge of a lumbar hemangioma causing neurogenic claudication and early cauda equina syndrome. Most hemangiomas causing neurologic symptoms occur in thoracic spine and cause spinal cord compression. Vertebroplasty as a method of hemostasis and for providing mechanical stability in this situation has not been discussed previously in the literature. L4 hemangioma was diagnosed in a 64-year-old woman with severe neurogenic claudication and early cauda equina syndrome. Preoperative angiograms showed no embolizable vessels. Posterior decompression was performed followed by bilateral transpedicular vertebroplasty. The patient received postoperative radiation to prevent recurrence. Complete relief of neurogenic claudication and cauda equina with less than 100 mL of blood loss. A lumbar hemangioma of the vertebral body, although rare, can cause neurogenic claudication and cauda equina syndrome. Intraoperative vertebroplasty can be an effective method of hemostasis and provide stability of the vertebra following posterior decompression.

  16. NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement.

    PubMed

    Leshinsky-Silver, E; Lebre, Anne-Sophie; Minai, Limor; Saada, Ann; Steffann, Julie; Cohen, Sarit; Rötig, Agnes; Munnich, Arnold; Lev, Dorit; Lerman-Sagie, Tally

    2009-07-01

    Complex I deficiency is a frequent cause of Leigh syndrome. We describe a non-consanguineous Ashkenazi-Sephardic Jewish patient with Leigh syndrome due to complex I deficiency. The clinical and neuroradiological presentation showed predominant brainstem involvement. Blue native polyacrylamide gel electrophoresis analysis revealed an impaired assembly of complex I. The patient was found to be compound heterozygous of two mutations in the NDUFS4 gene: p.Asp119His (a novel mutation) and p.Lys154fs (recently described in an Ashkenazi Jewish family). These findings support the suggestion that the p.Lys154fs mutation in NDUFS4 should be evaluated in Ashkenazi Jewish patients presenting with early onset Leigh syndrome even before enzymatic studies. Our results further demonstrated that NDUFS4 presents a hotspot of mutations in the genetic apparatus of oxidative phosphorylation and the correct assembly of the subunit it encodes is essential for completion of the assembly of complex I.

  17. Primary CNS lymphoma as a cause of Korsakoff syndrome.

    PubMed

    Toth, Cory; Voll, Chris; Macaulay, Robert

    2002-01-01

    Korsakoff syndrome presents with memory dysfunction with retrograde amnesia, anterograde amnesia, limited insight into dysfunction, and confabulation. The most common etiology of Korsakoff syndrome is thiamine deficiency secondary to alcoholism. There are limited case reports of structural lesions causing Korsakoff syndrome. A 46-year-old male with a long history of alcoholism presented with a history of confusion, amnesia, and confabulation with no localizing features on neurological examination. The patient showed no clinical change with intravenous thiamine. Computed tomography of the brain revealed a heterogenous, enhancing mass lesion centered within the third ventricle, with other lesions found throughout cortical and subcortical regions. The patient was given dexamethasone i.v. without noticeable clinical improvement but with marked radiological improvement with mass reduction. Stereotactic biopsy revealed a diagnosis of primary central nervous system (CNS) lymphoma. Most patients presenting with Korsakoff syndrome have thiamine deficiency; however, mass lesions can produce an identical clinical picture. This is the first case report of a patient with primary CNS lymphoma presenting as Korsakoff syndrome.

  18. Recent advances in bulbar syndromes: genetic causes and disease mechanisms.

    PubMed

    Manole, Andreea; Fratta, Pietro; Houlden, Henry

    2014-10-01

    With advances in next-generation gene sequencing, progress in deep phenotyping and a greater understanding of the pathogenesis of motor neuron disease, our knowledge of the progressive bulbar syndromes has significantly increased in recent years. This group of heterogeneous conditions, in which the primary disorder is focused around degeneration of the lower cranial nerves, can occur in children or adults and form a spectrum of severity, based around the common feature of bulbar dysfunction. Early genetic diagnosis may allow treatment in some bulbar syndromes. Brown-Vialetto-Van Laere and Fazio-Londe syndromes are the most recent childhood forms of progressive bulbar palsy to be genetically defined. The clinical phenotype of this group of childhood disorders was first reported over 120 years ago. Recently, it was demonstrated that in a third of these patients Brown-Vialetto-Van Laere is caused by mutations in the SLC52A2 and SLC52A3 genes, both of which encode riboflavin transporters. Importantly, supplementation of riboflavin can lead to significant clinical improvement if started early in the disease process. Here, we outline the clinical features, management and an update on the disease mechanisms and genetic causes of the progressive bulbar syndromes.

  19. Morvan syndrome: a rare cause of syndrome of inappropriate antidiuretic hormone secretion

    PubMed Central

    DEMIRBAS, SEREF; AYKAN, MUSA BARIS; ZENGIN, HAYDAR; MAZMAN, SEMIR; SAGLAM, KENAN

    2017-01-01

    The syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for an important part of hyponatremia cases. The causes of SIADH can be detected almost always. As a rare disorder, Morvan Syndrome can be defined by the sum of peripheral nerve hyperexcitability, autonomic instability and neuropsychiatric features. Antibodies to voltage-gated potassium channels (Anti – VGKC-Ab) including contactin associated protein-like 2 antibodies (CASPR2-Ab) and leucine-rich glioma inactivated protein 1 antibodies (LGI1-Ab) were previously known for the potential association with this condition. We present a Morvan Syndrome in a patient who presented with various neuropsychiatric symptoms and SIADH. PMID:28781533

  20. Morvan syndrome: a rare cause of syndrome of inappropriate antidiuretic hormone secretion.

    PubMed

    Demirbas, Seref; Aykan, Musa Baris; Zengin, Haydar; Mazman, Semir; Saglam, Kenan

    2017-01-01

    The syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for an important part of hyponatremia cases. The causes of SIADH can be detected almost always. As a rare disorder, Morvan Syndrome can be defined by the sum of peripheral nerve hyperexcitability, autonomic instability and neuropsychiatric features. Antibodies to voltage-gated potassium channels (Anti - VGKC-Ab) including contactin associated protein-like 2 antibodies (CASPR2-Ab) and leucine-rich glioma inactivated protein 1 antibodies (LGI1-Ab) were previously known for the potential association with this condition. We present a Morvan Syndrome in a patient who presented with various neuropsychiatric symptoms and SIADH.

  1. Mutations causing syndromic autism define an axis of synaptic pathophysiology.

    PubMed

    Auerbach, Benjamin D; Osterweil, Emily K; Bear, Mark F

    2011-11-23

    Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2(+/-) and Fmr1(-/y) mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.

  2. [Currarino syndrome a rare cause of recurrent purulent meningitis].

    PubMed

    Fitouri, Z; Ben Slima, S; Matoussi, N; Aloui, N; Bellagha, I; Kechrid, A; Ben Becher, S

    2007-12-01

    The authors report a case of partial Currarino syndrome in a three and a half year old child with a left hemisacrum agenesis and a presacral mature teratoma. The special aspect of the observation was the apparition of repetitive polymicrobial purulent meningitis (Escherichia coli, Streptococcus B, Haemophilus influenzae) treated several times with non-specific antibiotics without normalization of CSF, particularly the CSF glucose, which remained low, justifying the use of an antimycobacterial treatment, especially since there was no local or general cause explaining the relapse. During a relapse of meningitis after ten months of antituberculosis treatment, the teratoma was discovered by a spine MRI done to detect any cerebrospinal defect. The authors insist on the fact that the Currarino syndrome must be investigated in case of repetitive purulent meningitis after ruling out the usual causes of meningitis.

  3. [A rare cause of oral pain: The pterygoid hamulus syndrome].

    PubMed

    Bandini, M; Corre, P; Huet, P; Khonsari, R H

    2015-12-01

    Pterygoid hamulus syndrome (PHS) is a rare cause of orofacial and oropharyngeal pain. PHS can be associated with a hamulus hypertrophy or with a bursitis of the palatosalpingeus but it has not always an anatomic cause. A 36-year-old woman was seen for a constant posterior palatal pain spreading towards oropharynx, increasing during swallowing and lasting for more than 6 months. Physical examination showed an erythema of the soft palate, medially to the hamulus. Hamulus palpation was painful and revealed hamulus hypertrophia on both sides. A bilateral PHS was evocated. This observation is typical of a PHS. We propose a review of the literature of this little-known syndrome. Treatment is initially conservative (corticosteroids) but surgery can be proposed in case of morphological anomalies of the hamulus. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. Causes of death in 2877 patients with myelodysplastic syndromes.

    PubMed

    Nachtkamp, Kathrin; Stark, Romina; Strupp, Corinna; Kündgen, Andrea; Giagounidis, Aristoteles; Aul, Carlo; Hildebrandt, Barbara; Haas, Rainer; Gattermann, Norbert; Germing, Ulrich

    2016-05-01

    Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Düsseldorf registry who have been followed up for a median time of 21 months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71 years. At the time of analysis, 2877 patients (75.9 %) had deceased. In 1212 cases (42.1 %), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4 %) succumbed directly disease-related (AML (46.6 %), infection (27.0 %), bleeding (9.8 %)), whereas 277 patients (16.6 %) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease.

  5. Intronic splicing mutations in PTCH1 cause Gorlin syndrome.

    PubMed

    Bholah, Zaynab; Smith, Miriam J; Byers, Helen J; Miles, Emma K; Evans, D Gareth; Newman, William G

    2014-09-01

    Gorlin syndrome is an autosomal dominant disorder characterized by multiple early-onset basal cell carcinoma, odontogenic keratocysts and skeletal abnormalities. It is caused by heterozygous mutations in the tumour suppressor PTCH1. Routine clinical genetic testing, by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to confirm a clinical diagnosis of Gorlin syndrome, identifies a mutation in 60-90 % of cases. We undertook RNA analysis on lymphocytes from ten individuals diagnosed with Gorlin syndrome, but without known PTCH1 mutations by exonic sequencing or MLPA. Two altered PTCH1 transcripts were identified. Genomic DNA sequence analysis identified an intron 7 mutation c.1068-10T>A, which created a strong cryptic splice acceptor site, leading to an intronic insertion of eight bases; this is predicted to create a frameshift p.(His358Alafs*12). Secondly, a deep intronic mutation c.2561-2057A>G caused an inframe insertion of 78 intronic bases in the cDNA transcript, leading to a premature stop codon p.(Gly854fs*3). The mutations are predicted to cause loss of function of PTCH1, consistent with its tumour suppressor function. The findings indicate the importance of RNA analysis to detect intronic mutations in PTCH1 not identified by routine screening techniques.

  6. Mutations in CDK5RAP2 cause Seckel syndrome.

    PubMed

    Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

    2015-09-01

    Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

  7. Mutations in CDK5RAP2 cause Seckel syndrome

    PubMed Central

    Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

    2015-01-01

    Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152. PMID:26436113

  8. Bertolotti's syndrome. A cause of back pain in young people.

    PubMed

    Quinlan, J F; Duke, D; Eustace, S

    2006-09-01

    Bertolotti's syndrome is characterised by anomalous enlargement of the transverse process(es) of the most caudal lumbar vertebra which may articulate or fuse with the sacrum or ilium and cause isolated L4/5 disc disease. We analysed the elective MR scans of the lumbosacral spine of 769 consecutive patients with low back pain taken between July 2003 and November 2004. Of these 568 showed disc degeneration. Bertolotti's syndrome was present in 35 patients with a mean age of 32.7 years (15 to 60). This was a younger age than that of patients with multiple disc degeneration, single-level disease and isolated disc degeneration at the L4/5 level (p syndrome in our study was 4.6% (35 of 769). It was present in 11.4% (20 patients) of the under-30 age group. Our findings suggest that Bertolotti's syndrome must form part of a list of differential diagnoses in the investigation of low back pain in young people.

  9. Air Swallowing Caused Recurrent Ileus in Tourette’s Syndrome

    PubMed Central

    Frye, Richard E.; Hait, Elizabeth J.

    2008-01-01

    This report describes an adolescent boy who has Tourette’s syndrome and developed a subtle but significant increase in vocal tics after an 8-month respite. The increase in vocal tics was associated with an acute increase in psychological stressors and resulted in recurrent air swallowing, which, in turn, caused abdominal cramping, eructation, and flatus, eventually leading to aeroenteria. Air swallowing was recognized only after a second hospital admission for recurrent ileus. Air swallowing and associated symptoms were mitigated by reinstitution of psychopharmacologic treatment and an increase in the patient’s self-awareness of the air-swallowing behavior. Clinically significant air swallowing has not been described previously in Tourette syndrome or a tic disorder. This case is important for pediatricians and pediatric gastroenterologists because either may be the first to evaluate a child or an adolescent with unexplained recurrent ileus. This report also documents the importance of the connection between the brain and the body. PMID:16651280

  10. Frontal mucocele with intracranial extension causing frontal lobe syndrome.

    PubMed

    Weidmayer, Sara

    2015-06-01

    Mucoceles are mucus-containing cysts that form in paranasal sinuses; although mucoceles themselves are benign, this case report highlights the extensive damage they can cause as their expansion may lead to bony erosion and extension of the mucocele into the orbit and cranium; it also presents a rarely reported instance of frontal sinus mucocele leading to frontal lobe syndrome. A thorough discussion and review of mucoceles is included. A 68-year-old white man presented with intermittent diplopia and a pressure sensation in the right eye. He had a history of chronic sinusitis and had had endoscopic sinus surgery 5 years prior. A maxillofacial computed tomography scan revealed a large right frontal sinus mucocele, which had caused erosion along the medial wall of the right orbit and the outer and inner tables of the right frontal sinus. The mucocele had protruded both into the right orbit and intracranially, causing mass effect on the frontal lobe, which led to frontal lobe syndrome. The patient was successfully treated with endoscopic right ethmoidectomy, radial frontal sinusotomy, marsupialization of the mucocele, and transcutaneous irrigation. Paranasal sinus mucoceles may expand and lead to bony erosion and can become very invasive in surrounding structures such as the orbit and cranium. This case not only exhibits a very rare presentation of frontal sinus mucocele with intracranial extension and frontal lobe mass effect causing a frontal lobe syndrome but also demonstrates many of the ocular and visual complications commonly associated with paranasal sinus mucoceles. Early identification and surgical intervention is vital for preventing and reducing morbidity associated with invasive mucoceles, and the patient must be followed regularly to monitor for recurrence.

  11. A Rare Cause of Cyanosis: Hepatopulmonary Syndrome Caused by Congenital Extrahepatic Portosystemic Shunt

    PubMed Central

    Ding, Xue-Yan; Chen, Feng; Zhao, Xian-Xian; Wu, Hong; Chen, Shao-Ping; Qin, Yong-Wen

    2011-01-01

    A 19-year-old male patient presented cyanosis and dyspnoea because of the presence of multiple pulmonary arteriovenous fistulas resulting in oxygen desaturation. The CTA revealed that intestinal and splenic venous blood bypasses the liver and drains into the inferior vena cava. This is the first reported case of hepatopulmonary syndrome caused by congenital extrahepatic portosystemic shunt in which intestinal and splenic venous blood bypasses the liver and drains into the inferior vena cava. PMID:22937464

  12. GPR98 mutations cause Usher syndrome type 2 in males.

    PubMed

    Ebermann, I; Wiesen, M H J; Zrenner, E; Lopez, I; Pigeon, R; Kohl, S; Löwenheim, H; Koenekoop, R K; Bolz, H J

    2009-04-01

    Mutations in the large GPR98 gene underlie Usher syndrome type 2C (USH2C), and all patients described to date have been female. It was speculated that GPR98 mutations cause a more severe, and eventually lethal, phenotype in males. We describe for the first time two male patients with USH2 with novel GPR98 mutations. Clinical characterization of a male patient and his affected sister revealed a typical USH2 phenotype in both. GPR98 may have been excluded from systematic investigation in previous studies, and the proportion of patients with USH2C probably underestimated. GPR98 should be considered in patients with USH2 of both sexes.

  13. Proteus syndrome: A rare cause of gigantic limb.

    PubMed

    Chakrabarti, Nandini; Chattopadhyay, Chandan; Bhuban, Majhi; Pal, Salil Kumar

    2014-04-01

    A congenital disorder with variable manifestations, including partial gigantism of the hands and feet with hypertrophy of soles, nevi, hemihypertrophy, gynecomastia, macrocephaly and other skull abnormalities, and abdominal lipomatosis. The cause is unknown, although a genetic origin, generally of autosomal-dominant transmission, has been conjectured. Symptoms can be treated, but there is no known cure. We present the case of a young male with grotesque overgrowth of the right lower limb, splenomegaly and multiple nevi. Angiography revealed venous malformation within the limb. The findings are in conformity to the criteria for the Proteus syndrome.

  14. [Long QT syndrome. History, genetics, clinical symptoms, causes and therapy].

    PubMed

    Krönauer, T; Friederich, P

    2015-08-01

    The long QT syndrome is caused by a change in cardiac repolarization due to functional ion channel defects. A differentiation is made between a congenital (cLQTS) and an acquired (aLQTS) form of the disease. The disease results in the name-giving prolongation of the QT interval in the electrocardiogram and represents a predisposition for cardiac arrhythmia and sudden cardiac death. This article summarizes the current knowledge on the history, pathophysiology, clinical symptoms and therapy of cLQTS and aLQTS. This knowledge of pathophysiological features of the symptoms allows the underlying anesthesiological approach for individualized perioperative concepts for patients suffering from LQTS to be derived.

  15. Prehospital Dextrose Extravasation Causing Forearm Compartment Syndrome: A Case Report.

    PubMed

    Chinn, Matthew; Colella, M Riccardo

    2017-01-01

    A 57-year-old woman was found at home by paramedics to be hypoglycemic with altered mental status. She had multiple attempts at IV access and eventually a 22G IV was established and D50 was infused into her right forearm. Extravasation of the dextrose was noted after approximately 12 g of the medication was infused. She was given a dose of glucagon intramuscularly and her mental status improved. Shortly after her arrival to the emergency department, she was noted to have findings of compartment syndrome of her forearm at the site of the dextrose extravasation. She was evaluated by plastic surgery and taken to the operating room for emergent fasciotomy. She recovered well from the operation. D50 is well known to cause phlebitis and local skin necrosis as a complication. This case illustrates the danger of compartment syndrome after D50 extravasation. It is the first documented case of prehospital dextrose extravasation leading to compartment syndrome. There may be safer alternatives to D50 administration and providers must be acutely aware to monitor for D50 infusion complications.

  16. [Vertical retraction syndrome caused by anomalous orbital structures].

    PubMed

    Yang, Qiong; Jiao, Yong-hong; Man, Feng-yuan; Wang, Zhen-chang; Chang, Qing-lin; Lu, Wei; Wang, Jing-hui; Zhao, Kan-xing

    2011-11-01

    To described the clinical feature and MRI imaging of six children with vertical retraction syndrome. Six children with unilateral vertical retraction syndrome between 15 months and 8 years of age, mean age was (5.01 ± 1.27) years old. Strabismus examination included diopter, prism diopters, eye movement examination, binocular vision and fundus examination. Imaging of the ocular motor nerves at the brainstem was performed in 0.8 mm thickness image planes using 3D-FIESTA sequence, the orbits were imaged with FSE T1, T2WI using surface coils, and within 2.0 mm thick planes. Four children showed hypertropia, characterized by limited depression, a light retraction of the globe during downward gaze and eyelid lag. The MRI imaging showed anomalous orbital structure in the superonasal quadrant that between medial rectus and superior rectus or adjacent to the superior rectus. Two children showed intermittent exotropia, characterized by limited elevation, retraction of the globe and narrowing of the palpebral fissure during upward gaze. The MRI imaging showed anomalous orbital structure was present in the inferotemporal quadrant, one originate in inferior rectus and another close to the lateral rectus. Anomalous orbital structures are a main cause of vertical retraction syndrome. The presence of specific unusual eye movement and MRI imaging may assist in diagnosis. When the eyelid lag was found since the early age, anomalous orbital structures were implied.

  17. Hypomorphic Temperature-Sensitive Alleles of NSDHL Cause CK Syndrome

    PubMed Central

    McLarren, Keith W.; Severson, Tesa M.; du Souich, Christèle; Stockton, David W.; Kratz, Lisa E.; Cunningham, David; Hendson, Glenda; Morin, Ryan D.; Wu, Diane; Paul, Jessica E.; An, Jianghong; Nelson, Tanya N.; Chou, Athena; DeBarber, Andrea E.; Merkens, Louise S.; Michaud, Jacques L.; Waters, Paula J.; Yin, Jingyi; McGillivray, Barbara; Demos, Michelle; Rouleau, Guy A.; Grzeschik, Karl-Heinz; Smith, Raffaella; Tarpey, Patrick S.; Shears, Debbie; Schwartz, Charles E.; Gecz, Jozef; Stratton, Michael R.; Arbour, Laura; Hurlburt, Jane; Van Allen, Margot I.; Herman, Gail E.; Zhao, Yongjun; Moore, Richard; Kelley, Richard I.; Jones, Steven J.M.; Steiner, Robert D.; Raymond, F. Lucy; Marra, Marco A.; Boerkoel, Cornelius F.

    2010-01-01

    CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. PMID:21129721

  18. Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.

    PubMed

    McLarren, Keith W; Severson, Tesa M; du Souich, Christèle; Stockton, David W; Kratz, Lisa E; Cunningham, David; Hendson, Glenda; Morin, Ryan D; Wu, Diane; Paul, Jessica E; An, Jianghong; Nelson, Tanya N; Chou, Athena; DeBarber, Andrea E; Merkens, Louise S; Michaud, Jacques L; Waters, Paula J; Yin, Jingyi; McGillivray, Barbara; Demos, Michelle; Rouleau, Guy A; Grzeschik, Karl-Heinz; Smith, Raffaella; Tarpey, Patrick S; Shears, Debbie; Schwartz, Charles E; Gecz, Jozef; Stratton, Michael R; Arbour, Laura; Hurlburt, Jane; Van Allen, Margot I; Herman, Gail E; Zhao, Yongjun; Moore, Richard; Kelley, Richard I; Jones, Steven J M; Steiner, Robert D; Raymond, F Lucy; Marra, Marco A; Boerkoel, Cornelius F

    2010-12-10

    CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  19. Granulomatous Lobular Mastitis Following Drug-Induced Galactorrhea and Blunt Trauma.

    PubMed

    Cserni, Gábor; Szajki, Károly

    1999-11-01

    We report a single case of chronic granulomatous lobular mastitis following metoclopramide-related galactorrhea and a blunt trauma in a young parous woman who underwent two conservative operations before becoming symptom-free. We have found only two other literature cases associated with hyperprolactinemia, and our case could be another of this etiologic group. The absence of well-formed granulomas in the first histology specimen in the present case was misleading; it was reinterpreted as granulomatous mastitis only after the second specimen was examined. Reinterpretation was based on the lobular distribution of a lymphoplasmocytic infiltrate (nonspecific chronic lobulitis) and the presence of epithelioid cell sheets and neutrophils in the absence of well-formed granulomas. The case lends further support to the theory of a local immune response initiated by the secreted material or by one of its components in the formation of granulomas. However, contributory factors such as the trauma in this case (a blow from a shovel handle) or systemic disease in others may play a role in the development of the disease, which in some instances may represent a pattern of tissue reactions to different noxious agents.

  20. Hypokalemia causing rhabdomyolysis in a patient with short bowel syndrome.

    PubMed

    Balhara, Kamna S; Highet, Bridget; Omron, Rodney

    2015-04-01

    Rhabdomyolysis, usually in the setting of trauma or drug use, is frequently seen in the emergency setting, and often leads to hyperkalemia at presentation. Hypokalemia, however, is a potentially underrecognized cause of rhabdomyolysis. We present a case of rhabdomyolysis likely due to hypokalemia in the setting of short bowel syndrome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although less common, hypokalemia can be a significant cause of rhabdomyolysis via its effects on muscle. This scenario should be considered in the differential diagnosis of patients at risk for hypokalemia who present with weakness. Rapid recognition of this relationship and rapid correction of hypokalemia may prove very important in preventing the deleterious effects of rhabdomyolysis. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Catatonia in Down syndrome; a treatable cause of regression

    PubMed Central

    Ghaziuddin, Neera; Nassiri, Armin; Miles, Judith H

    2015-01-01

    Objective: The main aim of this case series report is to alert physicians to the occurrence of catatonia in Down syndrome (DS). A second aim is to stimulate the study of regression in DS and of catatonia. A subset of individuals with DS is noted to experience unexplained regression in behavior, mood, activities of daily living, motor activities, and intellectual functioning during adolescence or young adulthood. Depression, early onset Alzheimer’s, or just “the Down syndrome” are often blamed after general medical causes have been ruled out. Clinicians are generally unaware that catatonia, which can cause these symptoms, may occur in DS. Study design: Four DS adolescents who experienced regression are reported. Laboratory tests intended to rule out causes of motor and cognitive regression were within normal limits. Based on the presence of multiple motor disturbances (slowing and/or increased motor activity, grimacing, posturing), the individuals were diagnosed with unspecified catatonia and treated with anti-catatonic treatments (benzodiazepines and electroconvulsive therapy [ECT]). Results: All four cases were treated with a benzodiazepine combined with ECT and recovered their baseline functioning. Conclusion: We suspect catatonia is a common cause of unexplained deterioration in adolescents and young adults with DS. Moreover, pediatricians and others who care for individuals with DS are generally unfamiliar with the catatonia diagnosis outside schizophrenia, resulting in misdiagnosis and years of morbidity. Alerting physicians to catatonia in DS is essential to prompt diagnosis, appropriate treatment, and identification of the frequency and course of this disorder. PMID:25897230

  2. Pathology of Podocytopathies Causing Nephrotic Syndrome in Children.

    PubMed

    Ranganathan, Sarangarajan

    2016-01-01

    Nephrotic syndrome (NS) in children includes a diverse group of diseases that range from genetic diseases without any immunological defects to causes that are primarily due to immunological effects. Recent advances in molecular and genomic studies have resulted in a plethora of genetic defects that have been localized to the podocyte, the basic structure that is instrumental in normal filtration process. Although the disease can manifest from birth and into adulthood, the primary focus of this review would be to describe the novel genes and pathology of primary podocyte defects that cause NS in children. This review will restrict itself to the pathology of congenital NS, minimal change disease (MCD), and its variants and focal segmental glomerulosclerosis (FSGS). The two major types of congenital NS are Finnish type characterized by dilated sausage shaped tubules morphologically and diffuse mesangial sclerosis characterized by glomerulosclerosis. MCD has usually normal appearing biopsy features on light microscopy and needs electron microscopy for diagnosis, whereas FSGS in contrast has classic segmental sclerosing lesions identified in different portions of the glomeruli and tubular atrophy. This review summarizes the pathological characteristics of these conditions and also delves into the various genetic defects that have been described as the cause of these primary podocytopathies. Other secondary causes of NS in children, such as membranoproliferative and membranous glomerulonephritis, will not be covered in this review.

  3. Coracoid syndrome: a neglected cause of anterior shoulder pain.

    PubMed

    Gigante, Antonio; Bottegoni, Carlo; Barbadoro, Pamela

    2016-01-01

    the present prospective open-label study was designed to gain further insights into a condition thought to constitute a neglected but not uncommon syndrome characterized by anterior shoulder pain and tenderness to palpation over the apex of the coracoid process, not related to rotator cuff or pectoralis minor tendinopathy, long head of the biceps tendon disorders, or instability. The aim was to clarify its prevalence, clinical characteristics, differential diagnosis and response to corticosteroid injections. patients with primary anterior shoulder pain precisely reproduced by deep pressure on the apex of the coracoid process were recruited. Patients with clinical or instrumental signs of other shoulder disorders were excluded. Patients were given an injection of triamcinolone acetonide 40 mg/ml 1 ml at the coracoid trigger point. They were evaluated after 15, 30 and 60 days and at 2 years using Equal Visual Analog Scale (EQ-VAS) and the Italian version of the Simple Shoulder Test (SST). between January 1 and December 31 2010, we treated 15 patients aged 26-66 years. The majority were women (86.67%). At 15 days, 6 (40%) patients reported complete resolution of their symptoms, while 9 (60%) complained of residual symptoms and received another injection. At 30 days, 14 (93.33%) patients were pain-free and very satisfied. At 2 years, the 14 patients who had been asymptomatic at 30 days reported that they had experienced no further pain or impaired shoulder function. The analysis of variance for repeated measures showed a significant effect of time on EQ-VAS and SST scores. the present study documents the existence, and characteristics, of a "coracoid syndrome" characterized by anterior shoulder pain and tenderness to palpation over the apex of the coracoid process and showed that the pain is usually amenable to steroid treatment. This syndrome should be clearly distinguished from anterior shoulder pain due to other causes, in order to avoid inappropriate conservative

  4. Inflammatory peeling skin syndrome caused a novel mutation in CDSN.

    PubMed

    Telem, Dana Fuchs; Israeli, Shirli; Sarig, Ofer; Sprecher, Eli

    2012-04-01

    Generalized peeling skin syndrome (PSS) is a rare autosomal recessive dermatosis manifesting with continuous exfoliation of the stratum corneum. The inflammatory (type B) subtype of PSS was recently found to be caused by deleterious mutations in the CDSN gene encoding corneodesmosin, a major component of desmosomal junctions in the uppermost layers of the epidermis. In the present study, we assessed a 10-month-old baby, who presented with generalized superficial peeling of the skin. Using PCR amplification and direct sequencing, we identified the third PSS-associated mutation in CDSN, a homozygous 4 bp duplication in the second exon of the gene (c.164_167dup GCCT; p.Thr57ProfsX6). These data further support the notion that corneodesmosin deficiency impairs cell-cell adhesion in the upper epidermis, paving the way for an abnormal inflammatory response due to epidermal barrier disruption.

  5. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

    PubMed Central

    Bagni, Claudia; Tassone, Flora; Neri, Giovanni; Hagerman, Randi

    2012-01-01

    Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families. PMID:23202739

  6. A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome

    PubMed Central

    Taghdiri, Maryam; Dastsooz, Hassan; Fardaei, Majid; Mohammadi, Sanaz; Farazi Fard, Mohammad Ali; Faghihi, Mohammad Ali

    2017-01-01

    Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C) in our patient. Another gene (ERCC6), which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family. PMID:28848724

  7. A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome.

    PubMed

    Taghdiri, Maryam; Dastsooz, Hassan; Fardaei, Majid; Mohammadi, Sanaz; Farazi Fard, Mohammad Ali; Faghihi, Mohammad Ali

    2017-01-01

    Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C) in our patient. Another gene ( ERCC6 ), which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family.

  8. Transsphenoidal surgery for pituitary gigantism and galactorrhea in a 3.5 year old child.

    PubMed

    Flitsch, J; Lüdecke, D K; Stahnke, N; Wiebel, J; Saeger, W

    2000-05-01

    The management of pituitary macroadenomas which lead to gigantism may require multiple therapeutical approaches, including medical treatment, surgery, and radiation therapy. Transsphenoidal surgery (TSS) during early childhood that achieves total removal of a growth hormone (GH) secreting tumor is rarely reported. The surgeon is confronted with special problems regarding the infantile anatomy. In this case, a 3.5 year old child, the youngest successfully treated by TSS so far, suffered from a GH- and prolactin (PRL) secreting macroadenoma of the pituitary gland. The girl initially presented with an increasing growth rate, later with breast development, and finally, at the age of 2.8 years, with galactorrhea and secretion of blood from the nipples. Increased levels of GH [122 micrograms/l], insulin-like growth factor (IGF-1) [830 micrograms/l], insulin-like growth factor binding protein 3 (IGFBP-3) [8.6 mg/l] and PRL [590 micrograms/l] were found. MRI scans revealed a macroadenoma of 2.7 cm diameter. An eight-week trial of relatively low dose dopamine agonists led to a reduction of PRL, while the GH- and IGF-1 levels remained unchanged; the tumor showed only little shrinkage. Since there was chiasma compression, we opted for early TSS. A complete tumor removal was achieved despite the difficulties of a narrow approach. After TSS, low levels of GH, IGF-1, and PRL documented a complete tumor removal, but persistent diabetes insipidus and anterior lobe deficits resulted from surgery. In summary, if primary medical therapy alone is unable to adequately reduce hormone hypersecretion and tumor size in early childhood, TSS is recommended. Thus, radiation therapy may be reserved for surgical failure.

  9. The medial tibial stress syndrome. A cause of shin splints.

    PubMed

    Mubarak, S J; Gould, R N; Lee, Y F; Schmidt, D A; Hargens, A R

    1982-01-01

    The medial tibial stress syndrome is a symptom complex seen in athletes who complain of exercise-induced pain along the distal posterior-medial aspect of the tibia. Intramuscular pressures within the posterior compartments of the leg were measured in 12 patients with this disorder. These pressures were not elevated and therefore this syndrome is a not a compartment syndrome. Available information suggests that the medial tibial stress syndrome most likely represents a periostitis at this location of the leg.

  10. Mitochondrial disorder caused Charles Darwin's cyclic vomiting syndrome.

    PubMed

    Finsterer, Josef; Hayman, John

    2014-01-08

    Charles Darwin (CD), "father of modern biology," suffered from multisystem illness from early adulthood. The most disabling manifestation was cyclic vomiting syndrome (CVS). This study aims at finding the possible cause of CVS in CD. A literature search using the PubMed database was carried out, and CD's complaints, as reported in his personal writings and those of his relatives, friends, colleagues, biographers, were compared with various manifestations of mitochondrial disorders (MIDs), known to cause CVS, described in the literature. Organ tissues involved in CD's disease were brain, nerves, muscles, vestibular apparatus, heart, gut, and skin. Cerebral manifestations included episodic headache, visual disturbance, episodic memory loss, periodic paralysis, hysterical crying, panic attacks, and episodes of depression. Manifestations of polyneuropathy included numbness, paresthesias, increased sweating, temperature sensitivity, and arterial hypotension. Muscular manifestations included periods of exhaustion, easy fatigability, myalgia, and muscle twitching. Cardiac manifestations included episodes of palpitations and chest pain. Gastrointestinal manifestations were CVS, dental problems, abnormal seasickness, eructation, belching, and flatulence. Dermatological manifestations included painful lips, dermatitis, eczema, and facial edema. Treatments with beneficial effects to his complaints were rest, relaxation, heat, and hydrotherapy. CVS in CD was most likely due to a multisystem, nonsyndromic MID. This diagnosis is based upon the multisystem nature of his disease, the fact that CVS is most frequently the manifestation of a MID, the family history, the variable phenotypic expression between affected family members, the fact that symptoms were triggered by stress, and that only few symptoms could not be explained by a MID.

  11. Cardiovascular causes of maternal sudden death. Sudden arrhythmic death syndrome is leading cause in UK.

    PubMed

    Krexi, Dimitra; Sheppard, Mary N

    2017-05-01

    This study aims to determine the causes of sudden cardiac death during pregnancy and in the postpartum period and patients' characteristics. There are few studies in the literature. Eighty cases of sudden unexpected death due to cardiac causes in relation to pregnancy and postpartum period in a database of 4678 patients were found and examined macroscopically and microscopically. The mean age was 30±7 years with a range from 16 to 43 years. About 30% were 35 years old or older; 50% of deaths occurred during pregnancy and 50% during the postpartum period. About 59.18% were obese or overweight where body mass index data were available. The leading causes of death were sudden arrhythmic death syndrome (SADS) (53.75%) and cardiomyopathies (13.80%). Other causes include dissection of aorta or its branches (8.75%), congenital heart disease (2.50%) and valvular disease (3.75%). This study highlights sudden cardiac death in pregnancy or in the postpartum period, which is mainly due to SADS with underlying channelopathies and cardiomyopathy. We wish to raise awareness of these frequently under-recognised entities in maternal deaths and the need of cardiological screening of the family as a result of the diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Cardiovascular causes of maternal sudden death. Sudden Arrhythmic Death Syndrome is leading cause in UK.

    PubMed

    Krexi, Dimitra; Sheppard, Mary N

    2017-09-01

    This study aims to determine the causes of sudden cardiac death during pregnancy and in the postpartum period and patients' characteristics. There are few studies in the literature. Eighty cases of sudden unexpected death due to cardiac causes in relation to pregnancy and postpartum period in a database of 4678 patients were found and examined macroscopically and microscopically. The mean age was 30±7years with a range from 16 to 43 years. About 30% were 35 years old or older; 50% of deaths occurred during pregnancy and 50% during the postpartum period. About 59.18% were obese or overweight where body mass index data were available. The leading causes of death were sudden arrhythmic death syndrome (SADS) (53.75%) and cardiomyopathies (13.80%). Other causes include dissection of aorta or its branches (8.75%), congenital heart disease (2.50%) and valvular disease (3.75%). This study highlights sudden cardiac death in pregnancy or in the postpartum period, which is mainly due to SADS with underlying channelopathies and cardiomyopathy. We wish to raise awareness of these frequently under-recognised entities in maternal deaths and the need of cardiological screening of the family as a result of the diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Schmidt's syndrome: a rare cause of puberty menorrhagia.

    PubMed

    Sharma, J B; Tiwari, S; Gulati, N; Sharma, S

    1990-12-01

    Schmidt's syndrome, also known as polyglandular deficiency syndrome, is the presence of Addison's disease and hypothyrodism in a single patient. It is usually associated with other autoimmune disorders like vitiligo, diabetes mellitus, myasthenia gravis. A rare case of an 18-year-old girl having Schmidt's syndrome and vitiligo who presented with puberty menorrhagia is reported. A brief review of the literature is also given.

  14. Mitochondrial disorder caused Charles Darwin’s cyclic vomiting syndrome

    PubMed Central

    Finsterer, Josef; Hayman, John

    2014-01-01

    Background Charles Darwin (CD), “father of modern biology,” suffered from multisystem illness from early adulthood. The most disabling manifestation was cyclic vomiting syndrome (CVS). This study aims at finding the possible cause of CVS in CD. Methods A literature search using the PubMed database was carried out, and CD’s complaints, as reported in his personal writings and those of his relatives, friends, colleagues, biographers, were compared with various manifestations of mitochondrial disorders (MIDs), known to cause CVS, described in the literature. Results Organ tissues involved in CD’s disease were brain, nerves, muscles, vestibular apparatus, heart, gut, and skin. Cerebral manifestations included episodic headache, visual disturbance, episodic memory loss, periodic paralysis, hysterical crying, panic attacks, and episodes of depression. Manifestations of polyneuropathy included numbness, paresthesias, increased sweating, temperature sensitivity, and arterial hypotension. Muscular manifestations included periods of exhaustion, easy fatigability, myalgia, and muscle twitching. Cardiac manifestations included episodes of palpitations and chest pain. Gastrointestinal manifestations were CVS, dental problems, abnormal seasickness, eructation, belching, and flatulence. Dermatological manifestations included painful lips, dermatitis, eczema, and facial edema. Treatments with beneficial effects to his complaints were rest, relaxation, heat, and hydrotherapy. Conclusion CVS in CD was most likely due to a multisystem, nonsyndromic MID. This diagnosis is based upon the multisystem nature of his disease, the fact that CVS is most frequently the manifestation of a MID, the family history, the variable phenotypic expression between affected family members, the fact that symptoms were triggered by stress, and that only few symptoms could not be explained by a MID. PMID:24453499

  15. Streptococcal toxic shock syndrome caused by Streptococcus suis serotype 2.

    PubMed

    Tang, Jiaqi; Wang, Changjun; Feng, Youjun; Yang, Weizhong; Song, Huaidong; Chen, Zhihai; Yu, Hongjie; Pan, Xiuzhen; Zhou, Xiaojun; Wang, Huaru; Wu, Bo; Wang, Haili; Zhao, Huamei; Lin, Ying; Yue, Jianhua; Wu, Zhenqiang; He, Xiaowei; Gao, Feng; Khan, Abdul Hamid; Wang, Jian; Zhao, Guo-Ping; Wang, Yu; Wang, Xiaoning; Chen, Zhu; Gao, George F

    2006-05-01

    Streptococcus suis serotype 2 (S. suis 2, SS2) is a major zoonotic pathogen that causes only sporadic cases of meningitis and sepsis in humans. Most if not all cases of Streptococcal toxic shock syndrome (STSS) that have been well-documented to date were associated with the non-SS2 group A streptococcus (GAS). However, a recent large-scale outbreak of SS2 in Sichuan Province, China, appeared to be caused by more invasive deep-tissue infection with STSS, characterized by acute high fever, vascular collapse, hypotension, shock, and multiple organ failure. We investigated this outbreak of SS2 infections in both human and pigs, which took place from July to August, 2005, through clinical observation and laboratory experiments. Clinical and pathological characterization of the human patients revealed the hallmarks of typical STSS, which to date had only been associated with GAS infection. Retrospectively, we found that this outbreak was very similar to an earlier outbreak in Jiangsu Province, China, in 1998. We isolated and analyzed 37 bacterial strains from human specimens and eight from pig specimens of the recent outbreak, as well as three human isolates and two pig isolates from the 1998 outbreak we had kept in our laboratory. The bacterial isolates were examined using light microscopy observation, pig infection experiments, multiplex-PCR assay, as well as restriction fragment length polymorphisms (RFLP) and multiple sequence alignment analyses. Multiple lines of evidence confirmed that highly virulent strains of SS2 were the causative agents of both outbreaks. We report, to our knowledge for the first time, two outbreaks of STSS caused by SS2, a non-GAS streptococcus. The 2005 outbreak was associated with 38 deaths out of 204 documented human cases; the 1998 outbreak with 14 deaths out of 25 reported human cases. Most of the fatal cases were characterized by STSS; some of them by meningitis or severe septicemia. The molecular mechanisms underlying these human STSS

  16. Novel CLCNKB mutations causing Bartter syndrome affect channel surface expression.

    PubMed

    Keck, Mathilde; Andrini, Olga; Lahuna, Olivier; Burgos, Johanna; Cid, L Pablo; Sepúlveda, Francisco V; L'hoste, Sébastien; Blanchard, Anne; Vargas-Poussou, Rosa; Lourdel, Stéphane; Teulon, Jacques

    2013-09-01

    Mutations in the CLCNKB gene encoding the ClC-Kb Cl(-) channel cause Bartter syndrome, which is a salt-losing renal tubulopathy. Here, we investigate the functional consequences of seven mutations. When expressed in Xenopus laevis oocytes, four mutants carried no current (c.736G>C, p.Gly246Arg; c.1271G>A, p.Gly424Glu; c.1313G>A, p.Arg438His; c.1316T>C, p.Leu439Pro), whereas others displayed a 30%-60% reduction in conductance as compared with wild-type ClC-Kb (c.242T>C, p.Leu81Pro; c.274C>T, p.Arg92Trp; c.1052G>C, p.Arg351Pro). Anion selectivity and sensitivity to external Ca(2+) and H(+), typical of the ClC-Kb channel, were not modified in the partially active mutants. In oocytes, we found that all the mutations reduced surface expression with a profile similar to that observed for currents. In HEK293 cells, the currents in the mutants had similar profiles to those obtained in oocytes, except for p.Leu81Pro, which produced no current. Furthermore, p.Arg92Trp and p.Arg351Pro mutations did not modify the unit-conductance of closely related ClC-K1. Western blot analysis in HEK293 cells showed that ClC-Kb protein abundance was lower for the nonconducting mutants but similar to wild-type for other mutants. Overall, two classes of mutants can be distinguished: nonconducting mutants associated with low total protein expression, and partially conducting mutants with unaltered channel properties and ClC-Kb protein abundance. © 2013 WILEY PERIODICALS, INC.

  17. Food protein induced enterocolitis syndrome caused by rice beverage.

    PubMed

    Caminiti, Lucia; Salzano, Giuseppina; Crisafulli, Giuseppe; Porcaro, Federica; Pajno, Giovanni Battista

    2013-05-14

    Food protein-induced enterocolitis syndrome (FPIES) is an uncommon and potentially severe non IgE-mediated gastrointestinal food allergy. It is usually caused by cow's milk or soy proteins, but may also be triggered by ingestion of solid foods. The diagnosis is made on the basis of clinical history and symptoms. Management of acute phase requires fluid resuscitation and intravenous steroids administration, but avoidance of offending foods is the only effective therapeutic option.Infant with FPIES presented to our emergency department with vomiting, watery stools, hypothension and metabolic acidosis after ingestion of rice beverage. Intravenous fluids and steroids were administered with good clinical response. Subsequently, a double blind placebo control food challenge (DBPCFC) was performed using rice beverage and hydrolyzed formula (eHF) as placebo. The "rice based formula" induced emesis, diarrhoea and lethargy. Laboratory investigations reveal an increase of absolute count of neutrophils and the presence of faecal eosinophils. The patient was treated with both intravenous hydration and steroids. According to Powell criteria, oral food challenge was considered positive and diagnosis of FPIES induced by rice beverage was made. Patient was discharged at home with the indication to avoid rice and any rice beverage as well as to reintroduce hydrolyzed formula. A case of FPIES induced by rice beverage has never been reported. The present case clearly shows that also beverage containing rice proteins can be responsible of FPIES. For this reason, the use of rice beverage as cow's milk substitute for the treatment of non IgE-mediated food allergy should be avoided.

  18. Eosinophilic cellulitis (Wells’ syndrome) caused by a temporary henna tattoo

    PubMed Central

    Celegen, Mehmet; Karkıner, Canan Sule Unsal; Günay, Ilker; Diniz, Güllden; Can, Demet

    2014-01-01

    Eosinophilic cellulitis (Wells’ syndrome) is an uncommon condition of unknown etiology. Wells’ syndrome is usually seen in adulthood but very rare in childhood. Although pathogenesis of the disease is not very clear, it is a hypersensitivity reaction developing against a variety of exogenous and endogenous antigenic stimuli. Paraphenylenediamine is a strong allergen frequently used as a temporary henna tattoo, which makes the color darker. Here, a 9-year-old male patient with Wells’ syndrome is presented, which developed following a temporary henna tattoo and shown by the patch test sensitivity to paraphenylenediamine. PMID:25395929

  19. A Very Rare Cause of Anal Atresia: Currarino Syndrome

    PubMed Central

    Buyukbese Sarsu, Sevgi; Parmaksiz, Mehmet Ergun; Cabalar, Esra; Karapur, Ali; Kaya, Cihat

    2016-01-01

    Currarino syndrome (triad) is an extremely rare condition characterized by presacral mass, anorectal malformation, and sacral bone deformation. The complete form of this syndrome displays all three irregularities. Herein, we report a male case who was admitted to our hospital with symptoms of urinary system infection and persistent constipation 2 years after colostomy operation performed with the indication of rectovestibular fistula and anal atresia, diagnosed as Currarino syndrome based on imaging modalities. In a patient who was admitted because of the presence of anal atresia, in order to preclude potential complications, probable concomitancy of this syndrome should not be forgotten. Early diagnosis is important for the prevention of meningitis, urinary tract infections, and malignant change. PMID:27081429

  20. Acute radiation syndrome caused by accidental radiation exposure - therapeutic principles.

    PubMed

    Dörr, Harald; Meineke, Viktor

    2011-11-25

    Fortunately radiation accidents are infrequent occurrences, but since they have the potential of large scale events like the nuclear accidents of Chernobyl and Fukushima, preparatory planning of the medical management of radiation accident victims is very important. Radiation accidents can result in different types of radiation exposure for which the diagnostic and therapeutic measures, as well as the outcomes, differ. The clinical course of acute radiation syndrome depends on the absorbed radiation dose and its distribution. Multi-organ-involvement and multi-organ-failure need be taken into account. The most vulnerable organ system to radiation exposure is the hematopoietic system. In addition to hematopoietic syndrome, radiation induced damage to the skin plays an important role in diagnostics and the treatment of radiation accident victims. The most important therapeutic principles with special reference to hematopoietic syndrome and cutaneous radiation syndrome are reviewed.

  1. Elsberg syndrome: A rarely recognized cause of cauda equina syndrome and lower thoracic myelitis.

    PubMed

    Savoldi, Filippo; Kaufmann, Timothy J; Flanagan, Eoin P; Toledano, Michel; Weinshenker, Brian G

    2017-07-01

    Elsberg syndrome (ES) is an established but often unrecognized cause of acute lumbosacral radiculitis with myelitis related to recent herpes virus infection. We defined ES, determined its frequency in patients with cauda equina syndrome (CES) with myelitis, and evaluated its clinical, radiologic, and microbiologic features and outcomes. We searched the Mayo Clinic medical records for ES and subsequently for combinations of index terms to identify patients with suspected CES and myelitis. Our search yielded 30 patients, 2 diagnosed with ES and an additional 28 with clinical or radiologic evidence of CES retrospectively suspected of having ES. We classified patients in 5 groups according to diagnostic certainty. MRI and EMG confirmed that 2 had only myelitis, 5 only radiculitis, and 16 both. Two had preceding sacral herpes infection and 1 oral herpes simplex. Spinal cord lesions were commonly multiple, discontinuous, not expansile, and centrally or ventrally positioned. Lesions generally spared the distal conus. Nerve root enhancement was occasionally prominent and was smooth rather than nodular. Lymphocytic CSF pleocytosis was common. Thirteen patients (43%) had viral isolation studies, which were commonly delayed; the delay may have accounted for the low rate of viral detection. Acyclovir was administered to 6 patients. Most patients recovered with sequelae; 1 patient experienced encephalomyelitis and died. ES is a definable condition likely responsible for 10% of patients with combined CES and myelitis. Radiologic findings are not entirely specific but may help in differentiating ES from some competing diagnostic considerations. We propose criteria to facilitate diagnosis.

  2. Mutations in the G6PC3 gene cause Dursun syndrome.

    PubMed

    Banka, Siddharth; Newman, William G; Ozgül, R Koksal; Dursun, Ali

    2010-10-01

    Dursun syndrome is a triad of familial primary pulmonary hypertension, leucopenia, and atrial septal defect. Here we demonstrate that mutations in G6PC3 cause Dursun syndrome. Mutations in G6PC3 are known to also cause severe congenital neutropenia type 4. Identification of the genetic basis of Dursun syndrome expands the pre-existing knowledge about the phenotypic effects of mutations in G6PC3. We propose that Dursun syndrome should now be considered as a subset of severe congenital neutropenia type 4 with pulmonary hypertension as an important clinical feature. Copyright © 2010 Wiley-Liss, Inc.

  3. Confirmation that RIPK4 mutations cause not only Bartsocas-Papas syndrome but also CHAND syndrome.

    PubMed

    Busa, Tiffany; Jeraiby, Mohammed; Clémenson, Alix; Manouvrier, Sylvie; Granados, Viviana; Philip, Nicole; Touraine, Renaud

    2017-11-01

    CHAND syndrome is an autosomal recessive disorder characterized by curly hair, ankyloblepharon, and nail dysplasia. Only few patients were reported to date. A homozygous RIPK4 mutation was recently identified by homozygosity mapping and whole exome sequencing in three patients from an expanded consanguineous kindred with a clinical diagnosis of CHAND syndrome. RIPK4 was previously known to be implicated in Bartsocas-Papas syndrome, the autosomal recessive form of popliteal pterygium syndrome. We report here two cases of RIPK4 homozygous mutations in a fetus with severe Bartsocas-Papas syndrome and a patient with CHAND syndrome. The patient with CHAND syndrome harbored the same mutation as the one identified in the family previously reported. We thus confirm the implication of RIPK4 gene in CHAND syndrome in addition to Bartsocas-Papas syndrome and discuss genotype/phenotype correlations. © 2017 Wiley Periodicals, Inc.

  4. Systemic Multiple Aneurysms Caused by Vascular Ehlers-Danlos Syndrome.

    PubMed

    Gui, Xinyu; Li, Fangda; Wu, Lingeer; Zheng, Yuehong

    2016-07-01

    Systemic multiple aneurysms are rare and usually associated with collagen tissue disease, such as Ehlers-Danlos syndrome (EDS) or Marfan syndrome. In the present case, we describe a 39-year-old male patient with systemic multiple aneurysms and acute intraperitoneal hemorrhage who was clinically diagnosed with vascular EDS. Coil embolization of the distal segment of the common hepatic artery was performed, which resolved the patient's symptoms. With this case presentation, we aim to increase the awareness of vascular EDS among clinicians and emphasize the extreme fragility of the arteries in patients with vascular EDS. © The Author(s) 2016.

  5. Toxigenic and metabolic causes of ketosis and ketoacidotic syndromes.

    PubMed

    Cartwright, Martina M; Hajja, Waddah; Al-Khatib, Sofian; Hazeghazam, Maryam; Sreedhar, Dharmashree; Li, Rebecca Na; Wong-McKinstry, Edna; Carlson, Richard W

    2012-10-01

    Ketoacidotic syndromes are frequently encountered in acute care medicine. This article focuses on ketosis and ketoacidotic syndromes associated with intoxications, alcohol abuse, starvation, and certain dietary supplements as well as inborn errors of metabolism. Although all of these various processes are characterized by the accumulation of ketone bodies and metabolic acidosis, there are differences in the mechanisms, clinical presentations, and principles of therapy for these heterogeneous disorders. Pathophysiologic mechanisms that account for these disorders are presented, as well as guidance regarding identification and management. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation.

    PubMed

    Takanashi, J; Sugita, K; Tanabe, Y; Maemoto, T; Niimi, H

    1997-01-01

    Sodium dichloroacetate (DCA) was administered to a 1-year-old female case of Leigh syndrome, who had a T > G point mutation at nt 8993 of mitochondrial DNA. Her biochemical and clinical symptoms improved gradually, but proton magnetic resonance spectroscopy revealed reduction of the N-acetylaspartate/creatine ratio, and magnetic resonance imaging showed progressive cerebral atrophy despite the DCA therapy. These results suggest that DCA therapy may not retard the progress of the primary disease in Leigh syndrome, but produced clinical improvement most likely by reducing toxic accumulation of lactate.

  7. Leigh syndrome: One disorder, more than 75 monogenic causes.

    PubMed

    Lake, Nicole J; Compton, Alison G; Rahman, Shamima; Thorburn, David R

    2016-02-01

    Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in >75 genes have been identified, encoded by 2 genomes (mitochondrial and nuclear). More than one-third of these disease genes have been characterized in the past 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological, and metabolic features that can provide clues for diagnosis. We discuss the emergence of genotype-phenotype correlations, insights gleaned into the molecular basis of disease, and available therapeutic options. © 2015 American Neurological Association.

  8. Malformation syndromes caused by disorders of cholesterol synthesis

    PubMed Central

    Porter, Forbes D.; Herman, Gail E.

    2011-01-01

    Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome. PMID:20929975

  9. Injection sclerotherapy for haemorrhoids causing adult respiratory distress syndrome.

    PubMed

    Rashid, Muhammad Misbah; Murtaza, Badar; Gondal, Zafar Iqbal; Mehmood, Arshad; Shah, Shahzad Saleem; Abbasi, Muhammad Hanif; Tamimy, Muhammad Sarmad; Kazmi, Syed Tahawwar Mujtaba

    2006-05-01

    A young lady with first-degree haemorrhoids was administered injection sclerotherapy with 5% phenol in almond oil. Soon after the injection, she developed syncope and later signs and symptoms of acute respiratory distress syndrome (ARDS). She was kept on ventilatory support for 4 days, made a smooth recovery and was successfully weaned off from the ventilator.

  10. Can olanzapine be implicated in causing serotonin syndrome?

    PubMed

    Haslett, Christopher David; Kumar, Shailesh

    2002-10-01

    The present paper describes a case of serotonin syndrome (SS), which developed in a patient with bipolar affective disorder after the addition of olanzapine to her regimen of lithium and citalopram. This appears to be the first report that implicates olanzapine with SS. Clinicians should be aware of the risk of SS when adding atypical antipsychotics, such as olanzapine, to serotonergic agents.

  11. Anticholinergic Toxic Syndrome Caused by Atropa Belladonna Fruit (Deadly Nightshade): A Case Report

    PubMed Central

    Demirhan, Abdullah; Tekelioğlu, Ümit Yaşar; Yıldız, İsa; Korkmaz, Tanzer; Bilgi, Murat; Akkaya, Akcan; Koçoğlu, Hasan

    2013-01-01

    Atropa Belladonna poisoning may lead to anticholinergic syndrome. Ingestion of high amounts of the plant may cause lethargy, coma, and even a serious clinical picture leading to death. In this case report, we aimed to present a case with anticholinergic syndrome that developed after ingestion of the fruit called “Deadly Nightshade” in our country. PMID:27366377

  12. Causes of the "I Can Understand English but I Can't Speak" Syndrome in Turkey

    ERIC Educational Resources Information Center

    Coskun, Abdullah

    2016-01-01

    The saying "I can understand English but I can't speak" is so commonly used by Turkish people that it would be fair to state that not being able to speak English has almost become a syndrome in society. This study delves into the causes of this syndrome. In two state high schools, 293 high school students filled out a questionnaire…

  13. Determining the Amount, Timing and Causes of Mortality among Infants with Down Syndrome

    ERIC Educational Resources Information Center

    Goldman, S. E.; Urbano, R. C.; Hodapp, R. M.

    2011-01-01

    Objective: To examine the amount, timing and causes/correlates of infant mortality among newborns with Down syndrome. Methods: Using the Tennessee Department of Health Birth, Hospital Discharge and Death records, infants were identified who were born with Down syndrome from 1990 to 2006. Those who died during the first year were separated into…

  14. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

    PubMed Central

    Slavotinek, Anne M; Baranzini, Sergio E; Schanze, Denny; Labelle-Dumais, Cassandre; Short, Kieran M; Chao, Ryan; Yahyavi, Mani; Bijlsma, Emilia K; Chu, Catherine; Musone, Stacey; Wheatley, Ashleigh; Kwok, Pui-Yan; Marles, Sandra; Fryns, Jean-Pierre; Maga, A Murat; Hassan, Mohamed G; Gould, Douglas B; Madireddy, Lohith; Li, Chumei; Cox, Timothy C; Smyth, Ian; Chudley, Albert E; Zenker, Martin

    2014-01-01

    Background Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/ microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described. Methods and results This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1bat/bat mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome. Conclusions The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS–FREM complex diseases. PMID:21507892

  15. Prader-Willi Syndrome: Causes, Characteristics, Interventions, Long-Term Consequences.

    ERIC Educational Resources Information Center

    Otto, Tracy L.; Barber, William H.

    1992-01-01

    An overview of Prader-Willi syndrome, the most common form of dysmorphic genetic obesity associated with mental retardation, is presented, with an emphasis on associated causes, characteristics, diagnosis and counseling, intervention, and long-term consequences. (Author/DB)

  16. Review and update of mutations causing Waardenburg syndrome.

    PubMed

    Pingault, Véronique; Ente, Dorothée; Dastot-Le Moal, Florence; Goossens, Michel; Marlin, Sandrine; Bondurand, Nadège

    2010-04-01

    Waardenburg syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling. (c) 2010 Wiley-Liss, Inc.

  17. Venous Thoracic Outlet Syndrome as a Cause of Intractable Migraines.

    PubMed

    Chahwala, Veer; Tashiro, Jun; Li, Xiaoyi; Baqai, Atif; Rey, Jorge; Robinson, Handel R

    2017-02-01

    Thoracic outlet syndrome (TOS) refers to the compression of the neurovascular bundle within the thoracic outlet. Cases are classified by primary etiology-arterial, neurogenic, or venous. In addition to the typical symptoms of arm swelling and paresthesias, headaches have been reported as a potential symptom of TOS. In this report, we describe a patient with debilitating migraines, which were consistently preceded by unilateral arm swelling. Resolution of symptoms occurred only after thoracic outlet decompression. Patients with migraines and concomitant swelling and/or paresthesias, especially related to provocative arm maneuvers, should be considered a possible atypical presentation of TOS and evaluated in more detail. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Congenital pseudarthrosis of the clavicle causing thoracic outlet syndrome

    PubMed Central

    Watson, Hannah Isabella; Hopper, Graeme Philip; Kovacs, Peter

    2013-01-01

    A 7-year-old girl presented with an asymptomatic right supraclavicular swelling. Radiographs were interpreted as showing a non-union of her clavicle. No treatment was given at this time. However, she represented 12 years later with right upper limb pain and altered sensation. Examination revealed a positive Allen's test on the right. Repeat radiographs demonstrated a pseudarthrosis of the clavicle, associated with a secondary complication of thoracic outlet syndrome with vascular and neurological complications present. Non-operative management failed to relieve her symptoms. Operative intervention successfully treated her symptoms. PMID:23975919

  19. The trigeminal trophic syndrome: an unusual cause of nasal ulceration.

    PubMed

    Monrad, Seetha U; Terrell, Jeffrey E; Aronoff, David M

    2004-06-01

    Trigeminal trophic syndrome (TTS) is an unusual complication after peripheral or central damage to the trigeminal nerve, characterized by anesthesia, paresthesias, and ala nasi ulceration. We describe a patient with classic TTS after trigeminal rhizotomy who underwent several extensive evaluations for nasal ulceration and received prolonged immunosuppressive therapy for a presumed autoimmune disorder before the correct diagnosis was made. An understanding of the predisposing factors and clinical presentation of TTS is important to ensure a timely diagnosis of this difficult-to-treat illness. Differentiation of TTS from malignancy, infection, or vasculitis is possible on the basis of clinical history, tissue biopsy, and serologic evaluation.

  20. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

    PubMed

    Aoki, Yoko; Niihori, Tetsuya; Banjo, Toshihiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Ogata, Tsutomu; Takada, Fumio; Yano, Michihiro; Ando, Toru; Hoshika, Tadataka; Barnett, Christopher; Ohashi, Hirofumi; Kawame, Hiroshi; Hasegawa, Tomonobu; Okutani, Takahiro; Nagashima, Tatsuo; Hasegawa, Satoshi; Funayama, Ryo; Nagashima, Takeshi; Nakayama, Keiko; Inoue, Shin-Ichi; Watanabe, Yusuke; Ogura, Toshihiko; Matsubara, Yoichi

    2013-07-11

    RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome

    PubMed Central

    Aoki, Yoko; Niihori, Tetsuya; Banjo, Toshihiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Ogata, Tsutomu; Takada, Fumio; Yano, Michihiro; Ando, Toru; Hoshika, Tadataka; Barnett, Christopher; Ohashi, Hirofumi; Kawame, Hiroshi; Hasegawa, Tomonobu; Okutani, Takahiro; Nagashima, Tatsuo; Hasegawa, Satoshi; Funayama, Ryo; Nagashima, Takeshi; Nakayama, Keiko; Inoue, Shin-ichi; Watanabe, Yusuke; Ogura, Toshihiko; Matsubara, Yoichi

    2013-01-01

    RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. PMID:23791108

  2. Duane retraction syndrome: causes, effects and management strategies

    PubMed Central

    Kekunnaya, Ramesh; Negalur, Mithila

    2017-01-01

    Duane retraction syndrome (DRS) is a congenital eye movement anomaly characterized by variable horizontal duction deficits, with narrowing of the palpebral fissure and globe retraction on attempted adduction, occasionally accompanied by upshoot or down-shoot. The etiopathogenesis of this condition can be explained by a spectrum of mechanical, innervational, neurologic and genetic abnormalities occurring independently or which influence each other giving rise to patterns of clinical presentations along with a complex set of ocular and systemic anomalies. Huber type I DRS is the most common form of DRS with an earlier presentation, while Huber type II is the least common presentation. Usually, patients with unilateral type I Duane syndrome have esotropia more frequently than exotropia, those with type II have exotropia and those with type III have esotropia and exotropia occurring equally common. Cases of bilateral DRS may have variable presentation depending upon the type of presentation in each eye. As regards its management, DRS classification based on primary position deviation as esotropic, exotropic or orthotropic is more relevant than Huber’s classification before planning surgery. Surgical approach to these patients is challenging and must be individualized based on the amount of ocular deviation, abnormal head position, associated globe retraction and overshoots. PMID:29133973

  3. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.

    PubMed

    Bicknell, Louise S; Farrington-Rock, Claire; Shafeghati, Yousef; Rump, Patrick; Alanay, Yasemin; Alembik, Yves; Al-Madani, Navid; Firth, Helen; Karimi-Nejad, Mohammad Hassan; Kim, Chong Ae; Leask, Kathryn; Maisenbacher, Melissa; Moran, Ellen; Pappas, John G; Prontera, Paolo; de Ravel, Thomy; Fryns, Jean-Pierre; Sweeney, Elizabeth; Fryer, Alan; Unger, Sheila; Wilson, L C; Lachman, Ralph S; Rimoin, David L; Cohn, Daniel H; Krakow, Deborah; Robertson, Stephen P

    2007-02-01

    Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

  4. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes

    PubMed Central

    Putoux, Audrey; Thomas, Sophie; Coene, Karlien L M; Davis, Erica E; Alanay, Yasemin; Ogur, Gönül; Uz, Elif; Buzas, Daniela; Gomes, Céline; Patrier, Sophie; Bennett, Christopher L; Elkhartoufi, Nadia; Frison, Marie-Hélène Saint; Rigonnot, Luc; Joyé, Nicole; Pruvost, Solenn; Utine, Gulen Eda; Boduroglu, Koray; Nitschke, Patrick; Fertitta, Laura; Thauvin-Robinet, Christel; Munnich, Arnold; Cormier-Daire, Valérie; Hennekam, Raoul; Colin, Estelle; Akarsu, Nurten Ayse; Bole-Feysot, Christine; Cagnard, Nicolas; Schmitt, Alain; Goudin, Nicolas; Lyonnet, Stanislas; Encha-Razavi, Férechté; Siffroi, Jean-Pierre; Winey, Mark; Katsanis, Nicholas; Gonzales, Marie; Vekemans, Michel; Beales, Philip L; Attié-Bitach, Tania

    2012-01-01

    KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies. PMID:21552264

  5. Chronic fibrosing pulmonary aspergillosis: a cause of 'destroyed lung' syndrome.

    PubMed

    Kosmidis, Chris; Newton, Pippa; Muldoon, Eavan G; Denning, David W

    2017-04-01

    Chronic pulmonary aspergillosis (CPA) has substantial impact on quality of life. A subset of patients develops significant pulmonary fibrosis, identified either on biopsy or radiologically. The term chronic fibrosing pulmonary aspergillosis (CFPA) has been suggested. We describe 11 patients with CFPA referred to our centre. Mean age was 58.5 years and five were male. In nine, fibrosis was already evident on presentation, while in two it developed 3 and 6 years later. The predominant radiological feature was extensive or complete involvement of the entire lung, with minimal contralateral involvement. All patients received prolonged antifungal treatment. Two patients had surgical treatment; both developed post-operative complications. The contralateral lung remained free of significant disease in all but three patients. CFPA is a rare complication of CPA that is usually evident on presentation, but may develop after years in patients not on antifungals. Fibrosis resembles the 'destroyed lung' syndrome described after treated tuberculosis.

  6. 3M syndrome: an easily recognizable yet underdiagnosed cause of proportionate short stature.

    PubMed

    Al-Dosari, Mohammed S; Al-Shammari, Muneera; Shaheen, Ranad; Faqeih, Eissa; Alghofely, Mohammed A; Boukai, Ahmad; Alkuraya, Fowzan S

    2012-07-01

    To characterize, via clinical and molecul criteria, a cohort of patients with 3M syndrome and thereby increase awareness of this syndrome as a recognizable cause of proportionate short stature. We conducted a case series of patients referred to clinical genetics for proportionate short stature. CUL7, OBSL1, and CCDC8 genes were clinically phenotyped and sequenced. In 6 Saudi families with 3M syndrome, we identified three CUL7, one OBSL1, and one CCDC8 novel mutations, which we show result in a remarkably similar clinical phenotype. Despite their typical and easily discernible clinical phenotype, all these patients have been extensively investigated for alternative causes of their short stature and received erroneous diagnoses. Increased awareness about this syndrome among pediatricians and endocrinologists is needed to avoid a costly and unnecessary diagnostic odyssey. Copyright © 2012 Mosby, Inc. All rights reserved.

  7. A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome.

    PubMed

    Dinur Schejter, Yael; Ovadia, Adi; Alexandrova, Roumiana; Thiruvahindrapuram, Bhooma; Pereira, Sergio L; Manson, David E; Vincent, Ajoy; Merico, Daniele; Roifman, Chaim M

    2017-01-01

    Roifman syndrome (OMIM# 616651) is a complex syndrome encompassing skeletal dysplasia, immunodeficiency, retinal dystrophy and developmental delay, and is caused by compound heterozygous mutations involving the Stem II region and one of the other domains of the RNU4ATAC gene. This small nuclear RNA gene is essential for minor intron splicing. The Canadian Centre for Primary Immunodeficiency Registry and Repository were used to derive patient information as well as tissues. Utilising RNA sequencing methodologies, we analysed samples from patients with Roifman syndrome and assessed intron retention. We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome. Further, we demonstrate the same pattern of aberration in minor intron retention as found in cases with compound heterozygous mutations.

  8. Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I.

    PubMed

    Chen, Kaitian; Zhan, Yuan; Wu, Xuan; Zong, Ling; Jiang, Hongyan

    2018-01-01

    Waardenburg syndrome mutations are most often recurrent or de novo. The rate of familial recurrence is low and families with several affected children are extremely rare. In this study, we aimed to clarify the underlying hereditary cause of Waardenburg syndrome type I in two siblings in a Chinese family, with a mother affected by prelingual mild hearing loss and a father who was negative for clinical symptoms of Waardenburg syndrome and had a normal hearing threshold. Complete characteristic features of the family members were recorded and genetic sequencing and parent-child relationship analyses were performed. The two probands were found to share double mutations in the PAX3/GJB2 genes that caused concurrent hearing loss in Waardenburg syndrome type I. Their mother carried the GJB2 c.109G > A homozygous mutation; however, neither the novel PAX3 c.592delG mutation, nor the Waardenburg syndrome phenotype, was observed in either parent. These previously unreported digenic mutations in PAX3/GJB2 resulted in deafness associated with Waardenburg syndrome type I in this family. To our knowledge, this is the first report describing germinal mosaicism in Waardenburg syndrome. This concept is important because it complicates genetic counseling of this family regarding the risk of recurrence of the mutations in subsequent pregnancies. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. An uncommon cause of hypoglycemia: insulin autoimmune syndrome.

    PubMed

    Savas-Erdeve, Senay; Yılmaz Agladioglu, Sebahat; Onder, Asan; Peltek Kendirci, Havva Nur; Bas, Veysel Nijat; Sagsak, Elif; Cetinkaya, Semra; Aycan, Zehra

    2014-01-01

    Insulin autoimmune syndrome (IAS) is a condition characterized by hypoglycemia associated with the presence of autoantibodies to insulin in patients who have not been injected with insulin. A female patient (aged 16 years and 3 months) presented with the complaint of being overweight. Physical examination revealed a body weight of 78.2 kg (+2.6 SD) and a height of 167 cm (+0.73 SD). While the patient's fasting blood glucose level was found to be 40 mg/dl, blood ketone was negative and the serum insulin level was determined as 379 mIU/ml. The patient was diagnosed with hyperinsulinemic hypoglycemia. Abdominal ultrasound, pancreas MRI and endoscopic ultrasound were normal. The daily blood glucose profile revealed postprandial hyperglycemia and reactive hypoglycemia in addition to fasting hypoglycemia. The results of anti-insulin antibody measurements were as high as 41.8% (normal range 0-7%). A 1,600-calorie diet containing 40% carbohydrate and divided into 6 meals a day was given to the patient. Simple sugars were excluded from the diet. Hypoglycemic episodes were not observed, but during 2 years of observation, serum levels of insulin and anti-insulin antibodies remained elevated. In all hyperinsulinemic hypoglycemia cases, IAS should be considered in the differential diagnosis and insulin antibody measurements should be carried out. © 2014 S. Karger AG, Basel.

  10. Carpal Tunnel Syndrome: Symptoms, Causes and Treatment Options. Literature Reviev.

    PubMed

    Zamborsky, Radoslav; Kokavec, Milan; Simko, Lukas; Bohac, Martin

    2017-01-26

    Carpal Tunnel Syndrome (CTS) is the most common form of entrapment neuropathy. Several authors have investigated the anatomical and pathophysiological features of CTS and have identified several parameters that, in combination, play a significant role in its pathophysiology. Advancement in biological research on CTS has enabled the advent of efficient diagnostic techniques such as provocative tests and nerve conduction studies. Sophisticated technologies, such as magnetic resonance imaging (MRI) and ultrasonography (US), have facilitated the diagnosis of CTS. This review article aims at consolidating the relevant medical literature pertaining to the symptoms, pathophysiology, clinical diagnosis and treatment strategies of CTS. It also compares the various methods of diagnosis and discusses their benefits and disadvantages. Finally, it sheds light on the conservative vs. surgical approach to treatment and compares them. While the surgical approach has proved to be more efficient relative to the conservative methods of steroid injections and splinting, many studies have demonstrated both advantages and adverse effects of the surgical methods. Surgical options and complications are discussed in detail. This article comprehensively summarizes all medical aspects of CTS to update medical professionals' knowledge regarding the disease.

  11. Evidence of staphylococcal toxic shock syndrome caused by MRSA in a mother-newborn pair.

    PubMed

    Rostad, Christina A; Philipsborn, Rebecca Pass; Berkowitz, Frank E

    2015-04-01

    A neonate and his mother presented with fever and erythroderma. The mother met full diagnostic criteria for staphylococcal toxic shock syndrome, whereas the neonate lacked hypotension and multiorgan dysfunction. A wound culture from the neonate's circumcision site grew methicillin-resistant Staphylococcus aureus containing the tst gene. This provides evidence of the first reported case of toxic shock syndrome caused by methicillin-resistant Staphylococcus aureus in a mother-newborn pair.

  12. Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

    PubMed Central

    Runtuwene, Vincent; van Eekelen, Mark; Overvoorde, John; Rehmann, Holger; Yntema, Helger G.; Nillesen, Willy M.; van Haeringen, Arie; van der Burgt, Ineke; Burgering, Boudewijn; den Hertog, Jeroen

    2011-01-01

    SUMMARY Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras–mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome. PMID:21263000

  13. Toxic anterior segment syndrome: Update on the most common causes.

    PubMed

    Bodnar, Zachary; Clouser, Sue; Mamalis, Nick

    2012-11-01

    To determine how the most common risk factors for toxic anterior segment syndrome (TASS) have evolved over the past decade. John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. Cross-sectional study. This was a retrospective analysis of surveys from centers reporting cases of TASS from June 1, 2007, through March 1, 2012, and information from visits to afflicted sites between October 1, 2005, and December 31, 2011. Results from June 1, 2009, to March 1, 2012, were compared with those collected before June 1, 2009. The data from 130 questionnaires and 71 site visits were analyzed. The reporting centers performed approximately 69 000 surgeries and reported 1454 cases of TASS. Several trends were noted when comparing the most recent data with previously reported results. There was a 26% reduction in sites reporting inadequate handpiece flushing volumes and a 27% increase in sites using a deionized/distilled final rinse. At sites visited, there was a 36% reduction in the use of preserved epinephrine and a 36% reduction in the use of enzymatic detergents. However, there was a 21% increase in handling of intraocular lenses or instrument tips with gloved hands, a 47% increase in poor instrument maintenance, and a 34% increase in ultrasound bath use without adequate routine cleaning. Education may have improved some instrument-cleaning and perioperative practices that increase the risk for TASS; however, other practices may be headed in an unfavorable direction. No author has a financial or proprietary interest in any material or method mentioned. Copyright © 2012 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  14. [Orbital compartment syndrome. The most frequent cause of blindness following facial trauma].

    PubMed

    Klenk, Gusztáv; Katona, József; Kenderfi, Gábor; Lestyán, János; Gombos, Katalin; Hirschberg, Andor

    2017-09-01

    Although orbital compartment syndrome is a rare condition, it is still the most common cause of blindness following simple or complicated facial fractures. Its pathomechanism is similar to the compartment syndrome in the limb. Little extra fluid (blood, oedema, brain, foreign body) in a non-space yielding space results with increasingly higher pressures within a short period of time. Unless urgent surgical intervention is performed the blocked circulation of the central retinal artery will result irreversible ophthalmic nerve damage and blindness. Aim, material and method: A retrospective analysis of ten years, 2007-2017, in our hospital among those patients referred to us with facial-head trauma combined with blindness. 571 patients had fractures involving the orbit. 23 patients become blind from different reasons. The most common cause was orbital compartment syndrome in 17 patients; all had retrobulbar haematomas as well. 6 patients with retrobulbar haematoma did not develop compartment syndrome. Compartment syndrome was found among patient with extensive and minimal fractures such as with large and minimal haematomas. Early lateral canthotomy and decompression saved 7 patients from blindness. We can not predict and do not know why some patients develop orbital compartment syndrome. Compartment syndrome seems independent from fracture mechanism, comminution, dislocation, amount of orbital bleeding. All patients are in potential risk with midface fractures. We have a high suspicion that orbital compartment syndrome has been somehow missed out in the recommended textbooks of our medical universities and in the postgraduate trainings. Thus compartment syndrome is not recognized. Teaching, training and early surgical decompression is the only solution to save the blind eye. Orv Hetil. 2017; 158(36): 1410-1420.

  15. A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome.

    PubMed

    Oud, Machteld M; Bonnard, Carine; Mans, Dorus A; Altunoglu, Umut; Tohari, Sumanty; Ng, Alvin Yu Jin; Eskin, Ascia; Lee, Hane; Rupar, C Anthony; de Wagenaar, Nathalie P; Wu, Ka Man; Lahiry, Piya; Pazour, Gregory J; Nelson, Stanley F; Hegele, Robert A; Roepman, Ronald; Kayserili, Hülya; Venkatesh, Byrappa; Siu, Victoria M; Reversade, Bruno; Arts, Heleen H

    2016-01-01

    Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology. Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G > T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells. Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy.

  16. Long-term survival in pseudo-Meigs' syndrome caused by ovarian metastases from colon cancer.

    PubMed

    Tajima, Yosuke; Kameyama, Hitoshi; Yamada, Saki; Yagi, Ryoma; Nakano, Masato; Nagahashi, Masayuki; Shimada, Yoshifumi; Sakata, Jun; Kobayashi, Takashi; Umezu, Hajime; Wakai, Toshifumi

    2016-11-14

    Meigs' syndrome is defined as the co-existence of benign ovarian fibroma or fibroma-like tumor, ascites, and pleural effusion. In contrast, pseudo-Meigs' syndrome is defined as the co-existence of other ovarian or pelvic tumors, ascites, and pleural effusion. In Meigs' and pseudo-Meigs' syndromes, ascites and pleural effusion resolve promptly after the complete resection of the ovarian or pelvic tumor(s). Secondary ovarian tumors from colorectal gastrointestinal metastases rarely cause pseudo-Meigs' syndrome; only 11 cases of pseudo-Meigs' syndrome secondary to colorectal cancers have been reported in the literature. Therefore, the prognosis and etiology of pseudo-Meigs' syndrome caused by ovarian metastasis from colorectal cancers remain unclear. We report here a rare case of pseudo-Meigs' syndrome caused by ovarian metastases from sigmoid colon cancer with long-term survival. A 47-year-old woman presented with abdominal distention of 1-month duration. She developed acute dyspnea 2 weeks after the initial presentation. Colonoscopy and computed tomography revealed sigmoid colon cancer with an ovarian metastasis, along with massive ascites and bilateral pleural effusion. Emergency operation, including bilateral oophorectomy and sigmoidectomy, was performed. Subsequently, ascites and bilateral pleural effusion resolved rapidly. Curative hepatic resection was performed for liver metastases 29 months after the first operation, and as of this writing, the patient is alive with no evidence of a disease 78 months after the first operation. In general, colorectal cancer with ovarian metastasis is hard to cure, and long-term survival in patients with colorectal cancer with pseudo-Meigs' syndrome is rare. Our experience suggests that curative resection for pseudo-Meigs' syndrome caused by ovarian metastasis from colorectal cancer may offer long-term survival. Our experience suggests that pseudo-Meigs' syndrome can occur in a patient with colorectal cancer after metastasis

  17. Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey.

    PubMed

    Butler, Merlin G; Manzardo, Ann M; Heinemann, Janalee; Loker, Carolyn; Loker, James

    2017-06-01

    Prader-Willi syndrome (PWS) is a rare, complex, neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans and leads to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. The US Prader-Willi Syndrome Association (PWSA (USA)) syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA (USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox proportional hazards. A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 ± 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. These findings highlight the heightened vulnerability to obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS.Genet Med advance online publication 17 November 2016.

  18. [Auto-immune disorders as a possible cause of neuropsychiatric syndromes].

    PubMed

    Martinez-Martinez, P; Molenaar, P C; Losen, M; Hoffmann, C; Stevens, J; de Witte, L D; van Amelsvoort, T; van Os, J; Rutten, B P F

    2015-01-01

    Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

  19. De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

    PubMed

    Caro-Llopis, Alfonso; Rosello, Monica; Orellana, Carmen; Oltra, Silvestre; Monfort, Sandra; Mayo, Sonia; Martinez, Francisco

    2016-12-01

    Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.

  20. Identification of HIBCH gene mutations causing autosomal recessive Leigh syndrome: a gene involved in valine metabolism.

    PubMed

    Soler-Alfonso, Claudia; Enns, Gregory M; Koenig, Mary Kay; Saavedra, Heather; Bonfante-Mejia, Eliana; Northrup, Hope

    2015-03-01

    Leigh syndrome is a progressive neurodegenerative disorder with usual onset of symptoms during the first year of life. The disorder has been associated with mutations in over 30 genes. This difficulty with genetic heterogeneity makes whole exome sequencing a more cost-effective approach for investigation of etiology. We describe an individual with typical Leigh syndrome who was found to have compound heterozygous mutations in the gene HIBCH (3-hydroxyisobutyryl coenzyme A hydrolase), an enzyme involved in the catabolism of valine. She exhibited significant clinical improvement after a valine-restricted diet. A subset of patients with uncharacterized Leigh syndrome present with specific biochemical abnormalities. This report highpoints the challenges and restrictions of routine metabolic testing and features the recognition of inborn errors of metabolism as potential treatable causes of Leigh syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.

    PubMed

    Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

    2015-09-01

    Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. Copyright© Ferrata Storti

  2. [Webino syndrome caused by meningovascular syphilis. A rare entity with an unexpected cause].

    PubMed

    Rodríguez Calvo de Mora, M; Rodríguez Moreno, G; España Contreras, M

    2014-05-01

    The patient is a 57-year-old obese and hypertensive male. His chief complaints were double vision and dizziness, with mild exodeviation in both eyes in primary gaze position in the ocular motility examination, but more predominant in the left eye. The exotropia was noticeably more evident on the attempted upgaze. On horizontal gaze, the abducting eye deviated fully, but the adducting eye did not cross the midline. Nystagmus in the abducting eye and convergence impairment were found. Pupil size and testing were normal. Ataxia and areflexia were also present. Bilateral internuclear ophthalmoplegia was suspected and imaging and laboratory tests were performed. The CAT scan showed a right occipital hypo-attenuated lesion. In the MRI scan, a mesencephalic subacute ischemic lesion was found, involving the medial rectus sub-nuclei. Blood and cerebrospinal fluid test for syphilis were positive. Bilateral internuclear ophthalmoplegia is a very uncommon -and difficult to diagnose- condition. In the reported case the lesion involved the medial rectus sub-nuclei. This fact could explain the exotropia in the primary gaze position, and supports that is not possible to exclude the involvement of the medial rectus sub-nuclei in the webino syndrome. The rapid identification of the pathology contributed to the better prognosis of the patient. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  3. Iliac Vein Compression Syndrome due to Bladder Distention Caused by Urethral Calculi

    PubMed Central

    Ikegami, Akiko; Kondo, Takeshi; Tsukamoto, Tomoko; Ohira, Yoshiyuki; Ikusaka, Masatomi

    2015-01-01

    We report a rare case of iliac vein compression syndrome caused by urethral calculus. A 71-year-old man had a history of urethral stenosis. He complained of bilateral leg edema and dysuria for 1 week. Physical examination revealed bilateral distention of the superficial epigastric veins, so obstruction of both common iliac veins or the inferior vena cava was suspected. Plain abdominal computed tomography showed a calculus in the pendulous urethra, distention of the bladder (as well as the right renal pelvis and ureter), and compression of the bilateral common iliac veins by the distended bladder. Iliac vein compression syndrome was diagnosed. Bilateral iliac vein compression due to bladder distention (secondary to neurogenic bladder, benign prostatic hyperplasia, or urethral calculus as in this case) is an infrequent cause of acute bilateral leg edema. Detecting distention of the superficial epigastric veins provides a clue for diagnosis of this syndrome. PMID:25802794

  4. Dyke-Davidoff-Masson Syndrome. An unusual cause of status epilepticus.

    PubMed

    Zawar, Ifrah; Khan, Ashfa A; Sultan, Tipu; Rathore, Ahsan W

    2015-10-01

    The Dyke-Davidoff-Masson Syndrome (DDMS) results from an insult to the growing brain in utero or early infancy, which lead to loss of neurons compromising the growth of the brain. Clinical presentation includes seizures, hemiparesis, facial asymmetry, and learning disability. Radiological findings include cerebral atrophy on one side. Here, we present a case with status epilepticus who had underlying DDMS. It is a rare syndrome and uncommon cause for status epilepticus. Infections of CNS, hypoxic ischemic encephalopathy, intracranial bleed, trauma, congenital vascular malformations are the common causes of this syndrome. Diagnosis is established after clinical history, examination, and MRI. Intractable seizures can be controlled with appropriate anticonvulsants. Subsequently, these children may require physiotherapy, speech therapy, and occupational therapy in addition to the anticonvulsant medication. Outcome is better if the seizures are controlled.

  5. Guillain Barre syndrome: the leading cause of acute flaccid paralysis in Hazara division.

    PubMed

    Anis-ur-Rehman; Idris, Muhammad; Elahi, Manzoor; Jamshed; Arif, Adeel

    2007-01-01

    Acute flaccid paralysis (AFP) can be caused by a number of conditions. A common preventable cause is poliomyelitis which is still being reported in Pakistan, Guillain Barre Syndrome (GBS), also known as Acute Inflammatory Demyelinating Polyneuropathy, is another common cause of acute flaccid paralysis. It is important to recognize GBS in childhood as parents consider all acute flaccid paralysis to be due to poliomyelitis. The present study was designed to know the frequency of different causes of acute flaccid paralysis in Hazara division. This is a retrospective analysis of cases of acute flaccid paralysis reported from various districts of Hazara division during the period January 2003 to December 2004. Acute flaccid paralysis was diagnosed clinically through history and clinical examination. The underlying cause of acute flaccid paralysis was investigated by appropriate laboratory tests, such as serum electrolytes, cerebrospinal fluid analysis, electromyogram, nerve conduction study and stool culture for polio virus and other enteroviruses. Diagnosis of Poliomyelitis was confirmed by stool testing for poliovirus. 74 patients presented with AFP during the study period. 36 were male and 38 were female. Guillain Barre syndrome and enteroviral encephalopathy were the two leading causes of acute flaccid paralysis. Majority of the cases were reported from Mansehra district. Children of age groups 12 to 24 months and > 96 months constituted the majority (20% each). Guillian Barre syndrome was the leading cause of acute flaccid paralysis reported from various parts of Hazara division.

  6. Gastric invagination in adults as a rare cause of constitutional syndrome.

    PubMed

    Dávila Arias, Cristina; Milena Muñoz, Ana; Valero González, María Ángeles; Céspedes Mas, Mariano

    2017-02-01

    This article describes and illustrates the case of an adult patient with clinical symptoms of constitutional syndrome, postprandial discomfort and a mass in the left lateral abdominal region caused by a gastric intussusception with a fundal adenoma as the head of the invagination. The intussusception was diagnosed by MRI (magnetic resonance imaging).

  7. Genome Sequence of the Hemolytic-Uremic Syndrome-Causing Strain Escherichia coli NCCP15647

    PubMed Central

    Jeong, Haeyoung; Zhao, Fumei; Igori, Davaajargal; Oh, Kyung-Hwan; Kim, Seon-Young; Kang, Sung Gyun; Kim, Byung Kwon; Kwon, Soon-Kyeong; Lee, Choong Hoon; Song, Ju Yeon; Yu, Dong Su; Park, Mi-Sun

    2012-01-01

    Enterohemorrhagic Escherichia coli (EHEC) causes a disease involving diarrhea, hemorrhagic colitis, and hemolytic-uremic syndrome (HUS). Here we present the draft genome sequence of NCCP15647, an EHEC isolate from an HUS patient. Its genome exhibits features of EHEC, such as genes for verotoxins, a type III secretion system, and prophages. PMID:22740672

  8. Extreme sensitivity to ultraviolet light in the fungal pathogen causing white-nose syndrome of bats

    Jonathan M. Palmer; Kevin P. Drees; Jeffrey T. Foster; Daniel L. Lindner

    2018-01-01

    Bat white-nose syndrome (WNS), caused by the fungal pathogen Pseudogymnoascus destructans, has decimated North American hibernating bats since its emergence in 2006. Here, we utilize comparative genomics to examine the evolutionary history of this pathogen in comparison to six closely related nonpathogenic species....

  9. Streptococcal Toxic Shock Syndrome Caused by Group G Streptococcus, United Kingdom.

    PubMed

    Baxter, Melissa; Morgan, Marina

    2017-01-01

    We describe successful management of 3 patients with streptococcal toxic shock syndrome (STSS) attributable to group G Streptococcus infection. This small series supports recognition of group G Streptococcus in the etiology of STSS. We propose intravenous immunoglobulin be used in treatment as it is for STSS caused by group A Streptococcus.

  10. What causes dryness in Sjögren's syndrome patients and how can it be targeted?

    PubMed

    Pflugfelder, Stephen C

    2014-04-01

    Concepts regarding what causes dryness in Sjögren's syndrome have evolved over the past decade. Inflammation in the lacrimal functional unit contributes to development of dry eye by causing dysfunction and even death of tear secreting epithelium in the lacrimal gland and conjunctiva that alters tear composition and stability. Disease-relevant inflammatory mediators have been identified and therapies targeting these mediators are beginning to emerge.

  11. Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein–Taybi and Filippi syndromes

    PubMed Central

    de Vries, Tamar I; R Monroe, Glen; van Belzen, Martine J; van der Lans, Christian A; Savelberg, Sanne MC; Newman, William G; van Haaften, Gijs; Nievelstein, Rutger A; van Haelst, Mieke M

    2016-01-01

    Rubinstein–Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected. PMID:26956253

  12. Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes.

    PubMed

    de Vries, Tamar I; Monroe, Glen R; van Belzen, Martine J; van der Lans, Christian A; Savelberg, Sanne Mc; Newman, William G; van Haaften, Gijs; Nievelstein, Rutger A; van Haelst, Mieke M

    2016-08-01

    Rubinstein-Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected.

  13. Hypertensive Cerebral Hemorrhage in a Patient with Turner Syndrome Caused by Deletion in the Short Arm of the X Chromosome.

    PubMed

    Hori, Yusuke S; Ohkura, Takahiro; Ebisudani, Yuki; Umakoshi, Michiari; Ishi, Masato; Oda, Kazunori; Aoi, Mizuho; Inoue, Takushi; Furujo, Mahoko; Tanaka, Hiroyuki; Fukuhara, Toru

    2018-01-01

    Turner syndrome is a chromosomal disorder usually caused by complete deletion of an X chromosome, with deletion in the short arm of the X chromosome being a rare cause of the condition. Patients with Turner syndrome commonly develop hypertension, and associated vascular complications such as aortic dissection or cerebral hemorrhage have been reported. Cerebral hemorrhage in Turner syndrome is a rare complication, and only a few reports have been published. In these reports, all patients have XO karyotypes or a mosaic type as the cause of Turner syndrome, while no other Turner syndrome types have been documented. In this report, we present for the first time a patient with Turner syndrome caused by deletion in the short arm of the X chromosome who experienced hypertensive hemorrhage as a late complication. © 2017 S. Karger AG, Basel.

  14. Causes of Death in Prader-Willi Syndrome: Prader-Willi Syndrome Association (USA) 40-Year Mortality Survey

    PubMed Central

    Butler, Merlin G.; Manzardo, Ann M.; Heinemann, Janalee; Loker, Carolyn; Loker, James

    2016-01-01

    Background Prader-Willi syndrome (PWS) is a rare complex neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans leading to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. Methods PWSA (USA) mortality syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA(USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox Proportional Hazards. Results A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015 with mean age of 29.5 ± 16 years (2mo–67yrs), 70% occurring in adulthood. Respiratory failure was the most common cause accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries compared to females and cardiopulmonary factors. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. Conclusions These findings highlight the heightened vulnerability towards obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS. PMID:27854358

  15. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.

    PubMed

    Wiseman, Frances K; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L J; Fisher, Elizabeth M C; Strydom, André

    2015-09-01

    Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.

  16. [Paralysis, organic brain syndrome, and cardiac dysrhythmias caused by chronic laxative abuse (author's transl)].

    PubMed

    Dahlmann, W; Volles, E; Lüderitz, B

    1977-10-28

    A 39-year-old woman developed generalised paralysis, reversible organic brain syndrome, and cardiac dysrhythmias after 15 years of laxative abuse. Under continuous and cautious administration of potassium the cardiac rhythm became normal within four days and two days later the paralysis and organic brain syndrome almost disappeared. The cause of the psychiatric symptoms is thought to be cerebral potassium deficiency and an abnormal sodium/potassium equilibrium. Other clinical signs and symptoms due to extreme potassium depletion are presented. The importance of Na+/K+-activated membrane ATP-ase in myocardium and CNS is discussed.

  17. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

    PubMed Central

    Wiseman, Frances K.; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L. J.; Fisher, Elizabeth M. C.; Strydom, André

    2015-01-01

    Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) — an Alzheimer disease risk factor — although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population. PMID:26243569

  18. Minimally Invasive Treatment of Mirizzi Syndrome, a Rare Cause of Cholestasis in Childhood

    PubMed Central

    Yilmaz, Sezgin; Yavuz, Mustafa; Çetinkurşun, Salih

    2016-01-01

    Mirizzi syndrome is the compressive blockage of the cystic or choledochal duct caused by a biliary stone occupying the cystic canal or Hartmann's pouch. This occurrence is rare and, in English literature, three cases defined in children have been observed. In order to draw attention to this rare occurrence, we preferred a 14-year-old male patient with Mirizzi syndrome. In this case, ERCP was performed preoperatively and the diagnosis was carried out with the help of clear visualisation and identification of the tissue structures as well as the stent placed in bile duct; so we protected the patient from the possible iatrogenic injury occurring during surgery. PMID:27843664

  19. Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non‐syndromic corneal endothelial dystrophy

    PubMed Central

    Desir, Julie; Moya, Graciela; Reish, Orit; Van Regemorter, Nicole; Deconinck, Hilde; David, Karen L; Meire, Françoise M; Abramowicz, Marc J

    2007-01-01

    Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive perceptive deafness, and is transmitted as an autosomal recessive trait. CDPD and autosomal recessive, non‐syndromic congenital hereditary endothelial corneal dystrophy (CHED2) both map at overlapping loci at 20p13, and mutations of SLC4A11 were reported recently in CHED2. A genotype study on six families with CDPD and on one family with either CHED or CDPD, from various ethnic backgrounds (in the seventh family, hearing loss could not be assessed because of the proband's young age), is reported here. Novel SLC4A11 mutations were found in all patients. Why some mutations cause hearing loss in addition to corneal dystrophy is presently unclear. These findings extend the implication of the SLC4A11 borate transporter beyond corneal dystrophy to perceptive deafness. PMID:17220209

  20. [A commonly seen cause of abdominal pain: abdominal cutaneous nerve entrapment syndrome].

    PubMed

    Solmaz, Ilker; Talay, Mustafa; Tekindur, Şükrü; Kurt, Ercan

    2012-01-01

    Although abdominal cutaneous nerve entrapment syndrome (ACNES) is accepted as a rare condition, it is a syndrome that should be diagnosed more commonly when the clinical signs cannot explain the cause of abdominal pain. Abdominal pain is commonly considered by physicians to be based on intra-abdominal causes. Consequently, redundant tests and consultations are requested for these patients, and unnecessary surgical procedures may be applied. Patients with this type of pain are consulted to many clinics, and because their definitive diagnoses cannot be achieved, they are assessed as psychiatric patients. Actually, a common cause of abdominal wall pain is nerve entrapment on the lateral edge of the rectus abdominis muscle. In this paper, we would like to share information about the diagnosis and treatment of a patient who, prior to presenting to us, had applied to different clinics for chronic abdominal pain and had undergone many tests and consultations; abdominal surgery was eventually decided.

  1. Neuroendocrine carcinoma of the ampulla of Vater causing ectopic adrenocorticotropic hormone-dependent Cushing's syndrome.

    PubMed

    Kato, Akihisa; Hayashi, Kazuki; Naitoh, Itaru; Seno, Kyoji; Okada, Yukiko; Ban, Tesshin; Kondo, Hiromu; Nishi, Yuji; Umemura, Shuichiro; Hori, Yasuki; Natsume, Makoto; Joh, Takashi

    2016-07-01

    Ectopic adrenocorticotropic hormone (ACTH) is rarely secreted by neuroendocrine tumors. Although neuroendocrine tumors may occur at any site in the gastrointestinal system, they very rarely occur in the ampulla of Vater and have a poor prognosis. The present study described the first Cushing's syndrome as a result of ectopic ACTH arising from the ampulla of Vater neuroendocrine carcinoma. A 69-year-old female was admitted with clinical features of Cushing's syndrome, confirmed biochemically by hypokalemia, and elevated levels of ACTH and cortisol. In further investigations, a tumor of the ampulla of Vater and liver metastases were detected. Pathological analysis of the biopsy confirmed a neuroendocrine carcinoma, which was immunohistochemically positive for chromogranin A, synaptophysin, cluster of differentiation 56 and ACTH. Therefore, the present study diagnosed a functional and metastatic neuroendocrine carcinoma of the ampulla of Vater with ectopic ACTH production causing Cushing's syndrome. The patient succumbed to mortality 4 months later, despite administration of combined chemotherapy with irinotecan and cisplatin.

  2. Hepatitis E as a Cause of Acute Jaundice Syndrome in Northern Uganda, 2010–2012

    PubMed Central

    Gerbi, Gemechu B.; Williams, Roxanne; Bakamutumaho, Barnabas; Liu, Stephen; Downing, Robert; Drobeniuc, Jan; Kamili, Saleem; Xu, Fujie; Holmberg, Scott D.; Teshale, Eyasu H.

    2015-01-01

    Hepatitis E virus (HEV) is a common cause of acute viral hepatitis in developing countries; however, its contribution to acute jaundice syndrome is not well-described. A large outbreak of hepatitis E occurred in northern Uganda from 2007 to 2009. In response to this outbreak, acute jaundice syndrome surveillance was established in 10 district healthcare facilities to determine the proportion of cases attributable to hepatitis E. Of 347 acute jaundice syndrome cases reported, the majority (42%) had hepatitis E followed by hepatitis B (14%), malaria (10%), hepatitis C (5%), and other/unknown (29%). Of hepatitis E cases, 72% occurred in Kaboong district, and 68% of these cases occurred between May and August of 2011. Residence in Kaabong district was independently associated with hepatitis E (adjusted odds ratio = 13; 95% confidence interval = 7–24). The findings from this surveillance show that an outbreak and sporadic transmission of hepatitis E occur in northern Uganda. PMID:25448237

  3. X-linked Alport syndrome caused by splicing mutations in COL4A5.

    PubMed

    Nozu, Kandai; Vorechovsky, Igor; Kaito, Hiroshi; Fu, Xue Jun; Nakanishi, Koichi; Hashimura, Yuya; Hashimoto, Fusako; Kamei, Koichi; Ito, Shuichi; Kaku, Yoshitsugu; Imasawa, Toshiyuki; Ushijima, Katsumi; Shimizu, Junya; Makita, Yoshio; Konomoto, Takao; Yoshikawa, Norishige; Iijima, Kazumoto

    2014-11-07

    X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism. In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities. Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics. This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X

  4. Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients.

    PubMed

    Danis, Daniel; Brennerova, Katarina; Skopkova, Martina; Kurdiova, Timea; Ukropec, Jozef; Stanik, Juraj; Kolnikova, Miriam; Gasperikova, Daniela

    2018-04-01

    Leigh syndrome is a progressive early onset neurodegenerative disease typically presenting with psychomotor regression, signs of brainstem and/or basal ganglia disease, lactic acidosis, and characteristic magnetic resonance imaging findings. At molecular level, deficiency of respiratory complexes and/or pyruvate dehydrogenase complex is usually observed. Nuclear gene SURF1 encodes an assembly factor for cytochrome c-oxidase complex of the respiratory chain and autosomal recessive mutations in SURF1 are one of the most frequent causes of cytochrome c-oxidase-related Leigh syndrome cases. Here, we aimed to elucidate the genetic basis of Leigh syndrome in three Slovak families. Three probands presenting with Leigh syndrome were selected for DNA analysis. The first proband, presenting with atypical LS onset without abnormal basal ganglia magnetic resonance imaging findings, was analyzed with whole exome sequencing. In the two remaining probands, SURF1 was screened by Sanger sequencing. Four different heterozygous mutations were identified in SURF1: c.312_321delinsAT:p.(Pro104Profs*1), c.588+1G>A, c.823_833+7del:p. (?) and c.845_846del:p.(Ser282Cysfs*9). All the mutations are predicted to have a loss-of-function effect. We identified disease-causing mutations in all three probands, which points to the important role of SURF1 gene in etiology of Leigh syndrome in Slovakia. Our data showed that patients with atypical Leigh syndrome phenotype without lesions in basal ganglia may benefit from the whole exome sequencing method. In the case of probands presenting the typical phenotype, Sanger sequencing of the SURF1 gene seems to be an effective method of DNA analysis.

  5. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.

    PubMed

    Belaya, Katsiaryna; Rodríguez Cruz, Pedro M; Liu, Wei Wei; Maxwell, Susan; McGowan, Simon; Farrugia, Maria E; Petty, Richard; Walls, Timothy J; Sedghi, Maryam; Basiri, Keivan; Yue, Wyatt W; Sarkozy, Anna; Bertoli, Marta; Pitt, Matthew; Kennett, Robin; Schaefer, Andrew; Bushby, Kate; Parton, Matt; Lochmüller, Hanns; Palace, Jacqueline; Muntoni, Francesco; Beeson, David

    2015-09-01

    Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected

  6. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies

    PubMed Central

    Belaya, Katsiaryna; Rodríguez Cruz, Pedro M.; Liu, Wei Wei; Maxwell, Susan; McGowan, Simon; Farrugia, Maria E.; Petty, Richard; Walls, Timothy J.; Sedghi, Maryam; Basiri, Keivan; Yue, Wyatt W.; Sarkozy, Anna; Bertoli, Marta; Pitt, Matthew; Kennett, Robin; Schaefer, Andrew; Bushby, Kate; Parton, Matt; Lochmüller, Hanns; Palace, Jacqueline; Muntoni, Francesco

    2015-01-01

    Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected

  7. Inflammatory cause of metabolic syndrome via brain stress and NF-κB.

    PubMed

    Cai, Dongsheng; Liu, Tiewen

    2012-02-01

    Metabolic syndrome, a network of medical disorders that greatly increase the risk for developing metabolic and cardiovascular diseases, has reached epidemic levels in many areas of today's world. Despite this alarming medicare situation, scientific understandings on the root mechanisms of metabolic syndrome are still limited, and such insufficient knowledge contributes to the relative lack of effective treatments or preventions for related diseases. Recent interdisciplinary studies from neuroendocrinology and neuroimmunology fields have revealed that overnutrition can trigger intracellular stresses to cause inflammatory changes mediated by molecules that control innate immunity. This type of nutrition-related molecular inflammation in the central nervous system, particularly in the hypothalamus, can form a common pathogenic basis for the induction of various metabolic syndrome components such as obesity, insulin resistance, and hypertension. Proinflammatory NF-κB pathway has been revealed as a key molecular system for pathologic induction of brain inflammation, which translates overnutrition and resulting intracellular stresses into central neuroendocrine and neural dysregulations of energy, glucose, and cardiovascular homeostasis, collectively leading to metabolic syndrome. This article reviews recent research advances in the neural mechanisms of metabolic syndrome and related diseases from the perspective of pathogenic induction by intracellular stresses and NF-κB pathway of the brain.

  8. Refeeding syndrome as an unusual cause of anion gap metabolic acidosis.

    PubMed

    Singla, Manish; Perry, Alexandra; Lavery, Eric

    2012-11-01

    Refeeding syndrome is characterized by hypophosphatemia in the setting of malnutrition. It is commonly seen in patients with anorexia, alcoholism, or malignancy, and it is often a missed diagnosis. Because of the potential morbidity associated with missing the diagnosis of refeeding syndrome, it is important to monitor for this disease in any malnourished patient. We present a case of a 49-year-old male with chronic alcohol abuse who presented for alcohol detoxification and was found to have low phosphate, potassium, and magnesium on presentation, in addition to an elevated anion gap of unclear etiology. After extensive workup to evaluate the cause of his elevated anion gap and worsening of his electrolyte abnormalities despite replenishment, it was felt his symptoms were a result of refeeding syndrome. After oral intake was held and aggressive electrolyte replenishment was performed for 24 hours, the patient's anion gap closed and his electrolyte levels stabilized. This case demonstrates a unique presentation of refeeding syndrome given the patient's profound metabolic acidosis that provided a clue toward his eventual diagnosis. The standard workup for an anion gap metabolic acidosis was negative, and it was not until his refeeding syndrome had been treated that the anion gap closed.

  9. Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

    PubMed

    Russell-Eggitt, I M

    2000-12-01

    When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

  10. Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

    PubMed Central

    Roberts, Christian K.; Hevener, Andrea L.; Barnard, R. James

    2014-01-01

    Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity. PMID:23720280

  11. Hyperthyroidism due to thyroid-stimulating hormone secretion after surgery for Cushing's syndrome: a novel cause of the syndrome of inappropriate secretion of thyroid-stimulating hormone.

    PubMed

    Tamada, Daisuke; Onodera, Toshiharu; Kitamura, Tetsuhiro; Yamamoto, Yuichi; Hayashi, Yoshitaka; Murata, Yoshiharu; Otsuki, Michio; Shimomura, Iichiro

    2013-07-01

    Hyperthyroidism with the syndrome of inappropriate secretion of TSH (SITSH) occurred by a decrease in hydrocortisone dose after surgery for Cushing's syndrome. This is a novel cause of SITSH. The aim of this study was to describe and discuss 2 cases of SITSH patients that were found after surgery for Cushing's syndrome. We also checked whether SITSH occurred in 7 consecutive patients with Cushing's syndrome after surgery. A 45-year-old Japanese woman with ACTH-independent Cushing's syndrome and a 37-year-old Japanese man with ACTH-dependent Cushing's syndrome presented SITSH caused by insufficient replacement of hydrocortisone for postoperative adrenal insufficiency. When the dose of hydrocortisone was reduced to less than 20 mg/d within 18 days after surgery, SITSH occurred in both cases. We examined whether the change of the hydrocortisone dose induced the secretion of TSH. Free T₃ and TSH were normalized by the hydrocortisone dose increase of 30 mg/d, and these were elevated by the dose decrease of 10 mg/d. We also checked TSH and thyroid hormone levels of the 7 consecutive patients with Cushing's syndrome after surgery. Six (66.6 %) of 9 patients showed SITSH. This is the first report that insufficient replacement of hydrocortisone after surgery for Cushing's syndrome caused SITSH. Hyperthyroidism by SITSH as well as adrenal insufficiency can contribute to withdrawal symptoms of hydrocortisone replacement. We need to consider the possibility of SITSH for the pathological evaluation of withdrawal syndrome of hydrocortisone replacement.

  12. An unusual craniofacial cleft: amniotic band syndrome as a possible cause.

    PubMed

    Eichhorn, Mitchell G; Iacobucci, John J; Turfe, Zaahir

    2015-04-01

    We report the case of a no. 4 Tessier cleft in association with an unknown cleft of the mandible extending to the external auditory meatus. This has not been previously published in the literature and its underlying pathology remains undetermined. The nature of the cleft, possible classifications, and potential embryologic origins will be discussed. Amniotic band syndrome is the most likely cause of the cleft. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Cri du chat syndrome and primary ciliary dyskinesia: a common genetic cause on chromosome 5p.

    PubMed

    Shapiro, Adam J; Weck, Karen E; Chao, Kay C; Rosenfeld, Margaret; Nygren, Anders O H; Knowles, Michael R; Leigh, Margaret W; Zariwala, Maimoona A

    2014-10-01

    Cri du chat syndrome (CdCS) and primary ciliary dyskinesia (PCD) are rare diseases that present with frequent respiratory symptoms. PCD can be caused by hemizygous DNAH5 mutation in combination with a 5p segmental deletion attributable to CdCS on the opposite chromosome. Chronic oto-sino-pulmonary symptoms or organ laterality defects in CdCS should prompt an evaluation for PCD. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Cri du Chat Syndrome and Primary Ciliary Dyskinesia: A Common Genetic Cause on Chromosome 5p

    PubMed Central

    Shapiro, Adam J.; Weck, Karen E.; Chao, Kay C.; Rosenfeld, Margaret; Nygren, Anders O. H.; Knowles, Michael R.; Leigh, Margaret W.; Zariwala, Maimoona A.

    2014-01-01

    Cri du chat syndrome (CdCS) and primary ciliary dyskinesia (PCD) are rare diseases that present with frequent respiratory symptoms. PCD can be caused by hemizygous DNAH5 mutation in combination with a 5p segmental deletion attributable to CdCS on the opposite chromosome. Chronic oto-sino-pulmonary symptoms or organ laterality defects in CdCS should prompt an evaluation for PCD. PMID:25066065

  15. HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease

    PubMed Central

    Chen, Zhiyong; Migeon, Tiffany; Verpont, Marie-Christine; Zaidan, Mohamad; Sado, Yoshikazu; Kerjaschki, Dontscho; Ronco, Pierre

    2016-01-01

    Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman’s capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44, α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman’s capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders. PMID:26260163

  16. HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

    PubMed

    Chen, Zhiyong; Migeon, Tiffany; Verpont, Marie-Christine; Zaidan, Mohamad; Sado, Yoshikazu; Kerjaschki, Dontscho; Ronco, Pierre; Plaisier, Emmanuelle

    2016-04-01

    Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders. Copyright © 2016 by the American Society of Nephrology.

  17. Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.

    PubMed

    Gripp, Karen W; Robbins, Katherine M; Sobreira, Nara L; Witmer, P Dane; Bird, Lynne M; Avela, Kristiina; Makitie, Outi; Alves, Daniela; Hogue, Jacob S; Zackai, Elaine H; Doheny, Kimberly F; Stabley, Deborah L; Sol-Church, Katia

    2015-02-01

    Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL. © 2014 Wiley Periodicals, Inc.

  18. [Hantavirus infection as the cause of haemorrhagic fever with renal syndrome].

    PubMed

    Redal-Baigorri, Belén; Chen Nielsen, Xiaohui; Martin-Iguacel, Raquel

    2012-10-29

    Hantavirus is an RNA virus that can cause potentially fatal pulmonary and renal diseases in humans. Infections with Hantaviruses occur through inhalation of aerosol from rodent faeces, urine or saliva. The predominant virus type in Denmark is the Puumala virus, which causes the mildest form of haemorrhagic fever with renal syndrome, the so-called nephropathia epidemica (NE) with good prognosis (mortality 0.1-0.4%). The incidence of Hantavirus-infection in Denmark is about ten cases a year. The diagnosis of Hantavirus-infection is based on serology and/or polymerase chain reaction in blood or urine.

  19. Medial abrasion syndrome: a neglected cause of knee pain in middle and old age.

    PubMed

    Lyu, Shaw-Ruey; Lee, Ching-Chih; Hsu, Chia-Chen

    2015-04-01

    Knee pain is a prevailing health problem of middle and old age. Medial plica-related medial abrasion syndrome (MAS), although a well-known cause of knee pain in younger individuals, has rarely been investigated in older individuals. This prospective study was conducted to investigate the prevalence and clinical manifestations of this syndrome as a cause of knee pain in middle and old age. The outcomes of arthroscopic treatment for this syndrome were also evaluated.A total of 232 knees of 169 patients >40 years of age (41-82, median: 63 years old) suffering from chronic knee pain were analyzed. The clinical diagnosis, predisposing factors, presenting symptoms, and physical signs were investigated. The sensitivity and specificity of each parameter of the clinical presentation for the diagnosis of MAS were evaluated after confirmation by arthroscopy. For patients with MAS, the roentgenographic and arthroscopic manifestations were investigated, and arthroscopic medial release (AMR) was performed. The outcomes were evaluated by the changes in the pain domain of the Knee Society scoring system and by patient satisfaction. The prevalence of medial plica was 95%, and osteoarthritis (OA) was the most common clinical diagnosis. Symptoms of pain and crepitus in motion and local tenderness during physical examination were the most sensitive parameters for the diagnosis. A history of a single knee injury combined with local tenderness and a palpable band found during physical examination were the most specific parameters for the diagnosis. The majority of patients suffering from this syndrome were successfully treated using AMR, yielding a satisfaction rate of 85.5% after a minimum of 3 years.MAS is a common cause of knee pain in middle and old age and can be effectively treated by AMR. Its concomitance with OA warrants further investigation.

  20. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

    PubMed

    Gabriele, Michele; Vulto-van Silfhout, Anneke T; Germain, Pierre-Luc; Vitriolo, Alessandro; Kumar, Raman; Douglas, Evelyn; Haan, Eric; Kosaki, Kenjiro; Takenouchi, Toshiki; Rauch, Anita; Steindl, Katharina; Frengen, Eirik; Misceo, Doriana; Pedurupillay, Christeen Ramane J; Stromme, Petter; Rosenfeld, Jill A; Shao, Yunru; Craigen, William J; Schaaf, Christian P; Rodriguez-Buritica, David; Farach, Laura; Friedman, Jennifer; Thulin, Perla; McLean, Scott D; Nugent, Kimberly M; Morton, Jenny; Nicholl, Jillian; Andrieux, Joris; Stray-Pedersen, Asbjørg; Chambon, Pascal; Patrier, Sophie; Lynch, Sally A; Kjaergaard, Susanne; Tørring, Pernille M; Brasch-Andersen, Charlotte; Ronan, Anne; van Haeringen, Arie; Anderson, Peter J; Powis, Zöe; Brunner, Han G; Pfundt, Rolph; Schuurs-Hoeijmakers, Janneke H M; van Bon, Bregje W M; Lelieveld, Stefan; Gilissen, Christian; Nillesen, Willy M; Vissers, Lisenka E L M; Gecz, Jozef; Koolen, David A; Testa, Giuseppe; de Vries, Bert B A

    2017-06-01

    Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

    PubMed Central

    Stephen, Joshi; Vilboux, Thierry; Mian, Luhe; Kuptanon, Chulaluck; Sinclair, Courtney M.; Yildirimli, Deniz; Maynard, Dawn M.; Bryant, Joy; Fischer, Roxanne; Vemulapalli, Meghana; Mullikin, James C.; Huizing, Marjan; Gahl, William A.

    2017-01-01

    Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts. PMID:28220259

  2. Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.

    PubMed

    Stephen, Joshi; Vilboux, Thierry; Mian, Luhe; Kuptanon, Chulaluck; Sinclair, Courtney M; Yildirimli, Deniz; Maynard, Dawn M; Bryant, Joy; Fischer, Roxanne; Vemulapalli, Meghana; Mullikin, James C; Huizing, Marjan; Gahl, William A; Malicdan, May Christine V; Gunay-Aygun, Meral

    2017-04-01

    Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.

  3. Spinal intradural hydatid cyst causing arachnoiditis: A rare etiology of cauda equina syndrome

    PubMed Central

    Singh, Suyash; Sardhara, Jayesh; Singh, Amit Kumar; Srivastava, Arun Kumar; Bhaisora, Kamlesh Singh; Das, Kuntal Kanti; Mehrotra, Anant; Sahu, Rabi N; Jaiswal, Awadhesh Kumar; Behari, Sanjay

    2016-01-01

    This study aims to focus on a rare presentation of spinal hydatid cyst as cauda equine syndrome and misdiagnosed as intradural extramedullary (IDEM) benign lesion on magnetic resonance imaging. In this article, we report a case of spinal hydatid cyst masquerading as IDEM tumor, and intraoperatively, we accidently find clumped granuloma with severe arachnoiditis and hydatid cyst in lumber region, which was present as bilateral S1 radiculopathy with cauda equina syndrome. An 11-year-old boy who presented with symptoms and signs of cauda equina syndrome and planned for surgical excision. His radiological impression was IDEM possibly neurofibroma. To our surprise, we found multiple intradural cystic lesions with arachnoiditis. Dissecting in plane cyst was flushed out, and surgical cavity was irrigated with 3% saline. Postoperatively histopathology and serum tests confirmed the diagnosis of hydatid cyst. Hydatid disease is rare cause of cauda equine syndrome which can be miss diagnosed on radiological investigations. A high index of suspicion should be kept especially in a young patient from the Indian subcontinent. PMID:27891041

  4. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.

    PubMed

    Parvari, Ruti; Hershkovitz, Eli; Grossman, Nili; Gorodischer, Rafael; Loeys, Bart; Zecic, Alexandra; Mortier, Geert; Gregory, Simon; Sharony, Reuven; Kambouris, Marios; Sakati, Nadia; Meyer, Brian F; Al Aqeel, Aida I; Al Humaidan, Abdul Karim; Al Zanhrani, Fatma; Al Swaid, Abdulrahman; Al Othman, Johara; Diaz, George A; Weiner, Rory; Khan, K Tahseen S; Gordon, Ronald; Gelb, Bruce D

    2002-11-01

    The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

  5. Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.

    PubMed

    Woods, C G; Stricker, S; Seemann, P; Stern, R; Cox, J; Sherridan, E; Roberts, E; Springell, K; Scott, S; Karbani, G; Sharif, S M; Toomes, C; Bond, J; Kumar, D; Al-Gazali, L; Mundlos, S

    2006-08-01

    Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development.

  6. Mutations in WNT7A Cause a Range of Limb Malformations, Including Fuhrmann Syndrome and Al-Awadi/Raas-Rothschild/Schinzel Phocomelia Syndrome

    PubMed Central

    Woods, C. G.; Stricker, S.; Seemann, P.; Stern, R.; Cox, J.; Sherridan, E.; Roberts, E.; Springell, K.; Scott, S.; Karbani, G.; Sharif, S. M.; Toomes, C.; Bond, J.; Kumar, D.; Al-Gazali, L.; Mundlos, S.

    2006-01-01

    Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development. PMID:16826533

  7. A novel NHS mutation causes Nance-Horan Syndrome in a Chinese family.

    PubMed

    Tian, Qi; Li, Yunping; Kousar, Rizwana; Guo, Hui; Peng, Fenglan; Zheng, Yu; Yang, Xiaohua; Long, Zhigao; Tian, Runyi; Xia, Kun; Lin, Haiying; Pan, Qian

    2017-01-07

    Nance-Horan Syndrome (NHS) (OMIM: 302350) is a rare X-linked developmental disorder characterized by bilateral congenital cataracts, with occasional dental anomalies, characteristic dysmorphic features, brachymetacarpia and mental retardation. Carrier females exhibit similar manifestations that are less severe than in affected males. Here, we report a four-generation Chinese family with multiple affected individuals presenting Nance-Horan Syndrome. Whole-exome sequencing combined with RT-PCR and Sanger sequencing was used to search for a genetic cause underlying the disease phenotype. Whole-exome sequencing identified in all affected individuals of the family a novel donor splicing site mutation (NM_198270: c.1045 + 2T > A) in intron 4 of the gene NHS, which maps to chromosome Xp22.13. The identified mutation results in an RNA processing defect causing a 416-nucleotide addition to exon 4 of the mRNA transcript, likely producing a truncated NHS protein. The donor splicing site mutation NM_198270: c.1045 + 2T > A of the NHS gene is the causative mutation in this Nance-Horan Syndrome family. This research broadens the spectrum of NHS gene mutations, contributing to our understanding of the molecular genetics of NHS.

  8. [Sleep apnea syndrome -- cause of resistance to treatment of arterial hypertension].

    PubMed

    Frenţ, Stefan; Tudorache, Voicu; Ardelean, Carmen; Dimitriu, Diana; Lighezan, Daniel; Gaiţă, Dan; Mihăicuţă, Stefan

    2011-01-01

    The prevalence of sleep apnea syndrome is relatively high in population (5%). The mortality is significantly higher in those with apnea-hypopnea index >20. There is an increased rate of car accidents in the subjects with OSA compared to those who don't have this syndrome (31% versus 6%). The impact of OSA on mortality is also given by its association with a significant number of cardiovascular diseases. The association between OSA and hypertension has been much debated. The prevalence of hypertension among patients with OSA varies between 50-58%, while the prevalence of OSA in hypertensive patients is 30%. A particular association is OSA and resistant hypertension, i.e. blood pressure that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes, one to be a diuretic and all pharmacological agents being prescribed at recommended doses. Secondary causes of hypertension are common in patients with resistant hypertension. Among these causes, one of the most frequent is sleep apnea syndrome. Some of the mechanisms by which sleep apnea contributes to the development of hypertension are intermittent hypoxia and/or increased upper airway resistance associated with sleep apnea that induces a sustained increase in sympathetic nervous system activity. Treatment of sleep apnea with continuous positive airway pressure devices (CPAP) improves blood pressure control, although the benefit of CPAP evaluated in clinical trials is variable.

  9. Gram Positive Bacterial Superantigen Outside-In Signaling Causes Toxic Shock Syndrome

    PubMed Central

    Brosnahan, Amanda J.; Schlievert, Patrick M.

    2011-01-01

    Staphylococcus aureus and Streptococcus pyogenes (group A streptococci) are gram-positive pathogens capable of producing a variety of bacterial exotoxins known as superantigens. Superantigens interact with antigen-presenting cells (APCs) and T cells to induce T cell proliferation and massive cytokine production, which leads to fever, rash, capillary leak, and subsequent hypotension, the major symptoms of toxic shock syndrome. Both S. aureus and group A streptococci colonize mucosal surfaces, including the anterior nares and vagina for S. aureus, and the oropharynx and less commonly the vagina for group A streptococci. However, due to their abilities to secrete a variety of virulence factors, the organisms can also cause illnesses from the mucosa. This review provides an updated discussion of the biochemical and structural features of one group of secreted virulence factors, the staphylococcal and group A streptococcal superantigens, and their abilities to cause toxic shock syndrome from a mucosal surface. The main focus of this review, however, is the abilities of superantigens to induce cytokines and chemokines from epithelial cells, which has been linked to a dodecapeptide region that is relatively conserved among all superantigens and is distinct from the binding sites required for interactions with APCs and T cells. This phenomenon, termed outside-in signaling, acts to recruit adaptive immune cells to the submucosa, where the superantigens can then interact with those cells to initiate the final cytokine cascades that lead to toxic shock syndrome. PMID:21535475

  10. Gram-positive bacterial superantigen outside-in signaling causes toxic shock syndrome.

    PubMed

    Brosnahan, Amanda J; Schlievert, Patrick M

    2011-12-01

    Staphylococcus aureus and Streptococcus pyogenes (group A streptococci) are Gram-positive pathogens capable of producing a variety of bacterial exotoxins known as superantigens. Superantigens interact with antigen-presenting cells (APCs) and T cells to induce T cell proliferation and massive cytokine production, which leads to fever, rash, capillary leak and subsequent hypotension, the major symptoms of toxic shock syndrome. Both S. aureus and group A streptococci colonize mucosal surfaces, including the anterior nares and vagina for S. aureus, and the oropharynx and less commonly the vagina for group A streptococci. However, due to their abilities to secrete a variety of virulence factors, the organisms can also cause illnesses from the mucosa. This review provides an updated discussion of the biochemical and structural features of one group of secreted virulence factors, the staphylococcal and group A streptococcal superantigens, and their abilities to cause toxic shock syndrome from a mucosal surface. The main focus of this review, however, is the abilities of superantigens to induce cytokines and chemokines from epithelial cells, which has been linked to a dodecapeptide region that is relatively conserved among all superantigens and is distinct from the binding sites required for interactions with APCs and T cells. This phenomenon, termed outside-in signaling, acts to recruit adaptive immune cells to the submucosa, where the superantigens can then interact with those cells to initiate the final cytokine cascades that lead to toxic shock syndrome. © 2011 The Authors Journal compilation © 2011 FEBS.

  11. Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome.

    PubMed

    Bénit, P; Slama, A; Cartault, F; Giurgea, I; Chretien, D; Lebon, S; Marsac, C; Munnich, A; Rötig, A; Rustin, P

    2004-01-01

    Respiratory chain complex I deficiency represents a genetically heterogeneous group of diseases resulting from mutations in mitochondrial or nuclear genes. Mutations have been reported in 13 of the 14 subunits encoding the core of complex I (seven mitochondrial and six nuclear genes) and these result in Leigh or Leigh-like syndromes or cardiomyopathy. In this study, a combination of denaturing high performance liquid chromatography and sequence analysis was used to study the NDUFS3 gene in a series of complex I deficient patients. Mutations found in this gene (NADH dehydrogenase iron-sulphur protein 3), coding for the seventh and last subunit of complex I core, were shown to cause late onset Leigh syndrome, optic atrophy, and complex I deficiency. A biochemical diagnosis of complex I deficiency on cultured amniocytes from a later pregnancy was confirmed through the identification of disease causing NDUFS3 mutations in these cells. While mutations in the NDUFS3 gene thus result in Leigh syndrome, a dissimilar clinical phenotype is observed in mutations in the NDUFV2 and NDUFS2 genes, resulting in encephalomyopathy and cardiomyopathy. The reasons for these differences are uncertain.

  12. [Myocardial bridge as the only cause of acute coronary syndrome among the young patients].

    PubMed

    Miakinkova, Liudmila O; Teslenko, Yurii V; Tsyhanenko, Irina V

    2018-01-01

    Introduction: Myocardial bridge is an inborn anomaly of coronary artery development, when a part of it is submerged in a myocard, which is pressing the coronary artery to a systola and restrains coronary blood circulation. Generally this feature of coronary blood circulation does not cause any clinical symptoms because the 85% of coronary blood stream of the left ventricle is provided by diastolic filling. Hemodynamic changes in atherosclerosis, tahicardie, hypertrophie of myocard are leading to the manifestation of clinical symptoms of ischemia. The aim: The purpose of the investigation was to discover the features of clinical development of acute coronary syndrome caused by myocardial bridge of young patients without the features of atherosclerotical harm of coronary arteries. Materials and methods: Eight causes of acute coronary syndrome among patients of 28±8,5 years with myocardial bridge which was revealed during coronary angiography, were investigated. Standardized examination and conservative treatment of patients was held, except for three who have got interventional therapy. Results: According to our investigation, myocardial bridge of all investigated patients was located in the middle of the third front interventricular branch of the left coronary artery. Causes of acute coronary syndrome manifestation were tahicardia, spasms of coronary artery, inducted by iatrogenic factors hypertrophie of myocard, hypertrophic cardiomyopatie. Connection between the manifestation of clinical symptoms and length of tunneled segment which did not depend on the level of systolic compres was discovered. The results of conservative and interventional treatment were analyzed. Conclusions: Myocardial bridge can be the cause of myocardial ischemia among patients without signs of coronary atherosclerosis with additional hemodynamic risk facts such as tahicardia, spasms of coronary artery, hypertrophie of myocard. Clinical symptomatology of the acute coronary syndrome is more

  13. Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.

    PubMed

    Fernández, Raquel M; Núñez-Ramos, Raquel; Enguix-Riego, M Valle; Román-Rodríguez, Francisco José; Galán-Gómez, Enrique; Blesa-Sánchez, Emilio; Antiñolo, Guillermo; Núñez-Núñez, Ramón; Borrego, Salud

    2014-02-01

    Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases. © 2013 Wiley Periodicals, Inc.

  14. LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency.

    PubMed

    Debray, François-Guillaume; Morin, Charles; Janvier, Annie; Villeneuve, Josée; Maranda, Bruno; Laframboise, Rachel; Lacroix, Jacques; Decarie, Jean-Claude; Robitaille, Yves; Lambert, Marie; Robinson, Brian H; Mitchell, Grant A

    2011-03-01

    The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied. 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to >30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p<0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1-deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001). SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome.

  15. Classic Bartter syndrome: a rare cause of failure to thrive in a child.

    PubMed

    Vieira, Helena; Mendes, Leonor; Mendes, Patricia; da Silva, José Esteves

    2012-06-28

    Bartter syndrome is a group of rare autosomal-recessive disorders caused by a defect in distal tubule transport of sodium and chloride. Blood gases and plasma electrolytes raise suspicion of this diagnosis and the definitive diagnosis is made by genetic study. Early treatment improves prognosis. The authors present the case of an 11-month-old child with early failure to thrive and severe regurgitation. Blood gases revealed hypochloraemic metabolic alkalosis, hyponatraemia and hypokalaemia. Blood pressure was normal and polyuria was documented. She began therapy with potassium chloride supplementation and indomethacin. There was clinical improvement and plasma potassium and bicarbonate normalised. The molecular study confirmed it was the classic form of Bartter syndrome. Despite being rare in clinical practice, which may lead to unnecessary medical investigation and diagnosis delay, in a child with failure to thrive, hypochloraemic metabolic alkalosis and hypokalaemia, this diagnosis must be considered.

  16. Classic Bartter syndrome: a rare cause of failure to thrive in a child

    PubMed Central

    Vieira, Helena; Mendes, Leonor; Mendes, Patricia; da Silva, José Esteves

    2012-01-01

    Bartter syndrome is a group of rare autosomal-recessive disorders caused by a defect in distal tubule transport of sodium and chloride. Blood gases and plasma electrolytes raise suspicion of this diagnosis and the definitive diagnosis is made by genetic study. Early treatment improves prognosis. The authors present the case of an 11-month-old child with early failure to thrive and severe regurgitation. Blood gases revealed hypochloraemic metabolic alkalosis, hyponatraemia and hypokalaemia. Blood pressure was normal and polyuria was documented. She began therapy with potassium chloride supplementation and indomethacin. There was clinical improvement and plasma potassium and bicarbonate normalised. The molecular study confirmed it was the classic form of Bartter syndrome. Despite being rare in clinical practice, which may lead to unnecessary medical investigation and diagnosis delay, in a child with failure to thrive, hypochloraemic metabolic alkalosis and hypokalaemia, this diagnosis must be considered. PMID:22744244

  17. Manganese intoxication: the cause of an inexplicable epileptic syndrome in a 3 year old child.

    PubMed

    Herrero Hernandez, Elena; Discalzi, Gianluigi; Dassi, Patrizia; Jarre, Laura; Pira, Enrico

    2003-08-01

    Excess manganese (Mn) can cause several neurotoxic effects, however only a few studies have reported epileptic syndromes related to manganese intoxication. We describe an epileptic syndrome due to manganese intoxication in a 3 year old male child. His blood manganese was elevated, but no other abnormal values or toxic substances were found in blood or urine. The electroencephalogram (EEG) showed a picture of progressive encephalopathy, while brain magnetic resonance was normal. The patient's conditions rapidly worsened to epileptic status despite the use of antiepileptic drugs. Chelating treatment with CaNa(2)EDTA was initiated to remove excess manganese and promptly succeeded in reverting epileptic symptoms. Concurrently, manganese blood levels and electroencephalogram progressively normalized. Thereafter it has been possible to discontinue antiepileptic treatment, and the patient remains in excellent conditions without any treatment.

  18. Churg-Strauss Syndrome as an Unusual Cause of Dysphagia: Case Report.

    PubMed

    Park, Jihye; Im, Sun; Moon, Su-Jin; Park, Geun-Young; Jang, Yongjun; Kim, Yeonjin

    2015-06-01

    Systemic vasculitis is a rare disease, and the diagnosis is very difficult when patient shows atypical symptoms. We experienced an unusual case of dysphagia caused by Churg-Strauss syndrome with lower cranial nerve involvement. A 74-year-old man, with a past history of sinusitis, asthma, and hearing deficiency, was admitted to our department for evaluation of dysphagia. He also complained of recurrent bleeding of nasal cavities and esophagus. Brain magnetic resonance imaging did not show definite abnormality, and electrophysiologic findings were suggestive of mononeuritis multiplex. Dysphagia had not improved after conventional therapy. Biopsy of the nasal cavity showed extravascular eosinophilic infiltration. All these findings suggested a rare form of Churg-Strauss syndrome involving multiple lower cranial nerves. Dysphagia improved after steroid therapy.

  19. D-lactic acidosis: an unusual cause of encephalopathy in a patient with short bowel syndrome.

    PubMed

    Dahlqvist, G; Guillen-Anaya, M A; Vincent, M F; Thissen, J P; Hainaut, P

    2013-01-01

    A 24-year-old woman with a short bowel syndrome following post-ischemic small bowel resection, developed several episodes of lethargy, echolalia and ataxia. D-lactic acidosis was identified as the cause of neurological disturbances. This infrequent disorder can be precipitated by intake of a large amount of sugars, in patients with short bowel syndrome. It should be suspected in the presence of metabolic acidosis with increased anion gap and a normal level of L-lactic acid. The diagnosis relies on the specific dosage of D-lactic stereoisomer. Proper management involves rehydration, diet adaptation and oral administration of poorly absorbed antibiotics in order to modify the colonic flora responsible for D-lactic production.

  20. The subclavius posticus muscle: an unusual cause of thoracic outlet syndrome.

    PubMed

    Smayra, T; Nabhane, L; Tabet, G; Menassa-Moussa, L; Hachem, K; Haddad-Zebouni, S

    2014-09-01

    We present the case of a 30-year-old female, complaining of thoracic outlet compression symptoms caused by a supernumerary muscle, the subclavius posticus, accompanied by a caudally inserted middle scalenus muscle on the second rib. This rare anatomic variant was clearly shown on CT angiography and MRI images and surgical treatment was successful. As first described by Rosenmuller in 1800, subclavius posticus is a supernumerary muscle originating from the cranial surface of the sternal end of the first rib, running laterodorsally beneath the clavicle, and inserting into the superior border of the scapula. Its role in thoracic outlet syndrome has been seldom demonstrated in living patients nor described in imaging, although it is theoretically easily recognizable on modern imaging modalities. It should be taken into account during workout of patients with thoracic outlet syndrome, since it can be potentially treated.

  1. Cerebral fat embolism syndrome causing brain death after long-bone fractures and acetazolamide therapy.

    PubMed

    Walshe, Criona M; Cooper, James D; Kossmann, Thomas; Hayes, Ivan; Iles, Linda

    2007-06-01

    A 19-year-old woman with multiple fractures and mild brain injury developed severe cerebral fat embolism syndrome after "damage control" orthopaedic surgery. Acetazolamide therapy to manage ocular trauma, in association with hyperchloraemia, caused a profound metabolic acidosis with appropriate compensatory hypocapnia. During ventilator weaning, unexpected brainstem coning followed increased sedation and brief normalisation of arterial carbon dioxide concentration. Autopsy found severe cerebral fat embolism and brain oedema. In patients with multiple trauma, cerebral fat embolism syndrome is difficult to diagnose, and may be more common after delayed fixation of long-bone fractures. Acetazolamide should be used with caution, as sudden restoration of normocapnia during compensated metabolic acidosis in patients with raised intracranial pressure may precipitate coning.

  2. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA).

    PubMed

    Horváth, R; Abicht, A; Holinski-Feder, E; Laner, A; Gempel, K; Prokisch, H; Lochmüller, H; Klopstock, T; Jaksch, M

    2006-01-01

    Detailed clinical, neuroradiological, histological, biochemical, and genetic investigations were undertaken in a child suffering from Leigh syndrome. The clinical symptoms started at age five months and led to a severe progressive neurodegenerative disorder causing epilepsy, psychomotor retardation, and tetraspasticity. Biochemical measurement of skeletal muscle showed a severe decrease in mitochondrial complex II. Sequencing of SDHA revealed compound heterozygosity for a nonsense mutation in exon 4 (W119X) and a missense mutation in exon 3 (A83V), both absent in normal controls. In six additional patients--five with Leigh or Leigh-like syndrome and one with neuropathy and ataxia associated with isolated deficiency of complex II--mutations in SDHA were not detected, indicating genetic heterogeneity.

  3. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.

    PubMed

    Sznajer, Yves; Coldéa, Cristina; Meire, Françoise; Delpierre, Isabelle; Sekhara, Tayeb; Touraine, Renaud L

    2008-04-15

    Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified "de novo" splice site mutation (c.698-2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient. Copyright 2008 Wiley-Liss, Inc.

  4. Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.

    PubMed

    Brouillard, Pascal; Dupont, Laura; Helaers, Raphael; Coulie, Richard; Tiller, George E; Peeden, Joseph; Colige, Alain; Vikkula, Miikka

    2017-11-01

    Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.

    PubMed

    Clendenning, M; Senter, L; Hampel, H; Robinson, K Lagerstedt; Sun, S; Buchanan, D; Walsh, M D; Nilbert, M; Green, J; Potter, J; Lindblom, A; de la Chapelle, A

    2008-06-01

    When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis. We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency <0.05) at a single nucleotide polymorphism (SNP) in exon 11, and have been shown to possess a short common haplotype, allowing us to calculate that the mutation arose around 1625 years ago (65 generations; 95% confidence interval 22 to 120). Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are >10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.

  6. When the face says it all: dysmorphology in identifying syndromic causes of epilepsy.

    PubMed

    Dixit, Abhijit; Suri, Mohnish

    2016-04-01

    Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  7. Fanconi syndrome

    MedlinePlus

    De Toni-Fanconi syndrome ... Fanconi syndrome can be caused by faulty genes, or it may result later in life due to kidney damage. Sometimes the cause of Fanconi syndrome is unknown. Common causes of Fanconi syndrome in ...

  8. Subacute peripheral and optic neuropathy syndrome with no evidence of a toxic or nutritional cause.

    PubMed

    Allen, D; Riordan-Eva, P; Paterson, R W; Hadden, R D M

    2013-08-01

    The syndrome of subacute simultaneous peripheral neuropathy and bilateral optic neuropathy is known to occur in tropical countries, probably due to malnutrition or toxicity, but not often seen in developed countries. We report seven patients in London who were not malnourished or alcoholic, and in whom no clear cause was found. We retrospectively reviewed the case notes and arranged some further investigations. All patients developed peripheral and bilateral optic neuropathy within 6 months. Patients were aged 30-52, and all of Jamaican birth and race but lived in the UK. Most had subacute, painful ataxic sensory axonal neuropathy or neuronopathy, some with myelopathy. Nerve conduction studies revealed minor demyelinating features in two cases. The optic neuropathy was symmetrical, subacute and monophasic, usually with marked reduction in visual acuity. CSF protein concentration was usually elevated but other laboratory investigations were normal. Patients showed only modest improvement at follow-up. These patients share a common clinical and electrophysiological phenotype, age, ethnicity and elevated CSF protein, but otherwise normal laboratory investigations. The syndrome is a cause of significant morbidity in young people. The cause remains uncertain despite thorough investigation. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

    PubMed Central

    Canna, Scott W.; de Jesus, Adriana Almeida; Gouni, Sushanth; Brooks, Stephen R.; Marrero, Bernadette; Liu, Yin; DiMattia, Michael A.; Zaal, Kristien J.M.; Montealegre Sanchez, Gina A.; Kim, Hanna; Chapelle, Dawn; Plass, Nicole; Huang, Yan; Villarino, Alejandro V.; Biancotto, Angelique; Fleisher, Thomas A.; Duncan, Joseph A.; O’Shea, John J; Benseler, Susanne; Grom, Alexei; Deng, Zuoming; Laxer, Ronald M; Goldbach-Mansky, Raphaela

    2014-01-01

    Inflammasomes are innate immune sensors that respond to pathogen and damage-associated signals with caspase-1 activation, IL-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the Cryopyrin Associated Periodic Syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion, led to successful treatment with IL-1 blocking agents1. Herein, we report a de novo missense mutation, c.1009A>T, p.Thr337Ser, in the nucleotide-binding domain of inflammasome component NLRC4 (IPAF/CARD12) that causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, the latter exceeding levels in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in transduced cells and increased production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests novel targets for therapy. PMID:25217959

  10. Atypical amyoplasia congenita in an infant with Leigh syndrome: a mitochondrial cause of severe contractures?

    PubMed

    Wilnai, Yael; Seaver, Laurie H; Enns, Gregory M

    2012-09-01

    Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs. Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita. His development was normal until age 10.5 months, at which time he developed severe hypotonia and choreoathetosis following an episode of viral gastroenteritis. Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity. Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present. Copyright © 2012 Wiley Periodicals, Inc.

  11. Origins of the E. coli Strain Causing an Outbreak of Hemolytic–Uremic Syndrome in Germany

    PubMed Central

    Rasko, David A.; Webster, Dale R.; Sahl, Jason W.; Bashir, Ali; Boisen, Nadia; Scheutz, Flemming; Paxinos, Ellen E.; Sebra, Robert; Chin, Chen-Shan; Iliopoulos, Dimitris; Klammer, Aaron; Peluso, Paul; Lee, Lawrence; Kislyuk, Andrey O.; Bullard, James; Kasarskis, Andrew; Wang, Susanna; Eid, John; Rank, David; Redman, Julia C.; Steyert, Susan R.; Frimodt-Møller, Jakob; Struve, Carsten; Petersen, Andreas M.; Krogfelt, Karen A.; Nataro, James P.; Schadt, Eric E.; Waldor, Matthew K.

    2011-01-01

    BACKGROUND A large outbreak of diarrhea and the hemolytic–uremic syndrome caused by an unusual serotype of Shiga-toxin–producing Escherichia coli (O104:H4) began in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin–producing E. coli have been reported — 3167 without the hemolytic–uremic syndrome (16 deaths) and 908 with the hemolytic–uremic syndrome (34 deaths) — indicating that this strain is notably more virulent than most of the Shiga-toxin–producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. METHODS We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference strains belonging to other serotypes. Genomewide comparisons were performed with the use of these enteroaggregative E. coli genomes, as well as those of 40 previously sequenced E. coli isolates. RESULTS The enteroaggregative E. coli O104:H4 strains are closely related and form a distinct clade among E. coli and enteroaggregative E. coli strains. However, the genome of the German outbreak strain can be distinguished from those of other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic-resistance factors. CONCLUSIONS Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin–producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens. PMID:21793740

  12. The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome.

    PubMed

    Garrity, Deborah M; Childs, Sarah; Fishman, Mark C

    2002-10-01

    Holt-Oram syndrome is one of the autosomal dominant human "heart-hand" disorders, with a combination of upper limb malformations and cardiac defects. Holt-Oram syndrome is caused by mutations in the TBX5 gene, a member of a large family of T-box transcription factors that play important roles in cell-type specification and morphogenesis. In a screen for mutations affecting zebrafish cardiac function, we isolated the recessive lethal mutant heartstrings, which lacks pectoral fins and exhibits severe cardiac dysfunction, beginning with a slow heart rate and progressing to a stretched, non-functional heart. We mapped and cloned the heartstrings mutation and find it to encode the zebrafish ortholog of the TBX5 gene. The heartstrings mutation causes premature termination at amino acid 316. Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. The total absence of any fin bud differentiation distinguishes heartstrings from most other mutations that affect zebrafish fin development, suggesting that Tbx5 functions very early in the pectoral fin induction pathway. Moderate reduction of Tbx5 by morpholino causes fin malformations, revealing an additional early requirement for Tbx5 in coordinating the axes of fin outgrowth. The heart of heartstrings mutant embryos appears to form and function normally through the early heart tube stage, manifesting only a slight bradycardia compared with wild-type siblings. However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. Relative to mammals, fish require lower levels of Tbx5 to produce malformed appendages and display whole-heart rather than atrial-predominant cardiac defects. However, the syndromic deficiencies of tbx5 mutation are remarkably well retained between fish and mammals.

  13. Case Report: A Rare Cause of Complicated Urinary Tract Infection in a Woman with Herlyn-Werner-Wunderlich Syndrome.

    PubMed

    Tsai, Jun-Li; Tsai, Shang-Feng

    2016-11-01

    Urinary tract infection is a common disease in the general population. However, in patients with frequent urinary tract infection, it is important to determine any treatable cause to avoid recurrence. Herlyn-Werner-Wunderlich syndrome or OHVIRA syndrome is a very rare congenital anomaly with uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis. The earliest presentation of this syndrome is hematocolpos that develops during menstruation and results in dysmenorrhea and a pelvic mass shortly after menarche. Herein, we report a patient with Herlyn-Werner-Wunderlich syndrome manifested with unusual symptoms, delayed onset and without surgery. The unique point of this patient is the partial obstruction of cervico-vaginal junction. Early diagnosis and timely treatment of OHVIRA syndrome can prevent long-term complications, such as recurrent urinary tract infection and infertility. A high index of suspicion is required, even though OHVIRA syndrome is extremely rare and may have an atypical presentation.

  14. Gene Therapy for the Retinal Degeneration of Usher Syndrome Caused by Mutations in MYO7A.

    PubMed

    Lopes, Vanda S; Williams, David S

    2015-01-20

    Usher syndrome is a deaf-blindness disorder. One of the subtypes, Usher 1B, is caused by loss of function of the gene encoding the unconventional myosin, MYO7A. A variety of different viral-based delivery approaches have been tested for retinal gene therapy to prevent the blindness of Usher 1B, and a clinical trial based on one of these approaches has begun. This review evaluates the different approaches. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  15. Ascending aortic aneurysm causing hoarse voice: a variant of Ortner's syndrome

    PubMed Central

    Eccles, Sinan Robert; Banks, John; Kumar, Pankaj

    2012-01-01

    A 68-year-old man with a persistent hoarse voice was found to have a left vocal cord paralysis. Clinical examination revealed signs consistent with aortic regurgitation. Subsequent investigation revealed an ascending aortic aneurysm. He underwent aortic root and ascending aorta replacement and his hoarseness improved. Ortner's syndrome refers to hoarseness due to recurrent laryngeal nerve palsy secondary to a cardiovascular abnormality. Recurrent laryngeal nerve palsy due to aneurysmal dilation of the ascending aorta is extremely rare, with aneurysms of the aortic arch being a more common cause. PMID:23060380

  16. Intrauterine device infection causing concomitant streptococcal toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus bacteraemia

    PubMed Central

    Wu, Carolyn M Yu; Noska, Amanda

    2016-01-01

    Intrauterine devices (IUDs) are rarely associated with serious infections. We report an unusual concomitant infection of group A Streptococcus (GAS) causing toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus associated with an IUD in a healthy 50-year-old patient. The IUD was subsequently removed and the patient recovered on the appropriate antibiotics. This case highlights the importance of clinicians’ high index of suspicion of an IUD infection and prompt removal of the infected foreign body to obtain source control. PMID:26965406

  17. Intrauterine device infection causing concomitant streptococcal toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus bacteraemia.

    PubMed

    Wu, Carolyn M Yu; Noska, Amanda

    2016-03-10

    Intrauterine devices (IUDs) are rarely associated with serious infections. We report an unusual concomitant infection of group A Streptococcus (GAS) causing toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus associated with an IUD in a healthy 50-year-old patient. The IUD was subsequently removed and the patient recovered on the appropriate antibiotics. This case highlights the importance of clinicians' high index of suspicion of an IUD infection and prompt removal of the infected foreign body to obtain source control. 2016 BMJ Publishing Group Ltd.

  18. Andes Virus and First Case Report of Bermejo Virus Causing Fatal Pulmonary Syndrome

    PubMed Central

    Della Valle, Marcelo González; Alai, María Garcia; Cortada, Pedro; Villagra, Mario; Gianella, Alberto

    2002-01-01

    Two suspected hantavirus pulmonary syndrome (HPS) cases from Bolivia were confirmed by enzyme-linked immunosorbent assay. (ELISA)-ANDES was performed using N-Andes recombinant antigen serology in May and July 2000. Clot RNAs from the two patients were subjected to reverse transcription–polymerase chain reaction (PCR) amplification and sequencing. We describe two characterized cases of HPS. One was caused by infection with Bermejo virus and the other with Andes Nort viral lineage, both previously obtained from Oligoryzomys species. This is the first report of molecular identification of a human hantavirus associated with Bermejo virus. PMID:11971782

  19. Hypertrophic Pachymeningitis and the Syndrome of Inappropriate Antidiuretic Hormone Secretion: Coincidence or Cause?

    PubMed

    Harsch, Igor Alexander; Schiffer, Anne; Konturek, Peter C

    2017-01-01

    To investigate a potential cause of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). A 70-year-old female patient had nausea and collapsed. Although euvolemic, pathological laboratory findings showed hyponatremia and hypoosmolality, and cerebral magnetic resonance imaging showed hypertrophic pachymeningitis. Secondary hypertrophic pachymeningitis was excluded. Other nonneurological reasons for SIADH were also excluded. Moderate fluid restriction restored an almost normal serum osmolality and sodium. This case of SIADH was conservatively treated with moderate fluid restriction that almost restored normal serum osmolality and sodium levels. © 2017 S. Karger AG, Basel.

  20. Hypertrophic Pachymeningitis and the Syndrome of Inappropriate Antidiuretic Hormone Secretion: Coincidence or Cause?

    PubMed Central

    Harsch, Igor Alexander; Schiffer, Anne; Konturek, Peter C.

    2017-01-01

    Objective To investigate a potential cause of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Clinical Presentation and Intervention A 70-year-old female patient had nausea and collapsed. Although euvolemic, pathological laboratory findings showed hyponatremia and hypoosmolality, and cerebral magnetic resonance imaging showed hypertrophic pachymeningitis. Secondary hypertrophic pachymeningitis was excluded. Other nonneurological reasons for SIADH were also excluded. Moderate fluid restriction restored an almost normal serum osmolality and sodium. Conclusion This case of SIADH was conservatively treated with moderate fluid restriction that almost restored normal serum osmolality and sodium levels. PMID:28245481

  1. The infundibulo-tuberal syndrome caused by craniopharyngiomas: clinicopathological evidence from an historical French cohort (1705-1973).

    PubMed

    Castro-Dufourny, Inés; Carrasco, Rodrigo; Prieto, Ruth; Barrios, Laura; Pascual, José M

    2015-10-01

    Infundibulo-tuberal syndrome groups endocrine, metabolic and behavioral disturbances caused by lesions involving the upper neurohypophysis (median eminence) and adjacent basal hypothalamus (tuber cinereum). It was originally described by Henri Claude and Jean Lhermitte in 1917, in a patient with a craniopharyngioma. This study investigates the clinical, pathological and surgical evidence verifying the infundibulo-tuberal syndrome caused by craniopharyngiomas (CPs). A systematic retrospective review of craniopharyngiomas reported in French literature between 1705 and 1973 was conducted. A total of 128 well described reports providing a comprehensive clinical and pathological description of the tumors were selected. This series represents the historical French cohort of CPs reported in the pre-CT/MRI era. Three major syndromes caused by CPs were categorized: pituitary syndrome (35%), infundibulo-tuberal syndrome (52%) and hypothalamic syndrome (49%). CP topography was significantly related to the type of syndrome described (p < 0.001). Infundibulo-tuberal syndrome occurred in CPs which replaced or invaded the third ventricle floor. In contrast, the majority of sellar/suprasellar CPs growing below the third ventricle showed a pituitary syndrome (82%). Cases with hypothalamic syndrome were characterized by anatomical integrity of the pituitary gland and stalk (p = 0.033) and occurred predominantly in adults older than 41 years old (p < 0.005). Among infundibulo-tuberal symptoms, abnormal somnolence was not related with the presence of hydrocephalus. All squamous-papillary CPs presented psychiatric disturbances (p < 0.001). This historical CP cohort evidences a clinical-topographical correlation between the patient's type of syndrome and the anatomical structures involved by the tumor along the hypophysial-hypothalamic axis.

  2. Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

    PubMed Central

    O'Grady, Gina L.; Verschuuren, Corien; Yuen, Michaela; Webster, Richard; Menezes, Manoj; Fock, Johanna M.; Pride, Natalie; Best, Heather A.; Benavides Damm, Tatiana; Turner, Christian; Lek, Monkol; Engel, Andrew G.; North, Kathryn N.; Clarke, Nigel F.; MacArthur, Daniel G.; Kamsteeg, Erik-Jan

    2016-01-01

    Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans. PMID:27590285

  3. Hepatitis E as a cause of acute jaundice syndrome in northern Uganda, 2010-2012.

    PubMed

    Gerbi, Gemechu B; Williams, Roxanne; Bakamutumaho, Barnabas; Liu, Stephen; Downing, Robert; Drobeniuc, Jan; Kamili, Saleem; Xu, Fujie; Holmberg, Scott D; Teshale, Eyasu H

    2015-02-01

    Hepatitis E virus (HEV) is a common cause of acute viral hepatitis in developing countries; however, its contribution to acute jaundice syndrome is not well-described. A large outbreak of hepatitis E occurred in northern Uganda from 2007 to 2009. In response to this outbreak, acute jaundice syndrome surveillance was established in 10 district healthcare facilities to determine the proportion of cases attributable to hepatitis E. Of 347 acute jaundice syndrome cases reported, the majority (42%) had hepatitis E followed by hepatitis B (14%), malaria (10%), hepatitis C (5%), and other/unknown (29%). Of hepatitis E cases, 72% occurred in Kaboong district, and 68% of these cases occurred between May and August of 2011. Residence in Kaabong district was independently associated with hepatitis E (adjusted odds ratio = 13; 95% confidence interval = 7-24). The findings from this surveillance show that an outbreak and sporadic transmission of hepatitis E occur in northern Uganda. © The American Society of Tropical Medicine and Hygiene.

  4. The first Korean patient with Potocki-Shaffer syndrome: a rare cause of multiple exostoses.

    PubMed

    Sohn, Young Bae; Yim, Shin-Young; Cho, Eun-Hae; Kim, Ok-Hwa

    2015-02-01

    Potocki-Shaffer syndrome (PSS, OMIM #601224) is a rare contiguous gene deletion syndrome caused by haploinsufficiency of genes located on the 11p11.2p12. Affected individuals have a number of characteristic features including multiple exostoses, biparietal foramina, abnormalities of genitourinary system, hypotonia, developmental delay, and intellectual disability. We report here on the first Korean case of an 8-yr-old boy with PSS diagnosed by high resolution microarray. Initial evaluation was done at age 6 months because of a history of developmental delay, hypotonia, and dysmorphic face. Coronal craniosynostosis and enlarged parietal foramina were found on skull radiographs. At age 6 yr, he had severe global developmental delay. Multiple exostoses of long bones were detected during a radiological check-up. Based on the clinical and radiological features, PSS was highly suspected. Subsequently, chromosomal microarray analysis identified an 8.6 Mb deletion at 11p11.2 [arr 11p12p11.2 (Chr11:39,204,770-47,791,278)×1]. The patient continued rehabilitation therapy for profound developmental delay. The progression of multiple exostosis has being monitored. This case confirms and extends data on the genetic basis of PSS. In clinical and radiologic aspect, a patient with multiple exostoses accompanying with syndromic features, including craniofacial abnormalities and mental retardation, the diagnosis of PSS should be considered.

  5. Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family.

    PubMed

    Dantas, Vitor G L; Freitas, Erika L; Della-Rosa, Valter A; Lezirovitz, Karina; de Moraes, Ana Maria S M; Ramos, Silvia B; Oiticica, Jeanne; Alves, Leandro U; Pearson, Peter L; Rosenberg, Carla; Mingroni-Netto, Regina C

    2015-01-01

    To identify novel genetic causes of syndromic hearing loss in Brazil. To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.

  6. A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle.

    PubMed

    Agerholm, Jørgen S; McEvoy, Fintan J; Heegaard, Steffen; Charlier, Carole; Jagannathan, Vidhya; Drögemüller, Cord

    2017-08-02

    Surveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause. Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire. FDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given

  7. [Early diagnosis and treatment of compartment syndrome caused by landslides:a report of 20 cases].

    PubMed

    Xie, Hong-Bo; Peng, Zi-Lai; Liu, Xu-Bang; Chen, Lian

    2012-01-01

    To summarize early diagnosis and treatment methods of 20 patients with compartment syndrome caused by landslides during coal mine accidents in order to improve the level of diagnosis and treatment of compartment syndrome and reduce disability. From September 2006 to April 2010,20 patients with compartment syndrome were treated with the methods of early decompression, systemic support. All the patients were male with an average age of 42 years (ranged, 23 to 54). All the patients with high tension limb swelling, pain, referred pain passive positive; 5 extremities feeling diminish or disappear and the distal blood vessel beat were normal or weakened or disappeared; myoglobinuria, hyperkalemia, serum urea nitrogen and creatinine increased in 5 cases and oliguria in occurred 1 case. The function of affected limbs was observed according to disability ratings. Three cases complicated with infection of affected limb and 6 cases occurred with renal function insufficiency. Total recovery was in 16 cases, basically recovery in 3, amputation in 1 case. All patients were followed up for 6-15 months with an average of 12 months. The ability to work according to national standard identification--Employee work-related injuries and occupational disability rating classification (GB/T16180-2006) to assess, grade 5 was in 1 case, grade 8 in 2 cases, grade 10 in 1 case, no grade in 16 cases. Arteriopalmus of dorsalis pedis weaken and vanished can not be regard as an evidence in early diagnosis of compartment syndrome. Early diagnosis and decompression, systemic support and treatment is the key in reducing disability.

  8. Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations

    PubMed Central

    Ockeloen, Charlotte W; Willemsen, Marjolein H; de Munnik, Sonja; van Bon, Bregje WM; de Leeuw, Nicole; Verrips, Aad; Kant, Sarina G; Jones, Elizabeth A; Brunner, Han G; van Loon, Rosa LE; Smeets, Eric EJ; van Haelst, Mieke M; van Haaften, Gijs; Nordgren, Ann; Malmgren, Helena; Grigelioniene, Giedre; Vermeer, Sascha; Louro, Pedro; Ramos, Lina; Maal, Thomas JJ; van Heumen, Celeste C; Yntema, Helger G; Carels, Carine EL; Kleefstra, Tjitske

    2015-01-01

    Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases. PMID:25424714

  9. Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

    PubMed

    Ockeloen, Charlotte W; Willemsen, Marjolein H; de Munnik, Sonja; van Bon, Bregje W M; de Leeuw, Nicole; Verrips, Aad; Kant, Sarina G; Jones, Elizabeth A; Brunner, Han G; van Loon, Rosa L E; Smeets, Eric E J; van Haelst, Mieke M; van Haaften, Gijs; Nordgren, Ann; Malmgren, Helena; Grigelioniene, Giedre; Vermeer, Sascha; Louro, Pedro; Ramos, Lina; Maal, Thomas J J; van Heumen, Celeste C; Yntema, Helger G; Carels, Carine E L; Kleefstra, Tjitske

    2015-09-01

    Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

  10. NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes

    PubMed Central

    Douglas, Jenny; Hanks, Sandra; Temple, I. Karen; Davies, Sally; Murray, Alexandra; Upadhyaya, Meena; Tomkins, Susan; Hughes, Helen E.; Cole, Trevor R. P.; Rahman, Nazneen

    2003-01-01

    Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes. PMID:12464997

  11. Upper gastrointestinal bleeding caused by severe esophagitis: a unique clinical syndrome.

    PubMed

    Guntipalli, Prathima; Chason, Rebecca; Elliott, Alan; Rockey, Don C

    2014-12-01

    We have recognized a unique clinical syndrome in patients with upper gastrointestinal bleeding who are found to have severe esophagitis. We aimed to more clearly describe the clinical entity of upper gastrointestinal bleeding in patients with severe esophagitis. We conducted a retrospective matched case-control study designed to investigate clinical features in patients with carefully defined upper gastrointestinal bleeding and severe esophagitis. Patient data were captured prospectively via a Gastrointestinal Bleeding Healthcare Registry, which collects data on all patients admitted with gastrointestinal bleeding. Patients with endoscopically documented esophagitis (cases) were matched with randomly selected controls that had upper gastrointestinal bleeding caused by other lesions. Epidemiologic features in patients with esophagitis were similar to those with other causes of upper gastrointestinal bleeding. However, hematemesis was more common in patients with esophagitis 86% (102/119) than in controls 55% (196/357) (p < 0.0001), while melena was less common in patients with esophagitis 38% (45/119) than in controls 68% (244/357) (p < 0.0001). Additionally, the more severe the esophagitis, the more frequent was melena. Patients with esophagitis had less abnormal vital signs, lesser decreases in hematocrit, and lesser increases in BUN. Both pre- and postRockall scores were lower in patients with esophagitis compared with controls (p = 0.01, and p < 0.0001, respectively). Length of hospital stay (p = 0.002), rebleeding rate at 42 days (p = 0.0007), and mortality were less in patients with esophagitis than controls. Finally, analysis of patients with esophagitis and cirrhosis suggested that this group of patients had more severe bleeding than those without cirrhosis. We have described a unique clinical syndrome in patients with upper gastrointestinal bleeding who have erosive esophagitis. This syndrome is manifest by typical clinical features and is associated with

  12. Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.

    PubMed

    Lynch, Danielle C; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth J; Innes, A Micheil; Lamont, Ryan E; Lemire, Edmond G; Chodirker, Bernard N; Taylor, Juliet P; Zackai, Elaine H; McLeod, D Ross; Kirk, Edwin P; Hoover-Fong, Julie; Fleming, Leah; Savarirayan, Ravi; Majewski, Jacek; Jerome-Majewska, Loydie A; Parboosingh, Jillian S; Bernier, Francois P

    2014-07-22

    Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.

  13. Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome

    PubMed Central

    Lynch, Danielle C.; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth J.; Innes, A. Micheil; Lamont, Ryan E.; Lemire, Edmond G.; Chodirker, Bernard N.; Taylor, Juliet P.; Zackai, Elaine H.; McLeod, D. Ross; Kirk, Edwin P.; Hoover-Fong, Julie; Fleming, Leah; Savarirayan, Ravi; Boycott, Kym; MacKenzie, Alex; Brudno, Michael; Bulman, Dennis; Dyment, David; Majewski, Jacek; Jerome-Majewska, Loydie A.; Parboosingh, Jillian S.; Bernier, Francois P.

    2014-01-01

    Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro–costo–mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development. PMID:25047197

  14. Macroscopic hematuria caused by congenital portosystemic shunt and concomitant nutcracker syndrome.

    PubMed

    Lee, Sang Hyub; Lee, Dong-Gi

    2015-06-01

    Nutcracker syndrome (NCS) is an uncommon vascular abnormality that causes a variety of symptoms that range from asymptomatic microscopic hematuria to severe pelvic congestion. Congenital portosystemic shunt (CPSS) is an extremely rare anomaly that causes serious complications. Many cases of NCS and CPSS that have presented separately have been reported, but no cases of concomitant NCS and CPSS have been reported. We present a case of intermittent macroscopic hematuria in a patient with both NCS and CPSS. We diagnosed NCS on pressure gradient between the left renal vein (LRV) and the inferior vena cava. The presence of CPSS, which emerged from the LRV and connected to the extrahepatic portal vein, was confirmed on computed tomography. The interaction between NCS and CPSS resulted in mild intermittent macroscopic hematuria only, rather than the more common symptoms that occur when NCS or CPSS present separately. © 2015 Japan Pediatric Society.

  15. A mutation causing Alport syndrome with tardive hearing loss is common in the western United States

    SciT

    Barker, D.F.; Denison, J.C.; Atkin, C.L.

    1996-06-01

    Mutations in the COL4A5 gene, located at Xq22, cause Alport syndrome (AS), a nephritis characterized by progressive deterioration of the glomerular basement membrane and usually associated with progressive hearing loss. We have identified a novel mutation, L1649R, present in 9 of 121 independently ascertained families. Affected males shared the same haplotype of eight polymorphic markers tightly linked to COL4A5, indicating common ancestry. Genealogical studies place the birth of this ancestor >200 years ago. The L1649R mutation is a relatively common cause of Alport syndrome in the western United States, in part because of the rapid growth and migratory expansion ofmore » mid-nineteenth-century pioneer populations carrying the gene. L1649R affects a highly conserved residue in the NC1 domain, which is involved in key inter- and intramolecular interactions, but results in a relatively mild disease phenotype. Renal failure in an L1649R male typically occurs in the 4th or 5th decade and precedes the onset of significant hearing loss by {approximately}10 years. 45 refs., 5 figs.« less

  16. A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2.

    PubMed

    Isojima, Tsuyoshi; Doi, Koichiro; Mitsui, Jun; Oda, Yoichiro; Tokuhiro, Etsuro; Yasoda, Akihiro; Yorifuji, Tohru; Horikawa, Reiko; Yoshimura, Jun; Ishiura, Hiroyuki; Morishita, Shinichi; Tsuji, Shoji; Kitanaka, Sachiko

    2014-04-01

    Kenny-Caffey syndrome (KCS) is a rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form of KCS (KCS type 2 [KCS2]) is distinguished from the autosomal recessive form of KCS (KCS type 1 [KCS1]), which is caused by mutations of the tubulin-folding cofactor E (TBCE) gene, by the absence of mental retardation. In this study, we recruited four unrelated Japanese patients with typical sporadic KCS2, and performed exome sequencing in three patients and their parents to elucidate the molecular basis of KCS2. The possible candidate genes were explored by a de novo mutation detection method. A single gene, FAM111A (NM_001142519.1), was shared among three families. An identical missense mutation, R569H, was heterozygously detected in all three patients but not in the unaffected family members. This mutation was also found in an additional unrelated patient. These findings are in accordance with those of a recent independent report by a Swiss group that KCS2 is caused by a de novo mutation of FAM111A, and R569H is a hot spot mutation for KCS2. Although the function of FAM111A is not known, this study would provide evidence that FAM111A is a key molecule for normal bone development, height gain, and parathyroid hormone development and/or regulation. © 2014 American Society for Bone and Mineral Research.

  17. [Sepsis caused by Fusobacterium necrophorum (Lemierre syndrome): a rare complication of acute pharyngotonsilitis].

    PubMed

    Perović, Marta; Maretić, Tomislav; Begovac, Josip

    2006-12-01

    Lemierre syndrome is defined as an acute pharyngotonsillar infection that has spread into the lateral pharyngeal space causing thrombophlebitis of the internal jugular vein with consecutive metastatic emboli. The syndrome is most often caused by Fusobacterium (F.) necrophorum and usually involves young, previously healthy people. We present a healthy 20-year-old man who suddenly developed with high fever and sore throat followed by dyspnea, tachypnea and cough on the third day of illness. His condition worsened despite outpatient intramuscular penicillin therapy (1600 000 IU/day). He was admitted to Dr. Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, on the sixth day of his illness with clinical signs of sepsis. Chest radiograph showed bilateral multiple infiltrates. F. necrophorum was isolated from blood culture. Swelling of the neck was also observed on the fourteenth day of illness, however, thrombophlebitis of the jugular vein was not diagnosed on ultrasound examination. The patient was treated with clindamycin for five weeks and recovered completely.

  18. Mutations in the evolutionarily highly conserved KEOPS complex genes cause nephrotic syndrome with microcephaly

    PubMed Central

    Braun, Daniela A.; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A.; Schanze, Denny; Ashraf, Shazia; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I. Chiara; Sanchez-Ferras, Oraly; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E.; Pabst, Werner L.; Warejko, Jillian; Daga, Ankana; LeBerre, Tamara Basta; Matejas, Verena; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T.; Gipson, Patrick E.; Hsu, Chyong-Hsin; Kari, Jameela A.; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okasha; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth; Rump, Patrick; Schnur, Rhonda E.; Shiihara, Takashi; Sinha, Manish; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A.; Tsai, Wen-Hui; Tsai, Jeng-Daw; Vester, Udo; Viskochil, David H.; Vatanavicharn, Nithiwat; Waxler, Jessica L.; Wolf, Matthias T.F.; Wong, Sik-Nin; Poduri, Annapurna; Truglio, Gessica; Mane, Shrikant; Lifton, Richard P.; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Calleweart, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

    2018-01-01

    Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms. PMID:28805828

  19. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.

    PubMed

    Braun, Daniela A; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A; Schanze, Denny; Ashraf, Shazia; Ullmann, Jeremy F P; Hoogstraten, Charlotte A; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I Chiara; Sanchez-Ferras, Oraly; Hu, Jennifer F; Boschat, Anne-Claire; Sanquer, Sylvia; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E; Pabst, Werner L; Warejko, Jillian K; Daga, Ankana; Basta, Tamara; Matejas, Verena; Scharmann, Karin; Kienast, Sandra D; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T; Gaffney, Patrick M; Gipson, Patrick E; Hsu, Chyong-Hsin; Kari, Jameela A; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-Ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okashah; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Ozaltin, Fatih; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth R; Rump, Patrick; Schnur, Rhonda E; Shiihara, Takashi; Sinha, Manish D; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A; Tsai, Wen-Hui; Tsai, Jeng-Daw; Topaloglu, Rezan; Vester, Udo; Viskochil, David H; Vatanavicharn, Nithiwat; Waxler, Jessica L; Wierenga, Klaas J; Wolf, Matthias T F; Wong, Sik-Nin; Leidel, Sebastian A; Truglio, Gessica; Dedon, Peter C; Poduri, Annapurna; Mane, Shrikant; Lifton, Richard P; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Callewaert, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

    2017-10-01

    Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

  20. [Primary Neuroendocrine Carcinoma of Thymus Caused Cushing Syndrome: Surgical Treatment and Prognosis Analysis].

    PubMed

    Li, Li; Chen, Yeye; Li, Shanqing; Liu, Hongsheng; Huang, Cheng; Qin, Yingzhi

    2015-07-01

    Primary neuroendocrine carcinoma of thymus (pNECT) is a rare thymic neoplasm. Some pNECTs could produce an adrenocorticotropic hormone and cause Cushing syndrome (CS). The aim os this study is to discuss the diagnostic technique and surgical management of pNECT-caused CS and analyze prognosis factors to improve the clinical experience of the disease. The outcome of surgery and follow-up of 14 cases (eight males and six females) of pNECT-caused CS were retrospectively analyzed from November 1987 to June 2013. The median age of the patients was 29, and the median duration of the disease was four months (1 month-44 months). All cases exhibited clinical evidence for the diagnosis of CS, and thoracic computed tomography (CT) was used to detect thymic tumors. Surgical treatment significantly decreased the concentration of both serum cortisol and adrenocorticotropic hormone (P<0.01) but caused one death in the perioperative period. With multidisciplinary therapy, the median survival was 38 months. pNECT-caused CS is a rare disease with aggressive characteristics and unclear prognosis. Early diagnosis and therapy is a challenge for clinicians. Thoracic CT is important for disease location and preoperative evaluation and should be routinely applied to all CS patients to allow early surgery and improved prognosis.

  1. Impact of anaemia on mortality and its causes in elderly patients with acute coronary syndromes.

    PubMed

    Ariza-Solé, Albert; Formiga, Francesc; Salazar-Mendiguchía, Joel; Garay, Alberto; Lorente, Victòria; Sánchez-Salado, José C; Sánchez-Elvira, Guillermo; Gómez-Lara, Josep; Gómez-Hospital, Joan A; Cequier, Angel

    2015-06-01

    Prognostic impact of anaemia in the elderly with acute coronary syndromes has not been specifically analysed, and little information exists about causes of mortality in this setting. We prospectively included consecutive patients with acute coronary syndromes. Anaemia was defined as haemoglobin < 130 g/L in men, and < 120 g/L in women. Primary outcome was mid-term mortality and its causes. Analyses were performed by Cox regression method. We included 2128 patients, of whom 394 (18.6%) were aged 75 years or older. Anaemia was more common in the elderly (40.4% vs 19.5%, p <0.001). Mean follow-up was 386 days. Anaemia independently predicted overall mortality (HR 1.47, 95% CI 1.05-2.06), cardiac mortality (HR 1.76, 95% CI 1.06-2.94) and non-cardiac mortality (HR 1.59, 95% CI 1.03-2.45) in the overall cohort. In young patients the association between anaemia and mortality was significant only for non-cardiac causes. The association between anaemia and mortality was not significant in the elderly (HR 1.08, 95% CI 0.71-1.63, p 0.736). The impact of anaemia on cause specific of mortality seem to be different according to age subgroup. The association between anaemia and mortality was not observed in elderly patients from our series. Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  2. Domain analyses of Usher syndrome causing Clarin-1 and GPR98 protein models.

    PubMed

    Khan, Sehrish Haider; Javed, Muhammad Rizwan; Qasim, Muhammad; Shahzadi, Samar; Jalil, Asma; Rehman, Shahid Ur

    2014-01-01

    Usher syndrome is an autosomal recessive disorder that causes hearing loss, Retinitis Pigmentosa (RP) and vestibular dysfunction. It is clinically and genetically heterogeneous disorder which is clinically divided into three types i.e. type I, type II and type III. To date, there are about twelve loci and ten identified genes which are associated with Usher syndrome. A mutation in any of these genes e.g. CDH23, CLRN1, GPR98, MYO7A, PCDH15, USH1C, USH1G, USH2A and DFNB31 can result in Usher syndrome or non-syndromic deafness. These genes provide instructions for making proteins that play important roles in normal hearing, balance and vision. Studies have shown that protein structures of only seven genes have been determined experimentally and there are still three genes whose structures are unavailable. These genes are Clarin-1, GPR98 and Usherin. In the absence of an experimentally determined structure, homology modeling and threading often provide a useful 3D model of a protein. Therefore in the current study Clarin-1 and GPR98 proteins have been analyzed for signal peptide, domains and motifs. Clarin-1 protein was found to be without any signal peptide and consists of prokar lipoprotein domain. Clarin-1 is classified within claudin 2 super family and consists of twelve motifs. Whereas, GPR98 has a 29 amino acids long signal peptide and classified within GPCR family 2 having Concanavalin A-like lectin/glucanase superfamily. It was found to be consists of GPS and G protein receptor F2 domains and twenty nine motifs. Their 3D structures have been predicted using I-TASSER server. The model of Clarin-1 showed only α-helix but no beta sheets while model of GPR98 showed both α-helix and β sheets. The predicted structures were then evaluated and validated by MolProbity and Ramachandran plot. The evaluation of the predicted structures showed 78.9% residues of Clarin-1 and 78.9% residues of GPR98 within favored regions. The findings of present study has resulted in the

  3. Domain analyses of Usher syndrome causing Clarin-1 and GPR98 protein models

    PubMed Central

    Khan, Sehrish Haider; Javed, Muhammad Rizwan; Qasim, Muhammad; Shahzadi, Samar; Jalil, Asma; Rehman, Shahid ur

    2014-01-01

    Usher syndrome is an autosomal recessive disorder that causes hearing loss, Retinitis Pigmentosa (RP) and vestibular dysfunction. It is clinically and genetically heterogeneous disorder which is clinically divided into three types i.e. type I, type II and type III. To date, there are about twelve loci and ten identified genes which are associated with Usher syndrome. A mutation in any of these genes e.g. CDH23, CLRN1, GPR98, MYO7A, PCDH15, USH1C, USH1G, USH2A and DFNB31 can result in Usher syndrome or non-syndromic deafness. These genes provide instructions for making proteins that play important roles in normal hearing, balance and vision. Studies have shown that protein structures of only seven genes have been determined experimentally and there are still three genes whose structures are unavailable. These genes are Clarin-1, GPR98 and Usherin. In the absence of an experimentally determined structure, homology modeling and threading often provide a useful 3D model of a protein. Therefore in the current study Clarin-1 and GPR98 proteins have been analyzed for signal peptide, domains and motifs. Clarin-1 protein was found to be without any signal peptide and consists of prokar lipoprotein domain. Clarin-1 is classified within claudin 2 super family and consists of twelve motifs. Whereas, GPR98 has a 29 amino acids long signal peptide and classified within GPCR family 2 having Concanavalin A-like lectin/glucanase superfamily. It was found to be consists of GPS and G protein receptor F2 domains and twenty nine motifs. Their 3D structures have been predicted using I-TASSER server. The model of Clarin-1 showed only α-helix but no beta sheets while model of GPR98 showed both α-helix and β sheets. The predicted structures were then evaluated and validated by MolProbity and Ramachandran plot. The evaluation of the predicted structures showed 78.9% residues of Clarin-1 and 78.9% residues of GPR98 within favored regions. The findings of present study has resulted in the

  4. The pacemaker-twiddler's syndrome: an infrequent cause of pacemaker failure.

    PubMed

    Salahuddin, Mohammad; Cader, Fathima Aaysha; Nasrin, Sahela; Chowdhury, Mashhud Zia

    2016-01-20

    The pacemaker-twiddler's syndrome is an uncommon cause of pacemaker malfunction. It occurs due to unintentional or deliberate manipulation of the pacemaker pulse generator within its skin pocket by the patient. This causes coiling of the lead and its dislodgement, resulting in failure of ventricular pacing. More commonly reported among elderly females with impaired cognition, the phenomenon usually occurs in the first year following pacemaker implantation. Treatment involves repositioning of the dislodged leads and suture fixation of the lead and pulse generator within its pocket. An 87 year old Bangladeshi lady who underwent a single chamber ventricular pacemaker (VVI mode: i.e. ventricle paced, ventricle sensed, inhibitory mode) implantation with the indication of complete heart block, and presented to us again 7 weeks later, with syncopal attacks. She admitted to repeatedly manipulating the pacemaker generator in her left pectoral region. Physical examination revealed a heart rate of 42 beats/minute, blood pressure 140/80 mmHg and bilateral crackles on lung auscultation. She had no cognitive deficit. An immediate electrocardiogram showed complete heart block with pacemaker spikes and failure to capture. Chest X-ray showed coiled and retracted right ventricular lead and rotated pulse generator. An emergent temporary pace maker was set at a rate of 60 beats per minute. Subsequently, she underwent successful lead repositioning with strong counselling to avoid further twiddling. Twiddler's syndrome should be considered as a cause of pacemaker failure in elderly patients presenting with bradyarrythmias following pacemaker implantation. Chest X-ray and electrocardiograms are simple and easily-available first line investigations for its diagnosis. Lead repositioning is required, however proper patient education and counselling against further manipulation is paramount to long-term management.

  5. Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing's syndrome.

    PubMed

    Lacroix, A; Bolté, E; Tremblay, J; Dupré, J; Poitras, P; Fournier, H; Garon, J; Garrel, D; Bayard, F; Taillefer, R

    1992-10-01

    Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known. We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion. Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producting or aldosterone-producing adenomas responded to corticotropin but not to GIP. Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder.

  6. Short-Rib Polydactyly and Jeune Syndromes Are Caused by Mutations in WDR60

    PubMed Central

    McInerney-Leo, Aideen M.; Schmidts, Miriam; Cortés, Claudio R.; Leo, Paul J.; Gener, Blanca; Courtney, Andrew D.; Gardiner, Brooke; Harris, Jessica A.; Lu, Yeping; Marshall, Mhairi; Scambler, Peter J.; Beales, Philip L.; Brown, Matthew A.; Zankl, Andreas; Mitchison, Hannah M.; Duncan, Emma L.; Wicking, Carol

    2013-01-01

    Short-rib polydactyly syndromes (SRPS I–V) are a group of lethal congenital disorders characterized by shortening of the ribs and long bones, polydactyly, and a range of extraskeletal phenotypes. A number of other disorders in this grouping, including Jeune and Ellis-van Creveld syndromes, have an overlapping but generally milder phenotype. Collectively, these short-rib dysplasias (with or without polydactyly) share a common underlying defect in primary cilium function and form a subset of the ciliopathy disease spectrum. By using whole-exome capture and massive parallel sequencing of DNA from an affected Australian individual with SRPS type III, we detected two novel heterozygous mutations in WDR60, a relatively uncharacterized gene. These mutations segregated appropriately in the unaffected parents and another affected family member, confirming compound heterozygosity, and both were predicted to have a damaging effect on the protein. Analysis of an additional 54 skeletal ciliopathy exomes identified compound heterozygous mutations in WDR60 in a Spanish individual with Jeune syndrome of relatively mild presentation. Of note, these two families share one novel WDR60 missense mutation, although haplotype analysis suggested no shared ancestry. We further show that WDR60 localizes at the base of the primary cilium in wild-type human chondrocytes, and analysis of fibroblasts from affected individuals revealed a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme. These findings show that WDR60 mutations can cause skeletal ciliopathies and suggest a role for WDR60 in ciliogenesis. PMID:23910462

  7. Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60.

    PubMed

    McInerney-Leo, Aideen M; Schmidts, Miriam; Cortés, Claudio R; Leo, Paul J; Gener, Blanca; Courtney, Andrew D; Gardiner, Brooke; Harris, Jessica A; Lu, Yeping; Marshall, Mhairi; Scambler, Peter J; Beales, Philip L; Brown, Matthew A; Zankl, Andreas; Mitchison, Hannah M; Duncan, Emma L; Wicking, Carol

    2013-09-05

    Short-rib polydactyly syndromes (SRPS I-V) are a group of lethal congenital disorders characterized by shortening of the ribs and long bones, polydactyly, and a range of extraskeletal phenotypes. A number of other disorders in this grouping, including Jeune and Ellis-van Creveld syndromes, have an overlapping but generally milder phenotype. Collectively, these short-rib dysplasias (with or without polydactyly) share a common underlying defect in primary cilium function and form a subset of the ciliopathy disease spectrum. By using whole-exome capture and massive parallel sequencing of DNA from an affected Australian individual with SRPS type III, we detected two novel heterozygous mutations in WDR60, a relatively uncharacterized gene. These mutations segregated appropriately in the unaffected parents and another affected family member, confirming compound heterozygosity, and both were predicted to have a damaging effect on the protein. Analysis of an additional 54 skeletal ciliopathy exomes identified compound heterozygous mutations in WDR60 in a Spanish individual with Jeune syndrome of relatively mild presentation. Of note, these two families share one novel WDR60 missense mutation, although haplotype analysis suggested no shared ancestry. We further show that WDR60 localizes at the base of the primary cilium in wild-type human chondrocytes, and analysis of fibroblasts from affected individuals revealed a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme. These findings show that WDR60 mutations can cause skeletal ciliopathies and suggest a role for WDR60 in ciliogenesis. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  8. Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery.

    PubMed

    Fasshauer, Mathias; Lincke, Thomas; Witzigmann, Helmut; Kluge, Regine; Tannapfel, Andrea; Moche, Michael; Buchfelder, Michael; Petersenn, Stephan; Kratzsch, Juergen; Paschke, Ralf; Koch, Christian A

    2006-04-27

    ACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed. A 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled (111)In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results. This case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical locations may benefit from explorative

  9. Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery

    PubMed Central

    Fasshauer, Mathias; Lincke, Thomas; Witzigmann, Helmut; Kluge, Regine; Tannapfel, Andrea; Moche, Michael; Buchfelder, Michael; Petersenn, Stephan; Kratzsch, Juergen; Paschke, Ralf; Koch, Christian A

    2006-01-01

    Background ACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed. Case presentation A 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled 111In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results. Conclusion This case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical

  10. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.

    PubMed

    Ekvall, Sara; Sjörs, Kerstin; Jonzon, Anders; Vihinen, Mauno; Annerén, Göran; Bondeson, Marie-Louise

    2014-03-01

    Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present. © 2013 Wiley Periodicals, Inc.

  11. Association of metabolic syndrome and its components with all-cause and cardiovascular mortality in the elderly

    PubMed Central

    Ju, Sang-Yhun; Lee, June-Young; Kim, Do-Hoon

    2017-01-01

    Abstract There is increasing evidence regarding the relationship between metabolic syndrome and mortality. However, previous research examining metabolic syndrome and mortality in older populations has produced mixed results. In addition, there is a clear need to identify and manage individual components of metabolic syndrome to decrease cardiovascular disease (CVD) mortality. In this meta-analysis, we searched the MEDLINE databases using PubMed, Cochrane Library, and EMBASE databases. Based on 20 prospective cohort studies, metabolic syndrome was associated with a higher risk of all-cause mortality [relative risk (RR), 1.23; 95% confidence interval (CI), 1.15–1.32; I2 = 55.9%] and CVD mortality (RR, 1.24; 95% CI, 1.11–1.39; I2 = 58.1%). The risk estimates of all-cause mortality for single components of metabolic syndrome were significant for higher values of waist circumference or body mass index (RR, 0.94; 95% CI, 0.88–1.00), higher values of blood glucose (RR, 1.19; 95% CI, 1.05–1.34), and lower values of high-density lipoprotein (HDL) cholesterol (RR, 1.11; 95% CI, 1.02–1.21). In the elderly population, metabolic syndrome was associated with an increased risk of all-cause and CVD mortality. Among the individual components of metabolic syndrome, increased blood glucose and HDL cholesterol levels were significantly associated with increased mortality. However, older obese or overweight individuals may have a decreased mortality risk. Thus, the findings of the current meta-analysis raise questions about the utility of the definition of metabolic syndrome in predicting all-cause mortality and CVD mortality in the elderly population. PMID:29137039

  12. [Invasive infection caused Streptococcus group A and streptococcal toxic shock syndrome].

    PubMed

    Danilova, T A

    2001-01-01

    Modern data on the etiology and pathogenesis of invasive streptococcal infection and the syndrome of streptococcal toxic shock are presented. In the course of the last 10-15 years essential changes in the system of interaction of group A streptococci and the macroorganism have been noted. The growth of morbidity in severe invasive forms of streptococcal infection with different clinical manifestations, including the syndrome of toxic shock, is observed. Most often this disease develops in elderly people, making up a group of risk, but sometimes affects healthy young people. Different pathogenicity factors of streptococci, capable of inducing the development of infection, are analyzed. Special attention is given to superantigens: pyrogenic toxins and M-protein. The suggestion that the development of the disease is seemingly linked with the state of specific protective immunity is substantiated. In spite of achievements in the field of the microbiology and immunology of group A streptococci, the causes of the appearance and development of invasive streptococcal infection have not yet been determined.

  13. Current status of prenatal diagnosis in Cuba: causes of low prevalence of Down syndrome.

    PubMed

    Méndez-Rosado, L A; Hechavarría-Estenoz, D; de la Torre, M E; Pimentel-Benitez, H; Hernández-Gil, J; Perez, B; Barrios-Martínez, A; Morales-Rodriguez, E; Soriano-Torres, M; Garcia, M; Suarez-Mayedo, U; Cedeño-Aparicio, N; Blanco, I; Díaz-Véliz, P; Vidal-Hernández, B; Mitjans-Torres, M; Miñoso, S; Alvarez-Espinosa, D; Reyes-Hernández, E; Angulo-Cebada, E; Torres-Palacios, M; Lozano-Lezcano, L; Lima-Rodriguez, U; Mayeta, M; Noblet, M; Benítez, Y; Lardoeyt-Ferrer, R; Yosela-Martin, S; Carbonell, P; Pérez-Ramos, M; de León, N; Perez, M; Carbonell, J

    2014-11-01

    To analyze trends in cytogenetic prenatal diagnosis in Cuba and to analyze possible causes leading to a low Down syndrome prevalence in a country where the triple test is not available. An analysis of the Cuban program in prenatal cytogenetic diagnosis from 1984 to 2012 was conducted. Results are described, with particular emphasis on indications, abnormal results, types of invasive procedures, and terminations of pregnancy. Cytogenetic prenatal diagnostic analyses (n = 75,095) were conducted; maternal age was the indication for 77.9% of the amniocenteses and chorionic villus samplings. The detection rate of chromosomally abnormal pregnancies was 2.3% for maternal age and increased to 8-9% for other indications. When a chromosomal abnormality was identified, 88.5% terminated the pregnancy. In 2002, the live birth prevalence of Down syndrome was 8.4 per 10,000 live births, and in 2012, 7 per 10,000. Prenatal diagnosis in Cuba has contributed to a significant reduction in chromosomal aberrations. The impact increased because of the demographic trends of the population, the high index of terminations of pregnancy, and the establishment of a network of cytogenetic laboratories throughout Cuba. © 2014 John Wiley & Sons, Ltd.

  14. Congenital extrahepatic portosystemic shunt: an underdiagnosed but treatable cause of hepatopulmonary syndrome.

    PubMed

    Fu, Lijun; Wang, Qian; Wu, Jinjin; Guo, Ying; Huang, Meirong; Liu, Tingliang; Chen, Qimin; Li, Fen

    2016-02-01

    Congenital extrahepatic portosystemic shunt (CEPS) is a rare malformation of the mesenteric vasculature, which may lead to severe complications. In this report, we describe a case series of three children with type II CEPS (presenting as hypoxemia) and hepatopulmonary syndrome (HPS). The first patient was a 4-year-old male who did not receive any specific treatment and subsequently died of brain abscess 5 years after the diagnosis. The second patient was a 10-year-old female with a 5-year history of cyanosis and dyspnea on exertion. She had partial regression of hypoxemia and improved exercise tolerance at 8 months after a surgical shunt closure. The third patient was a 4-year-old male with a 3-year history of cyanosis and decreased exercise tolerance. He had full regression of hypoxemia at 3 months after a transcatheter shunt closure. These results indicate that CEPS may present in children with unexplained hypoxemia, which may lead to devastating clinical consequences. Closure of portosystemic shunts may result in resolution of HPS in type II CEPS and the length of period for resolution varies depending on the severity of HPS. Congenital extrahepatic portosystemic shunt (CEPS) is a rare cause of hepatopulmonary syndrome (HPS). There have been few reports in the literature about the management and outcome of HPS in children with CEPS. CEPS may present in children with unexplained hypoxemia, which may lead to devastating clinical consequences. Closure of portosystemic shunts may result in resolution of HPS in type II CEPS.

  15. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause Microcephaly-Capillary Malformation syndrome

    PubMed Central

    McDonell, Laura M.; Mirzaa, Ghayda M.; Alcantara, Diana; Schwartzentruber, Jeremy; Carter, Melissa T.; Lee, Leo J.; Clericuzio, Carol L.; Graham, John M.; Morris-Rosendahl, Deborah J.; Polster, Tilman; Acsadi, Gyula; Townshend, Sharron; Williams, Simon; Halbert, Anne; Isidor, Bertrand; Smyser, Christopher D.; Paciorkowski, Alex R.; Willing, Marcia; Woulfe, John; Das, Soma; Beaulieu, Chandree L.; Marcadier, Janet; Geraghty, Michael T.; Frey, Brendan J.; Majewski, Jacek; Bulman, Dennis E.; Dobyns, William B.; O’Driscoll, Mark; Boycott, Kym M.

    2014-01-01

    Microcephaly-capillary malformation (MIC-CAP) syndrome exhibits severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We employed whole-exome sequencing of five patients with MIC-CAP syndrome and identified novel recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein)/AMSH (Associated Molecule with the SH3 domain of STAM), that plays a key role in cell surface receptor-mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is significant considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis, implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP. PMID:23542699

  16. Stent Implantation for Superior Vena Cava Syndrome of Malignant Cause.

    PubMed

    Büstgens, Felix A; Loose, Reinhard; Ficker, Joachim H; Wucherer, Michael; Uder, Michael; Adamus, Ralf

    2017-05-01

    Purpose  The purpose of this paper is the retrospective analysis of endovascular therapy for the treatment of superior vena cava syndrome (SVCS) of malignant cause. This study focuses on the effectiveness of the therapy regarding the duration of remission, symptom control and practicability. Materials and Methods  From January 2003 to November 2012, therapeutic implantation of one or more stents was performed in 141 patients suffering from SVCS. The medical history was retrospectively researched using digitalized patient files. If those were incomplete, secondary research was conducted using the cancer registry of the General Hospital Nuremberg, the cancer registry of the tumor center at Friedrich-Alexander-University Erlangen-Nuremberg (FAU) or information given by physicians in private practice. This data was collected using Microsoft Office Excel ® and statistically analyzed using IBM SPSS Statistics 22 ® . Results  168 stents were implanted in 141 patients (median age: 64.6 years; range: 36 - 84), 86 being male and 55 being female. In 121 patients, SVCS was caused by lung cancer (85.8 %), in 9 patients by mediastinal metastasis of an extrathoracic carcinoma (6.4 %), in 3 patients by mesothelioma of the pleura (2.1 %) and in 1 patient by Hodgkin's disease (0.7 %). There was no histological diagnosis in 7 cases (4.9 %). The primary intervention was successful in 138 patients (97.9 %). Immediate thrombosis in the stent occurred in the remaining 3 cases. Recurrence of SVCS was observed in 22 patients (15.6 %), including 5 early and 17 late occlusions. Stent dislocation or breakage was not observed. As expected, the survival after implantation was poor. The median survival was 101 days, and the median occlusion-free survival was 80 days. Conclusion  The symptomatic therapy of SVCS with endovascular stents is effective and safe. Despite effective symptom control and a low rate of recurrence, the patients' prognosis is poor. Key

  17. Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations

    PubMed Central

    Jaureguiberry, Graciana; De la Dure-Molla, Muriel; Parry, David; Quentric, Mickael; Himmerkus, Nina; Koike, Toshiyasu; Poulter, James; Klootwijk, Enriko; Robinette, Steven L.; Howie, Alexander J.; Patel, Vaksha; Figueres, Marie-Lucile; Stanescu, Horia C.; Issler, Naomi; Nicholson, Jeremy K.; Bockenhauer, Detlef; Laing, Christopher; Walsh, Stephen B.; McCredie, David A.; Povey, Sue; Asselin, Audrey; Picard, Arnaud; Coulomb, Aurore; Medlar, Alan J.; Bailleul-Forestier, Isabelle; Verloes, Alain; Le Caignec, Cedric; Roussey, Gwenaelle; Guiol, Julien; Isidor, Bertrand; Logan, Clare; Shore, Roger; Johnson, Colin; Inglehearn, Christopher; Al-Bahlani, Suhaila; Schmittbuhl, Matthieu; Clauss, François; Huckert, Mathilde; Laugel, Virginie; Ginglinger, Emmanuelle; Pajarola, Sandra; Spartà, Giuseppina; Bartholdi, Deborah; Rauch, Anita; Addor, Marie-Claude; Yamaguti, Paulo M.; Safatle, Heloisa P.; Acevedo, Ana Carolina; Martelli-Júnior, Hercílio; dos Santos Netos, Pedro E.; Coletta, Ricardo D.; Gruessel, Sandra; Sandmann, Carolin; Ruehmann, Denise; Langman, Craig B.; Scheinman, Steven J.; Ozdemir-Ozenen, Didem; Hart, Thomas C.; Hart, P. Suzanne; Neugebauer, Ute; Schlatter, Eberhard; Houillier, Pascal; Gahl, William A.; Vikkula, Miikka; Bloch-Zupan, Agnès; Bleich, Markus; Kitagawa, Hiroshi; Unwin, Robert J.; Mighell, Alan; Berdal, Ariane; Kleta, Robert

    2013-01-01

    Background/Aims Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis. PMID:23434854

  18. Lemierre's Syndrome – A rare cause of disseminated sepsis requiring multi-organ support

    PubMed Central

    Misselbrook, Katie

    2017-01-01

    Lemierre's syndrome is a rare complication of acute pharyngitis characterised by septicaemia with infective thrombophlebitis of the internal jugular vein, most commonly due to Fusobacterium necrophorum. It characteristically affects healthy young adults causing persistent pyrexia and systemic sepsis presenting several days after an initial pharyngitis. Septic emboli seed via the bloodstream to distant sites including the lung, joints, skin, liver, spleen and brain. Prolonged antimicrobial therapy is required and admission to intensive care common. This once rare condition is increasing in incidence but awareness amongst clinicians is low. We present a classic case in a young man who developed multi-organ failure requiring intensive care support and describe the epidemiology, pathophysiology, microbiology, clinical features and management of the disease. PMID:29123565

  19. A PLK4 mutation causing azoospermia in a man with Sertoli cell-only syndrome.

    PubMed

    Miyamoto, T; Bando, Y; Koh, E; Tsujimura, A; Miyagawa, Y; Iijima, M; Namiki, M; Shiina, M; Ogata, K; Matsumoto, N; Sengoku, K

    2016-01-01

    About 15% of couples wishing to have children are infertile; approximately half these cases involve a male factor. Polo-like kinase 4 (PLK-4) is a member of the polo protein family and a key regulator of centriole duplication. Male mice with a point mutation in the Plk4 gene show azoospermia associated with germ cell loss. Mutational analysis of 81 patients with azoospermia and Sertoli cell-only syndrome (SCOS) identified one man with a heterozygous 13-bp deletion in the Ser/Thr kinase domain of PLK4. Division of centrioles occurred in wild-type PLK4-transfected cells, but was hampered in PLK-4-mutant transfectants, which also showed abnormal nuclei. Thus, this PLK4 mutation might be a cause of human SCOS and nonobstructive azoospermia. © 2015 American Society of Andrology and European Academy of Andrology.

  20. Cervical spondylotic myelopathy caused by violent motor tics in a child with Tourette syndrome.

    PubMed

    Ko, Da-Young; Kim, Seung-Ki; Chae, Jong-Hee; Wang, Kyu-Chang; Phi, Ji Hoon

    2013-02-01

    We report a case of a 9-year-old boy with Tourette syndrome (TS) who developed progressive quadriparesis that was more severe in the upper extremities. He had experienced frequent and violent motor tics consisting of hyperflexion and hyperextension for years. Magnetic resonance imaging (MRI) revealed a focal high-signal intensity cord lesion and adjacent cervical spondylotic changes. Initially, the patient was observed for several months because of diagnostic uncertainty; his neurological status had improved and later worsened again. Anterior cervical discectomy of C3-4 and fusion immediately followed by posterior fixation were performed. After surgery, the neck collar was applied for 6 months. His neurological signs and symptoms improved dramatically. TS with violent neck motion may cause cervical spondylotic myelopathy at an early age. The optimal management is still unclear and attempts to control tics should be paramount. Circumferential fusion with neck bracing represents a viable treatment option.

  1. Extreme sensitivity to ultraviolet light in the fungal pathogen causing white-nose syndrome of bats.

    PubMed

    Palmer, Jonathan M; Drees, Kevin P; Foster, Jeffrey T; Lindner, Daniel L

    2018-01-02

    Bat white-nose syndrome (WNS), caused by the fungal pathogen Pseudogymnoascus destructans, has decimated North American hibernating bats since its emergence in 2006. Here, we utilize comparative genomics to examine the evolutionary history of this pathogen in comparison to six closely related nonpathogenic species. P. destructans displays a large reduction in carbohydrate-utilizing enzymes (CAZymes) and in the predicted secretome (~50%), and an increase in lineage-specific genes. The pathogen has lost a key enzyme, UVE1, in the alternate excision repair (AER) pathway, which is known to contribute to repair of DNA lesions induced by ultraviolet (UV) light. Consistent with a nonfunctional AER pathway, P. destructans is extremely sensitive to UV light, as well as the DNA alkylating agent methyl methanesulfonate (MMS). The differential susceptibility of P. destructans to UV light in comparison to other hibernacula-inhabiting fungi represents a potential "Achilles' heel" of P. destructans that might be exploited for treatment of bats with WNS.

  2. Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

    PubMed

    Le Guen, Tangui; Jullien, Laurent; Touzot, Fabien; Schertzer, Michael; Gaillard, Laetitia; Perderiset, Mylène; Carpentier, Wassila; Nitschke, Patrick; Picard, Capucine; Couillault, Gérard; Soulier, Jean; Fischer, Alain; Callebaut, Isabelle; Jabado, Nada; Londono-Vallejo, Arturo; de Villartay, Jean-Pierre; Revy, Patrick

    2013-08-15

    Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

  3. Insulin autoimmune syndrome caused by an adhesive skin patch containing loxoprofen-sodium.

    PubMed

    Okazaki-Sakai, Satoko; Yoshimoto, Sachiko; Yagi, Kunimasa; Wakasugi, Takanobu; Takeda, Yoshiyu; Yamagishi, Masakazu

    2013-01-01

    A 62-year-old woman complained of repeated hypoglycemic events. A 75 g oral glucose tolerance test (75 gOGTT) showed a marked increase in the plasma insulin level and impaired glucose tolerance. The patient exhibited a high titer of plasma anti-insulin autoantibodies. Her diagnosis was insulin autoimmune syndrome (IAS). Following the cessation of loxoprofen-sodium (LOXs), she experienced no further hypoglycemic episodes. However, the hypoglycemic attacks recurred following the accidental readministration of LOXs in an adhesive skin patch. Considering the changes in the titer of anti-insulin autoantibodies, the repeated 75 gOGTT and the repeated Scatchard analysis, we determined LOXs to be the cause of the IAS and evaluated the characteristics of the autoantibodies.

  4. Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation.

    PubMed

    Bogdanova-Mihaylova, Petya; Alexander, Michael D; Murphy, Raymond P J; Murphy, Sinéad M

    2017-09-01

    Waardenburg syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes. © 2017 Peripheral Nerve Society.

  5. Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome.

    PubMed

    Baertling, Fabian; Sánchez-Caballero, Laura; Timal, Sharita; van den Brand, Mariël Am; Ngu, Lock Hock; Distelmaier, Felix; Rodenburg, Richard Jt; Nijtmans, Leo Gj

    2017-03-01

    NDUFAF3 is an assembly factor of mitochondrial respiratory chain complex I. Variants in NDUFAF3 have been identified as a cause of severe multisystem mitochondrial disease. In a patient presenting with Leigh syndrome, which has hitherto not been described as a clinical feature of NDUFAF3 deficiency, we identified a novel homozygous variant and confirmed its pathogenicity in patient fibroblasts studies. Furthermore, we present an analysis of complex I assembly routes representative of each functional module and, thereby, link NDUFAF3 to a specific step in complex I assembly. Therefore, our report expands the phenotype of NDUFAF3 deficiency and further characterizes the role of NDUFAF3 in complex I biogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Guillain-Barre syndrome caused by hepatitis E infection: case report and literature review.

    PubMed

    Zheng, Xiaoqin; Yu, Liang; Xu, Qiaomai; Gu, Silan; Tang, Lingling

    2018-01-23

    Hepatitis E infection is a global disorder that causes substantial morbidity. Numerous neurologic illnesses, including Guillain-Barre syndrome (GBS), have occurred in patients with hepatitis E virus (HEV) infection. We report a 58 year-old non-immunocompromised man who presented with progressive muscle weakness in all extremities during an episode of acute HEV infection, which was confirmed by measuring the anti-HEV IgM antibodies in the serum. Both cerebrospinal fluid examination and electrophysiological study were in agreement with the diagnosis of HEV-associated GBS. Following the treatment with intravenous immunoglobulin, the patient's neurological condition improved rapidly. HEV infection should be strongly considered in patients with neurological symptoms, especially those with elevated levels of liver enzymes.

  7. A rare cause of Cushing's syndrome: an ACTH-secreting phaeochromocytoma.

    PubMed

    Folkestad, Lars; Andersen, Marianne Skovsager; Nielsen, Anne Lerberg; Glintborg, Dorte

    2014-10-08

    Excess glucocorticoid levels cause Cushing's syndrome (CS) and may be due to pituitary, adrenal or ectopic tumours. Adrenocorticotropic hormone (ACTH) levels are useful in identifying adrenal tumours. In rare cases, ACTH-producing phaeochromocytomas are the cause of CS. We present two cases of ACTH-secreting phaeochromocytoma as the underlying cause of CS. In both cases, female patients presented with the classical clinical signs of CS and an adrenal mass. High ACTH levels raised the suspicion of an ACTH-secreting phaeochromocytoma. The diagnosis was confirmed by urinary catecholamine levels and positive fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) CT (Case 1) and fluorodeoxyglucose PET-CT (Case 2). Both patients were treated with an α-blocker prior to surgical intervention. The two cases underline the importance of thorough diagnostic workup in patients with CS. An ACTH-secreting phaeochromocytoma should be checked for in patients with an adrenal mass and elevated ACTH levels. 2014 BMJ Publishing Group Ltd.

  8. A rare cause of Cushing's syndrome: an ACTH-secreting phaeochromocytoma

    PubMed Central

    Folkestad, Lars; Andersen, Marianne Skovsager; Nielsen, Anne Lerberg; Glintborg, Dorte

    2014-01-01

    Excess glucocorticoid levels cause Cushing's syndrome (CS) and may be due to pituitary, adrenal or ectopic tumours. Adrenocorticotropic hormone (ACTH) levels are useful in identifying adrenal tumours. In rare cases, ACTH-producing phaeochromocytomas are the cause of CS. We present two cases of ACTH-secreting phaeochromocytoma as the underlying cause of CS. In both cases, female patients presented with the classical clinical signs of CS and an adrenal mass. High ACTH levels raised the suspicion of an ACTH-secreting phaeochromocytoma. The diagnosis was confirmed by urinary catecholamine levels and positive fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) CT (Case 1) and fluorodeoxyglucose PET-CT (Case 2). Both patients were treated with an α-blocker prior to surgical intervention. The two cases underline the importance of thorough diagnostic workup in patients with CS. An ACTH-secreting phaeochromocytoma should be checked for in patients with an adrenal mass and elevated ACTH levels. PMID:25297883

  9. Obstructive sleep apnea syndrome as a novel cause for Ménière's disease.

    PubMed

    Nakayama, Meiho; Kabaya, Kayoko

    2013-10-01

    Several recent reports have described the relation between sleep disorders and inner ear function. There are also many reports that insomnia is observed in Ménière's patients. However, the possibility that obstructive sleep apnea syndrome (OSAS) might affect Ménière's disease or other neurotological consequences was not noticed, until studies using polysomnography for these patients. OSAS may cause not only vestibular but also auditory dysfunction. Several reports suggest that insufficient supply of blood via the vertebral basilar artery, which supplies the inner ear, may cause hydropic distension of the endolymphatic system and lead to Ménière's disease. However, few people noticed that in OSAS this insufficient supply might be exacerbated in the night while patients are sleeping. Even more, we should note that Ménière's patients may not only suffer from insomnia, but also that the impaired sleep might be caused by OSAS. Physicians routinely prescribe benzodiazepines or other drugs that have hypnotic, muscle relaxing, antianxiety, and anticonvulsant properties for insomnia, but these properties may have the effect of aggravating OSAS symptoms. Continuous positive airway pressure (CPAP) is an effective therapy used worldwide for the treatment of OSAS. CPAP or surgeries for OSAS may also be useful as one aspect of treatment for Ménière's disease patients with OSAS.

  10. Risk factors for automobile accidents caused by falling asleep while driving in obstructive sleep apnea syndrome.

    PubMed

    Arita, Aki; Sasanabe, Ryujiro; Hasegawa, Rika; Nomura, Atsuhiko; Hori, Reiko; Mano, Mamiko; Konishi, Noriyuki; Shiomi, Toshiaki

    2015-12-01

    We examined the risk factors for automobile accidents caused by falling asleep while driving in subjects with obstructive sleep apnea syndrome (OSAS). We asked licensed drivers with history of snoring and excessive daytime sleepiness who had undergone polysomnography (PSG) at the Department of Sleep Medicine/Sleep Disorders Center at Aichi Medical University Hospital to complete the questionnaires on accidents caused by falling asleep while driving. As a subjective measure of sleepiness, we used the Epworth sleepiness scale (ESS). Based on PSG results, 2387 subjects diagnosed with OSAS were divided into three groups according to apnea-hypopnea index (AHI): mild-to-moderate (5 ≤ AHI < 30), severe (30 ≤ AHI < 60), and very severe (AHI ≥ 60). We performed univariate and multivariate logistic regression on variables that might explain falling asleep at the wheel. We compared results between each group and simple snorers (394 subjects with AHI < 5) and found the group with very severe OSAS reported significantly higher rates of driving when drowsy and having accidents in the past 5 years due to falling asleep. Our multivariate analysis suggests that scores on the ESS and patient-reported frequency of feeling drowsy while regular driving and working are related to automobile accidents caused by falling asleep while driving.

  11. Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families†

    PubMed Central

    Chang, Wendy; Winder, Thomas L.; LeDuc, Charles A.; Simpson, Lynn L.; Millar, William S.; Dungan, Jeffrey; Ginsberg, Norman; Plaga, Stacey; Moore, Steven A.; Chung, Wendy K.

    2009-01-01

    Objective Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (α-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS. Method We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis. Results We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults. Conclusion These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population. PMID:19266496

  12. Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.

    PubMed

    Chang, Wendy; Winder, Thomas L; LeDuc, Charles A; Simpson, Lynn L; Millar, William S; Dungan, Jeffrey; Ginsberg, Norman; Plaga, Stacey; Moore, Steven A; Chung, Wendy K

    2009-06-01

    Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS. We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis. We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults. These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population. Copyright (c) 2009 John Wiley & Sons, Ltd.

  13. A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl.

    PubMed

    Yuge, Kotaro; Iwama, Kazuhiro; Yonee, Chihiro; Matsufuji, Mayumi; Sano, Nozomi; Saikusa, Tomoko; Yae, Yukako; Yamashita, Yushiro; Mizuguchi, Takeshi; Matsumoto, Naomichi; Matsuishi, Toyojiro

    2018-06-01

    Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3 years of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  14. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

    PubMed Central

    Nelson-Williams, Carol; Stiegler, Amy L; Loring, Erin; Choi, Murim; Overton, John; Meffre, Eric; Khokha, Mustafa K; Huttner, Anita J; West, Brian; Podoltsev, Nikolai A; Boggon, Titus J; Kazmierczak, Barbara I; Lifton, Richard P

    2014-01-01

    Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs), whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multi-protein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever, and inflammatory cell death (pyroptosis)1,2. Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features3. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal/near-fatal episodes of autoinflammation caused by a de novo gain-of-function mutation (p.V341A) in the HD1 domain of NLRC4 that co-segregates with disease. Mutant NLRC4 causes constitutive Interleukin-1 family cytokine production and macrophage cell death. Infected patient macrophages are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings describe and reveal the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. PMID:25217960

  15. Activating mutations affecting the Dbl homology domain of SOS2 cause Noonan syndrome

    PubMed Central

    Cordeddu, Viviana; Yin, Jiani C.; Gunnarsson, Cecilia; Virtanen, Carl; Drunat, Séverine; Lepri, Francesca; De Luca, Alessandro; Rossi, Cesare; Ciolfi, Andrea; Pugh, Trevor J.; Bruselles, Alessandro; Priest, James R.; Pennacchio, Len A.; Lu, Zhibin; Danesh, Arnavaz; Quevedo, Rene; Hamid, Alaa; Martinelli, Simone; Pantaleoni, Francesca; Gnazzo, Maria; Daniele, Paola; Lissewski, Christina; Bocchinfuso, Gianfranco; Stella, Lorenzo; Odent, Sylvie; Philip, Nicole; Faivre, Laurence; Vlckova, Marketa; Seemanova, Eva; Digilio, Cristina; Zenker, Martin; Zampino, Giuseppe; Verloes, Alain; Dallapiccola, Bruno; Roberts, Amy E.; Cavé, Hélène; Gelb, Bruce D.; Neel, Benjamin G.; Tartaglia, Marco

    2015-01-01

    The RASopathies constitute a family of autosomal dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering son of sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its auto-inhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the Dbl homology domain. PMID:26173643

  16. Recent Advances in Cerebellar Ischemic Stroke Syndromes Causing Vertigo and Hearing Loss.

    PubMed

    Kim, Hyun-Ah; Yi, Hyon-Ah; Lee, Hyung

    2016-12-01

    Cerebellar ischemic stroke is one of the common causes of vascular vertigo. It usually accompanies other neurological symptoms or signs, but a small infarct in the cerebellum can present with vertigo without other localizing symptoms. Approximately 11 % of the patients with isolated cerebellar infarction simulated acute peripheral vestibulopathy, and most patients had an infarct in the territory of the medial branch of the posterior inferior cerebellar artery (PICA). A head impulse test can differentiate acute isolated vertigo associated with PICA territory cerebellar infarction from more benign disorders involving the inner ear. Acute hearing loss (AHL) of a vascular cause is mostly associated with cerebellar infarction in the territory of the anterior inferior cerebellar artery (AICA), but PICA territory cerebellar infarction rarely causes AHL. To date, at least eight subgroups of AICA territory infarction have been identified according to the pattern of neurotological presentations, among which the most common pattern of audiovestibular dysfunction is the combined loss of auditory and vestibular functions. Sometimes acute isolated audiovestibular loss can be the initial symptom of impending posterior circulation ischemic stroke (particularly within the territory of the AICA). Audiovestibular loss from cerebellar infarction has a good long-term outcome than previously thought. Approximately half of patients with superior cerebellar artery territory (SCA) cerebellar infarction experienced true vertigo, suggesting that the vertigo and nystagmus in the SCA territory cerebellar infarctions are more common than previously thought. In this article, recent findings on clinical features of vertigo and hearing loss from cerebellar ischemic stroke syndrome are summarized.

  17. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

    PubMed

    Burrage, Lindsay C; Charng, Wu-Lin; Eldomery, Mohammad K; Willer, Jason R; Davis, Erica E; Lugtenberg, Dorien; Zhu, Wenmiao; Leduc, Magalie S; Akdemir, Zeynep C; Azamian, Mahshid; Zapata, Gladys; Hernandez, Patricia P; Schoots, Jeroen; de Munnik, Sonja A; Roepman, Ronald; Pearring, Jillian N; Jhangiani, Shalini; Katsanis, Nicholas; Vissers, Lisenka E L M; Brunner, Han G; Beaudet, Arthur L; Rosenfeld, Jill A; Muzny, Donna M; Gibbs, Richard A; Eng, Christine M; Xia, Fan; Lalani, Seema R; Lupski, James R; Bongers, Ernie M H F; Yang, Yaping

    2015-12-03

    Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  18. Does the Genetic Cause of Prader-Willi Syndrome Explain the Highly Variable Phenotype?

    PubMed

    Dobrescu, Andreea-Iulia; Chirita-Emandi, Adela; Andreescu, Nicoleta; Farcas, Simona; Puiu, Maria

    2016-09-01

    Prader-Willi syndrome (PWS) is characterized by extensive clinical and genetic variability caused by lack of expression of imprinted genes of the chromosomal region 15q11.2-q13. The genotye-phenotype correlation has not been yet fully elucidated. To analyze these correlations in order to determine the role of specifi c geneic alterations in the development of clinical symptoms in PWS. We retrospectively analyzed data routinely collected as part of the clinical care of 52 patients with clinical suspicion of PWS. FISH test was performed in all patients; in case of negative results, methylation test was performed. PWS was confi rmed in 35 patients that were divided in two groups according to the genetic cause of PWS: group A-21 patients with 15q11-q13 region deletion, mean age at evaluation 8.1 years (SD= 5.6) and mean of clinical score 9.4 ± 1.8; group B-14 patients with positive methylation test, with mean age at evaluation 6.7 years (SD= 4.6) and mean of clinical score 10.1 ± 1.9. Facial dysmorphism and neonatal hypotonia were present in all evaluated patients; while, higher frequency of major and minor PWS criteria were noted in the group A. Onset of hyperphagia, was around the age of 2 years in most patients, however one patient from group B had normal eating behavior and normal weight beyond age 5 years. In our study, the various genotypes did not seem to explain the diff erence in phenotype in PWS patients. We found a delayed time until diagnosis in these patients, although all had neonatal hypotonia and other suggestive phenotypic features, underlining once more the need for increased awareness of this syndrome, as well as easier accessibility to genetic counseling.

  19. Structural basis of Bloom syndrome (BS) causing mutations in the BLM helicase domain.

    PubMed Central

    Rong, S. B.; Väliaho, J.; Vihinen, M.

    2000-01-01

    BACKGROUND: Bloom syndrome (BS) is characterized by mutations within the BLM gene. The Bloom syndrome protein (BLM) has similarity to the RecQ subfamily of DNA helicases, which contain seven conserved helicase domains and share significant sequence and structural similarity with the Rep and PcrA DNA helicases. We modeled the three-dimensional structure of the BLM helicase domain to analyze the structural basis of BS-causing mutations. MATERIALS AND METHODS: The sequence alignment was performed for RecQ DNA helicases and Rep and PcrA helicases. The crystal structure of PcrA helicase (PDB entry 3PJR) was used as the template for modeling the BLM helicase domain. The model was used to infer the function of BLM and to analyze the effect of the mutations. RESULTS: The structural model with good stereochemistry of the BLM helicase domain contains two subdomains, 1A and 2A. The electrostatic potential of the model is highly negative over most of the surface, except for the cleft between subdomains 1A and 2A which is similar to the template protein. The ATP-binding site is located inside the model between subdomains 1A and 2A; whereas, the DNA-binding region is situated at the surface cleft, with positive potential between 1A and 2A. CONCLUSIONS: The three-dimensional structure of the BLM helicase domain was modeled and applied to interpret BS-causing mutations. The mutation I841T is likely to weaken DNA binding, while the mutations C891R, C901Y, and Q672R presumably disturb the ATP binding. In addition, other critical positions are discussed. PMID:10965492

  20. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome

    PubMed Central

    Burrage, Lindsay C.; Charng, Wu-Lin; Eldomery, Mohammad K.; Willer, Jason R.; Davis, Erica E.; Lugtenberg, Dorien; Zhu, Wenmiao; Leduc, Magalie S.; Akdemir, Zeynep C.; Azamian, Mahshid; Zapata, Gladys; Hernandez, Patricia P.; Schoots, Jeroen; de Munnik, Sonja A.; Roepman, Ronald; Pearring, Jillian N.; Jhangiani, Shalini; Katsanis, Nicholas; Vissers, Lisenka E.L.M.; Brunner, Han G.; Beaudet, Arthur L.; Rosenfeld, Jill A.; Muzny, Donna M.; Gibbs, Richard A.; Eng, Christine M.; Xia, Fan; Lalani, Seema R.; Lupski, James R.; Bongers, Ernie M.H.F.; Yang, Yaping

    2015-01-01

    Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5′ end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1st coding exon), c.16A>T (p.Lys6∗) and c.35_38delTCAA (p.Ile12Lysfs∗4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5′ end of the geminin protein. All three GMNN mutations identified alter sites 5′ to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS. PMID:26637980

  1. Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome.

    PubMed

    Cameron, Jessie M; MacKay, Nevena; Feigenbaum, Annette; Tarnopolsky, Mark; Blaser, Susan; Robinson, Brian H; Schulze, Andreas

    2015-09-01

    Two siblings with hypertrophic cardiomyopathy and brain atrophy were diagnosed with Complex I deficiency based on low enzyme activity in muscle and high lactate/pyruvate ratio in fibroblasts. Whole exome sequencing results of fibroblast gDNA from one sibling was narrowed down to 190 SNPs or In/Dels in 185 candidate genes by selecting non-synonymous coding sequence base pair changes that were not present in the SNP database. Two compound heterozygous mutations were identified in both siblings in NDUFV2, encoding the 24 kDa subunit of Complex I. The intronic mutation (c.IVS2 + 1delGTAA) is disease causing and has been reported before. The other mutation is novel (c.669_670insG, p.Ser224Valfs*3) and predicted to cause a pathogenic frameshift in the protein. Subsequent investigation of 10 probands with complex I deficiency from different families revealed homozygosity for the intronic c.IVS2 + 1delGTAA mutation in a second, consanguineous family. In this family three of five siblings were affected. Interestingly, they presented with Leigh syndrome but no cardiac involvement. The same genotype had been reported previously in a two families but presenting with hypertrophic cardiomyopathy, trunk hypotonia and encephalopathy. We have identified NDUFV2 mutations in two families with Complex I deficiency, including a novel mutation. The diagnosis of Leigh syndrome expands the clinical phenotypes associated with the c.IVS2 + 1delGTAA mutation in this gene. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  2. Cushing syndrome

    MedlinePlus

    Hypercortisolism; Cortisol excess; Glucocorticoid excess - Cushing syndrome ... The most common cause of Cushing syndrome is taking too much ... Cushing syndrome . Prednisone, dexamethasone, and prednisolone ...

  3. Cervical neuro-muscular syndrome: discovery of a new disease group caused by abnormalities in the cervical muscles.

    PubMed

    Matsui, Takayoshi; Ii, Kunio; Hojo, Shuntaro; Sano, Keiji

    2012-01-01

    Our previous study of whiplash injury found that abnormalities in the cervical muscles cause autonomic dystonia. Further research has found that abnormalities in the cervical muscles cause headache, chronic fatigue syndrome, vertigo, and dizziness. We named this group of diseases cervical neuro-muscular syndrome. Patients treated within a 2-year period from April 1, 2002 to March 31, 2004 reported good outcomes in 83.8% for headache, 88.4% for vertigo and dizziness, 84.5% for chronic fatigue syndrome, 88.0% for autonomic dystonia, and 83.7% for whiplash-associated disorder. A large number of outpatients present with general malaise, including many general physical complaints without identifiable cause. We propose that treatment of the cervical muscle is effective for general malaise.

  4. Pilot Study: Colostomy and Urine Collection Protocol for Investigating Potential Inciting Causes of Hen Diuresis Syndrome.

    PubMed

    Jones, Kelli; Turner, Bradley; Brandão, João; Hubbard, Sue Ann; Magee, Danny; Baughman, Brittany; Wills, Robert; Tully, Thomas

    2015-06-01

    Hen diuresis syndrome has emerged over the past 5 yr as a significant cause of mortality in the U.S. broiler breeder industry. The condition affects hens in production and is characterized by transient muscle weakness in the vent region, transient diuresis, and often urate deposits on the skin below the vent. Affected hens are often seen straining to lay an egg, which suggests oviduct contraction is also impaired. Related hen mortality, often reaching 1% or more a week, is believed to be primarily the result of male aggression of the vent region (Turner et al., "Investigating Causes of Excessive Urate Production in Broiler Breeder Hens Associated with Peritonitis and Cannibalism Mortality," Oral Presentation at The American Association of Avian Pathologists Annual Meeting, p. 139, 2010). The exact association between the cause of mortality and this syndrome is unknown, but it may be the consequence of transient partial to full oviduct prolapse, which predisposes or stimulates cannibalism and aggression. Based on unpublished work done prior to this study (Turner et al., ibid.), the evidence suggests the underlying problem is metabolic. We feel that urine collection and analysis is an essential component to understanding this condition. This study serves as a pilot study for future investigations that attempt to identify the nature and cause of the metabolic disturbance through paired urine and serum collection and analysis. For the purpose of this study, a small sample of 10 affected and 10 unaffected birds was used for sample collection. In order to collect pure urine, the birds were surgically colostomized. Colostomy did prove to be a useful means of collecting urine free of feces, and for the purposes of our study it yielded adequate urine samples for analysis. There were statistically relevant urine values observed. Affected birds had a higher presence of blood in the urine, a lower uric acid excretion rate (mg/hr), higher concentration (mEq/L) of urine Na+, and

  5. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations.

    PubMed

    Smith, Miriam J; Beetz, Christian; Williams, Simon G; Bhaskar, Sanjeev S; O'Sullivan, James; Anderson, Beverley; Daly, Sarah B; Urquhart, Jill E; Bholah, Zaynab; Oudit, Deemesh; Cheesman, Edmund; Kelsey, Anna; McCabe, Martin G; Newman, William G; Evans, D Gareth R

    2014-12-20

    Heterozygous germline PTCH1 mutations are causative of Gorlin syndrome (naevoid basal cell carcinoma), but detection rates > 70% have rarely been reported. We aimed to define the causative mutations in individuals with Gorlin syndrome without PTCH1 mutations. We undertook exome sequencing on lymphocyte DNA from four unrelated individuals from families with Gorlin syndrome with no PTCH1 mutations found by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or RNA analysis. A germline heterozygous nonsense mutation in SUFU was identified in one of four exomes. Sanger sequencing of SUFU in 23 additional PTCH1-negative Gorlin syndrome families identified a SUFU mutation in a second family. Copy-number analysis of SUFU by MLPA revealed a large heterozygous deletion in a third family. All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts. Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma. We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. Our study redefines the risk of medulloblastoma in Gorlin syndrome, dependent on the underlying causative gene. Previous reports have found a 5% risk of medulloblastoma in Gorlin syndrome. We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals. Our data suggest childhood brain magnetic resonance imaging surveillance is justified in SUFU-related, but not PTCH1-related, Gorlin syndrome. © 2014 by American Society of Clinical Oncology.

  6. Experimental infection of bats with Geomyces destructans causes white-nose syndrome

    Lorch, J.M.; Meteyer, C.U.; Behr, M.J.; Boyles, J.G.; Cryan, P.M.; Hicks, A.C.; Ballmann, A.E.; Coleman, J.T.H.; Redell, D.N.; Reeder, D.M.; Blehert, D.S.

    2011-01-01

    White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America. The disease's name derives from a visually apparent white growth of the newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats. Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS. However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction. Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported, has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS. Here we demonstrate that exposure of healthy little brown bats (Myotis lucifugus) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen. We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals. Demonstration of causality is an instrumental step in elucidating the pathogenesis and epidemiology of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease. ?? 2011 Macmillan Publishers Limited. All rights reserved.

  7. Gene repair of an Usher syndrome causing mutation by zinc-finger nuclease mediated homologous recombination.

    PubMed

    Overlack, Nora; Goldmann, Tobias; Wolfrum, Uwe; Nagel-Wolfrum, Kerstin

    2012-06-26

    Human Usher syndrome (USH) is the most frequent cause of inherited deaf-blindness. It is clinically and genetically heterogeneous, assigned to three clinical types of which the most severe type is USH1. No effective treatment for the ophthalmic component of USH exists. Gene augmentation is an attractive strategy for hereditary retinal diseases. However, several USH genes, like USH1C, are expressed in various isoforms, hampering gene augmentation. As an alternative treatment strategy, we applied the zinc-finger nuclease (ZFN) technology for targeted gene repair of an USH1C, causing mutation by homologous recombination. We designed ZFNs customized for the p.R31X nonsense mutation in Ush1c. We evaluated ZFNs for DNA cleavage capability and analyzed ZFNs biocompatibilities by XTT assays. We demonstrated ZFNs mediated gene repair on genomic level by digestion assays and DNA sequencing, and on protein level by indirect immunofluorescence and Western blot analyses. The specifically designed ZFNs did not show cytotoxic effects in a p.R31X cell line. We demonstrated that ZFN induced cleavage of their target sequence. We showed that simultaneous application of ZFN and rescue DNA induced gene repair of the disease-causing mutation on the genomic level, resulting in recovery of protein expression. In our present study, we analyzed for the first time ZFN-activated gene repair of an USH gene. The data highlight the ability of ZFNs to induce targeted homologous recombination and mediate gene repair in USH. We provide further evidence that the ZFN technology holds great potential to recover disease-causing mutations in inherited retinal disorders.

  8. Staphylococcal scalded skin syndrome in a premature newborn caused by methicillin-resistant Staphylococcus aureus: case report.

    PubMed

    Hörner, Andreas; Hörner, Rosmari; Salla, Adenilde; Nunes, Melise Silveira; Garzon, Litiérri Razia; Rampelotto, Roberta Filipini; Martini, Rosiéli; Santos, Silvana Oliveira dos; Gindri, Lívia; Rodrigues, Mônica de Abreu; Giacomolli, Cláudia

    2015-01-01

    Staphylococcal scalded skin syndrome is an exfoliative skin disease. Reports of this syndrome in newborns caused by methicillin-resistant Staphylococcus aureus are rare but, when present, rapid diagnosis and treatment is required in order to decrease morbidity and mortality. A premature newly born girl weighing 1,520 g, born with a gestational age of 29 weeks and 4 days, developed staphylococcal scalded skin syndrome on the fifth day of life. Cultures on blood samples collected on the first and fourth days were negative, but Pseudomonas aeruginosa and Enterococcus sp. (vancomycin-sensitive) developed in blood cultures performed on the day of death (seventh day), and Pseudomonas aeruginosa and Serratia marcescens were identified in cultures on nasopharyngeal, buttock and abdominal secretions. In addition to these two Gram-negative bacilli, methicillin-resistant Staphylococcus aureus was isolated in a culture on the umbilical stump (seventh day). The diagnosis of staphylococcal scalded skin syndrome was based on clinical criteria.

  9. Toxic Shock Syndrome Caused by Methicillin-Resistant Staphylococcus aureus (MRSA) After Expander-Based Breast Reconstruction.

    PubMed

    Suga, Hirotaka; Shiraishi, Tomohiro; Takushima, Akihiko; Harii, Kiyonori

    2016-01-01

    Toxic shock syndrome is a rare but life-threatening complication after plastic surgery procedures. We experienced 2 cases of toxic shock syndrome after expander-based breast reconstruction caused by methicillin-resistant Staphylococcus aureus. The first patient took a severe clinical course due to the delayed diagnosis and treatment, and the second patient recovered rapidly after the early diagnosis and treatment based on our experience of the first case. Fever, rash, and gastrointestinal symptoms (diarrhea and/or vomiting) were characteristic and important for the early diagnosis of toxic shock syndrome. Considering the increased prevalence of methicillin-resistant Staphylococcus aureus, we should suspect methicillin-resistant Staphylococcus aureus in cases of toxic shock syndrome that occur postoperatively, and the empiric administration of vancomycin should be initiated in such cases.

  10. First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome

    PubMed Central

    Beygo, J.; Buiting, K.; Seland, S.; Lüdecke, H.-J.; Hehr, U.; Lich, C.; Prager, B.; Lohmann, D.R.; Wieczorek, D.

    2012-01-01

    Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1. PMID:22712005

  11. First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome.

    PubMed

    Beygo, J; Buiting, K; Seland, S; Lüdecke, H-J; Hehr, U; Lich, C; Prager, B; Lohmann, D R; Wieczorek, D

    2012-01-01

    Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1.

  12. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.

    PubMed

    Schubert, Julian; Siekierska, Aleksandra; Langlois, Mélanie; May, Patrick; Huneau, Clément; Becker, Felicitas; Muhle, Hiltrud; Suls, Arvid; Lemke, Johannes R; de Kovel, Carolien G F; Thiele, Holger; Konrad, Kathryn; Kawalia, Amit; Toliat, Mohammad R; Sander, Thomas; Rüschendorf, Franz; Caliebe, Almuth; Nagel, Inga; Kohl, Bernard; Kecskés, Angela; Jacmin, Maxime; Hardies, Katia; Weckhuysen, Sarah; Riesch, Erik; Dorn, Thomas; Brilstra, Eva H; Baulac, Stephanie; Møller, Rikke S; Hjalgrim, Helle; Koeleman, Bobby P C; Jurkat-Rott, Karin; Lehman-Horn, Frank; Roach, Jared C; Glusman, Gustavo; Hood, Leroy; Galas, David J; Martin, Benoit; de Witte, Peter A M; Biskup, Saskia; De Jonghe, Peter; Helbig, Ingo; Balling, Rudi; Nürnberg, Peter; Crawford, Alexander D; Esguerra, Camila V; Weber, Yvonne G; Lerche, Holger

    2014-12-01

    Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

  13. Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation.

    PubMed

    Zhong, Franklin L; Mamaï, Ons; Sborgi, Lorenzo; Boussofara, Lobna; Hopkins, Richard; Robinson, Kim; Szeverényi, Ildikó; Takeichi, Takuya; Balaji, Reshmaa; Lau, Aristotle; Tye, Hazel; Roy, Keya; Bonnard, Carine; Ahl, Patricia J; Jones, Leigh Ann; Baker, Paul J; Lacina, Lukas; Otsuka, Atsushi; Fournie, Pierre R; Malecaze, François; Lane, E Birgitte; Akiyama, Masashi; Kabashima, Kenji; Connolly, John E; Masters, Seth L; Soler, Vincent J; Omar, Salma Samir; McGrath, John A; Nedelcu, Roxana; Gribaa, Moez; Denguezli, Mohamed; Saad, Ali; Hiller, Sebastian; Reversade, Bruno

    2016-09-22

    Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Paraspinal muscle impingement causing acute Brown-Sequard syndrome after posterior cervical decompression.

    PubMed

    Jost, Patrick W; Marawar, Satyajit; O'Leary, Patrick F

    2010-04-01

    A case report. To present a previously unreported cause of neurologic compromise after cervical spine surgery. Several different causes of postoperative neurologic deficit have been reported in the literature. The authors present a case of acute postoperative paralysis after posterior cervical decompression by a mechanism that has not yet been reported in the literature. A 54-year-old muscular, short-statured man underwent posterior cervical laminectomy from C3-C5 without instrumentation and left C5 foraminotomy. Within hours of leaving the operating room, he began to develop postoperative neurologic deficits in his extremities, which progressed to a classic Brown-Sequard syndrome. Magnetic resonance imaging revealed regional kyphosis and large swollen paraspinal muscles impinging on the spinal cord without epidural hematoma. Emergent operative re-exploration confirmed these findings; large, swollen paraspinal muscles, a functioning drain, and no hematoma were found. The patient was treated with immediate corticosteroids at the time of initial diagnosis, and emergent re-exploration and debulking of the paraspinal muscles. The patient had complete recovery of neurologic function to his preoperative baseline after the second procedure but required a third procedure in which anterior discectomy and fusion at C4-C5 was performed, which led to improvement of his preoperative symptoms. When performing posterior cervical decompression, surgeons must be aware of the potential for loss of normal lordosis and anterior displacement of paraspinal muscles against the spinal cord, especially in muscular patients.

  15. Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia.

    PubMed

    Chen, Wuyan; Perritt, Ashley F; Morissette, Rachel; Dreiling, Jennifer L; Bohn, Markus-Frederik; Mallappa, Ashwini; Xu, Zhi; Quezado, Martha; Merke, Deborah P

    2016-09-01

    Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity. © 2016 WILEY PERIODICALS, INC.

  16. Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.

    PubMed

    Koenighofer, M; Hung, C Y; McCauley, J L; Dallman, J; Back, E J; Mihalek, I; Gripp, K W; Sol-Church, K; Rusconi, P; Zhang, Z; Shi, G-X; Andres, D A; Bodamer, O A

    2016-03-01

    RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Duck egg-drop syndrome caused by BYD virus, a new Tembusu-related flavivirus.

    PubMed

    Su, Jingliang; Li, Shuang; Hu, Xudong; Yu, Xiuling; Wang, Yongyue; Liu, Peipei; Lu, Xishan; Zhang, Guozhong; Hu, Xueying; Liu, Di; Li, Xiaoxia; Su, Wenliang; Lu, Hao; Mok, Ngai Shing; Wang, Peiyi; Wang, Ming; Tian, Kegong; Gao, George F

    2011-03-24

    Since April 2010, a severe outbreak of duck viral infection, with egg drop, feed uptake decline and ovary-oviduct disease, has spread around the major duck-producing regions in China. A new virus, named BYD virus, was isolated in different areas, and a similar disease was reproduced in healthy egg-producing ducks, infecting with the isolated virus. The virus was re-isolated from the affected ducks and replicated well in primary duck embryo fibroblasts and Vero cells, causing the cytopathic effect. The virus was identified as an enveloped positive-stranded RNA virus with a size of approximately 55 nm in diameter. Genomic sequencing of the isolated virus revealed that it is closely related to Tembusu virus (a mosquito-borne Ntaya group flavivirus), with 87-91% nucleotide identity of the partial E (envelope) proteins to that of Tembusu virus and 72% of the entire genome coding sequence with Bagaza virus, the most closely related flavivirus with an entirely sequenced genome. Collectively our systematic studies fulfill Koch's postulates, and therefore, the causative agent of the duck egg drop syndrome occurring in China is a new flavivirus. Flavivirus is an emerging and re-emerging zoonotic pathogen and BYD virus that causes severe egg-drop, could be disastrous for the duck industry. More importantly its public health concerns should also be evaluated, and its epidemiology should be closely watched due to the zoonotic nature of flaviviruses.

  18. Computational Modeling of Molecular Effects of Mutations Causing Snyder-Robinson Syndrome

    NASA Astrophysics Data System (ADS)

    Zhang, Zhe; Teng, Shaolei; Alexov, Emil

    2009-11-01

    Snyder-Robinson syndrome is an X-linked mental retardation disorder disease. The disease is associated with defects in a particular biomolecule, the spermine synthase (SMS) protein. Specifically, three missense mutations, G56S, I150T and V132G in SMS were identified to cause the disease, but molecular mechanism of their effect is unknown. We apply single-point energy calculations, molecular dynamics simulations and pKa calculations to reveal the effects of these mutations on SMS's stability, flexibility and interactions. It is demonstrated that even saddle changes as very conservative mutations can significantly affect wild type properties of SMS protein. While the mutations do not involve ionizable groups, still slight changes in the protonation of neighboring amino acids are suggested by the computational protocol. The dynamics of SMS was also affected by the mutations resulting in larger structural fluctuations in the mutant protein compared to the wild type. At the same time, the effect on SMS's stability was found to depend on the location of the mutation site with respect to the surface of the protein. Our investigation suggests that the disease is caused by diverse molecular mechanisms depending on the site of mutation and amino acid type substitution.

  19. Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant.

    PubMed

    Graziano, Claudio; Wischmeijer, Anita; Pippucci, Tommaso; Fusco, Carlo; Diquigiovanni, Chiara; Nõukas, Margit; Sauk, Martin; Kurg, Ants; Rivieri, Francesca; Blau, Nenad; Hoffmann, Georg F; Chaubey, Alka; Schwartz, Charles E; Romeo, Giovanni; Bonora, Elena; Garavelli, Livia; Seri, Marco

    2015-04-01

    The causative variant in a consanguineous family in which the three patients (two siblings and a cousin) presented with intellectual disability, Marfanoid habitus, craniofacial dysmorphisms, chronic diarrhea and progressive kyphoscoliosis, has been identified through whole exome sequencing (WES) analysis. WES study identified a homozygous DDC variant in the patients, c.1123C>T, resulting in p.Arg375Cys missense substitution. Mutations in DDC cause a recessive metabolic disorder (aromatic amino acid decarboxylase, AADC, deficiency, OMIM #608643) characterized by hypotonia, oculogyric crises, excessive sweating, temperature instability, dystonia, severe neurologic dysfunction in infancy, and specific abnormalities of neurotransmitters and their metabolites in the cerebrospinal fluid (CSF). In our family, analysis of neurotransmitters and their metabolites in patient's CSF shows a pattern compatible with AADC deficiency, although the clinical signs are different from the classic form. Our work expands the phenotypic spectrum associated with DDC variants, which therefore can cause an additional novel syndrome without typical movement abnormalities. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Mouse Models of Down Syndrome as a Tool to Unravel the Causes of Mental Disabilities

    PubMed Central

    Rueda, Noemí; Flórez, Jesús; Martínez-Cué, Carmen

    2012-01-01

    Down syndrome (DS) is the most common genetic cause of mental disability. Based on the homology of Hsa21 and the murine chromosomes Mmu16, Mmu17 and Mmu10, several mouse models of DS have been developed. The most commonly used model, the Ts65Dn mouse, has been widely used to investigate the neural mechanisms underlying the mental disabilities seen in DS individuals. A wide array of neuromorphological alterations appears to compromise cognitive performance in trisomic mice. Enhanced inhibition due to alterations in GABAA-mediated transmission and disturbances in the glutamatergic, noradrenergic and cholinergic systems, among others, has also been demonstrated. DS cognitive dysfunction caused by neurodevelopmental alterations is worsened in later life stages by neurodegenerative processes. A number of pharmacological therapies have been shown to partially restore morphological anomalies concomitantly with cognition in these mice. In conclusion, the use of mouse models is enormously effective in the study of the neurobiological substrates of mental disabilities in DS and in the testing of therapies that rescue these alterations. These studies provide the basis for developing clinical trials in DS individuals and sustain the hope that some of these drugs will be useful in rescuing mental disabilities in DS individuals. PMID:22685678

  1. Incidence and Causes of Intentional Fetal or Neonatal Demise in Twin-Twin Transfusion Syndrome

    PubMed Central

    Spruijt, Marjolijn S.; Tameeris, Ellen; Zhao, De-Peng; Middeldorp, Johanna M.; Haak, Monique C.; Oepkes, Dick; Lopriore, Enrico

    2018-01-01

    Introduction The aim of this study is to evaluate the incidence and causes of intentional fetal and neonatal demise in twin-twin transfusion syndrome (TTTS). Material and Methods All TTTS pregnancies managed at our centre between 2000 and 2014 were included. We evaluated incidence and causes of intentional fetal/neonatal demise, defined as termination of pregnancy, selective fetal reduction, or withdrawal of neonatal intensive care. Results Intentional fetal/neonatal demise occurred in 9.8% (110/1,122) of fetuses and was due to termination of pregnancy (2.2%), selective fetal reduction (4.2%), or withdrawal of neonatal intensive care (3.4%). Reasons for termination of pregnancy included complications of laser treatment (72.0%), severe fetal anomaly (20.0%), and unwanted pregnancy (8.0%). Reasons for selective fetal reduction were technical difficulties to perform laser surgery (51.1%), fetal complications (38.3%), and parental preference for fetal reduction rather than laser treatment (10.6%). Reasons for withdrawal of neonatal intensive care treatment were severe cerebral injury (47.4%), severe pulmonary complications (15.8%), birth asphyxia (5.3%), multiple complications of TTTS and/or prematurity combined (21.1%), or other (10.5%). Conclusions Intentional fetal or neonatal demise in TTTS occurs frequently and is often due to complications after laser surgery and/or severe (cerebral) injury in affected fetuses or neonates. PMID:28285310

  2. ANLN truncation causes a familial fatal acute respiratory distress syndrome in Dalmatian dogs

    PubMed Central

    Syrjä, Pernilla; Arumilli, Meharji; Järvinen, Anna-Kaisa; Rajamäki, Minna

    2017-01-01

    Acute respiratory distress syndrome (ARDS) is the leading cause of death in critical care medicine. The syndrome is typified by an exaggerated inflammatory response within the lungs. ARDS has been reported in many species, including dogs. We have previously reported a fatal familial juvenile respiratory disease accompanied by occasional unilateral renal aplasia and hydrocephalus, in Dalmatian dogs. The condition with a suggested recessive mode of inheritance resembles acute exacerbation of usual interstitial pneumonia in man. We combined SNP-based homozygosity mapping of two ARDS-affected Dalmatian dogs and whole genome sequencing of one affected dog to identify a case-specific homozygous nonsense variant, c.31C>T; p.R11* in the ANLN gene. Subsequent analysis of the variant in a total cohort of 188 Dalmatians, including seven cases, indicated complete segregation of the variant with the disease and confirmed an autosomal recessive mode of inheritance. Low carrier frequency of 1.7% was observed in a population cohort. The early nonsense variant results in a nearly complete truncation of the ANLN protein and immunohistochemical analysis of the affected lung tissue demonstrated the lack of the membranous and cytoplasmic staining of ANLN protein in the metaplastic bronchial epithelium. The ANLN gene encodes an anillin actin binding protein with a suggested regulatory role in the integrity of intercellular junctions. Our study suggests that defective ANLN results in abnormal cellular organization of the bronchiolar epithelium, which in turn predisposes to acute respiratory distress. ANLN has been previously linked to a dominant focal segmental glomerulosclerosis in human without pulmonary defects. However, the lack of similar renal manifestations in the affected Dalmatians suggest a novel ANLN-related pulmonary function and disease association. PMID:28222102

  3. Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations.

    PubMed

    Guergueltcheva, Velina; Müller, Juliane S; Dusl, Marina; Senderek, Jan; Oldfors, Anders; Lindbergh, Christopher; Maxwell, Susan; Colomer, Jaume; Mallebrera, Cecilia Jimenez; Nascimento, Andres; Vilchez, Juan J; Muelas, Nuria; Kirschner, Janbernd; Nafissi, Shahriar; Kariminejad, Ariana; Nilipour, Yalda; Bozorgmehr, Bita; Najmabadi, Hossein; Rodolico, Carmelo; Sieb, Jörn P; Schlotter, Beate; Schoser, Benedikt; Herrmann, Ralf; Voit, Thomas; Steinlein, Ortrud K; Najafi, Abdolhamid; Urtizberea, Andoni; Soler, Doriette M; Muntoni, Francesco; Hanna, Michael G; Chaouch, Amina; Straub, Volker; Bushby, Kate; Palace, Jacqueline; Beeson, David; Abicht, Angela; Lochmüller, Hanns

    2012-05-01

    Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).

  4. A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

    PubMed

    Quinonez, Shane C; Gelehrter, Thomas D; Uhlmann, Wendy R

    2017-01-01

    Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4

    PubMed Central

    Liu, Qian; Chen, Haoqian; Ojode, Teresa; Gao, Xiangxi; Anaya-O'Brien, Sandra; Turner, Nicholas A.; Ulrick, Jean; DeCastro, Rosamma; Kelly, Corin; Cardones, Adela R.; Gold, Stuart H.; Hwang, Eugene I.; Wechsler, Daniel S.; Malech, Harry L.; Murphy, Philip M.

    2012-01-01

    WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4R334X, the most common truncation mutation in WHIM syndrome, CXCR4E343K mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4E343K had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling. PMID:22596258

  6. ABCD syndrome is caused by a homozygous mutation in the EDNRB gene.

    PubMed

    Verheij, Joke B G M; Kunze, Jürgen; Osinga, Jan; van Essen, Anthonie J; Hofstra, Robert M W

    2002-03-15

    ABCD syndrome is an autosomal recessive syndrome characterized by albinism, black lock, cell migration disorder of the neurocytes of the gut (Hirschsprung disease [HSCR]), and deafness. This phenotype clearly overlaps with the features of the Shah-Waardenburg syndrome, comprising sensorineural deafness; hypopigmentation of skin, hair, and irides; and HSCR. Therefore, we screened DNA of the index patient of the ABCD syndrome family for mutations in the endothelin B receptor (EDNRB) gene, a gene known to be involved in Shah-Waardenburg syndrome. A homozygous nonsense mutation in exon 3 (R201X) of the EDNRB gene was found. We therefore suggest that ABCD syndrome is not a separate entity, but an expression of Shah-Waardenburg syndrome.

  7. Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

    PubMed

    Salo-Mullen, Erin E; Lynn, Patricio B; Wang, Lu; Walsh, Michael; Gopalan, Anuradha; Shia, Jinru; Tran, Christina; Man, Fung Ying; McBride, Sean; Schattner, Mark; Zhang, Liying; Weiser, Martin R; Stadler, Zsofia K

    2018-01-01

    Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.

  8. Bartter and Gitelman syndromes: Spectrum of clinical manifestations caused by different mutations

    PubMed Central

    Al Shibli, Amar; Narchi, Hassib

    2015-01-01

    Bartter and Gitelman syndromes (BS and GS) are inherited disorders resulting in defects in renal tubular handling of sodium, potassium and chloride. Previously considered as genotypic and phenotypic heterogeneous diseases, recent evidence suggests that they constitute a spectrum of disease caused by different genetic mutations with the molecular defects of chloride reabsorption originating at different sites of the nephron in each condition. Although they share some characteristic metabolic abnormalities such as hypokalemia, metabolic alkalosis, hyperplasia of the juxtaglomerular apparatus with hyperreninemia, hyperaldosteronism, the clinical and laboratory manifestations may not always allow distinction between them. Diuretics tests, measuring the changes in urinary fractional excretion of chloride from baseline after administration of either hydrochlorothiazide or furosemide show very little change (< 2.3%) in the fractional excretion of chloride from baseline in GS when compared with BS, except when BS is associated with KCNJ1 mutations where a good response to both diuretics exists. The diuretic test is not recommended for infants or young children with suspected BS because of a higher risk of volume depletion in such children. Clinical symptoms and biochemical markers of GS and classic form of BS (type III) may overlap and thus genetic analysis may specify the real cause of symptoms. However, although genetic analysis is available, its use remains limited because of limited availability, large gene dimensions, lack of hot-spot mutations, heavy workup time and costs involved. Furthermore, considerable overlap exists between the different genotypes and phenotypes. Although BS and GS usually have distinct presentations and are associated with specific gene mutations, there remains considerable overlap between their phenotypes and genotypes. Thus, they are better described as a spectrum of clinical manifestations caused by different gene mutations. PMID:26140272

  9. Reduced exercise capacity in persons with Down syndrome: cause, effect, and management

    PubMed Central

    Mendonca, Goncalo V; Pereira, Fernando D; Fernhall, Bo

    2010-01-01

    Persons with Down syndrome (DS) have reduced peak and submaximal exercise capacity. Because ambulation is one predictor of survival among adults with DS, a review of the current knowledge of the causes, effects, and management of reduced exercise capacity in these individuals would be important. Available data suggest that reduced exercise capacity in persons with DS results from an interaction between low peak oxygen uptake (VO2peak) and poor exercise economy. Of several possible explanations, chronotropic incompetence has been shown to be the primary cause of low VO2peak in DS. In contrast, poor exercise economy is apparently dependent on disturbed gait kinetics and kinematics resulting from joint laxity and muscle hypotonia. Importantly, there is enough evidence to suggest that such low levels of physical fitness (reduced exercise capacity and muscle strength) limit the ability of adults with DS to perform functional tasks of daily living. Consequently, clinical management of reduced exercise capacity in DS seems important to ensure that these individuals remain productive and healthy throughout their lives. However, few prospective studies have examined the effects of structured exercise training in this population. Existent data suggest that exercise training is beneficial for improving exercise capacity and physiological function in persons with DS. This article reviews the current knowledge of the causes, effects, and management of reduced exercise capacity in DS. This review is limited to the acute and chronic responses to submaximal and peak exercise intensities because data on supramaximal exercise capacity of persons with DS have been shown to be unreliable. PMID:21206759

  10. Recurrent Cubital Tunnel Syndrome Caused by Ganglion: A Report of Nine Cases.

    PubMed

    Komatsu, Masatoshi; Uchiyama, Shigeharu; Kimura, Takumi; Suenaga, Naoki; Hayashi, Masanori; Kato, Hiroyuki

    2018-06-01

    Cubital tunnel syndrome (CuTS) is generally treated successfully by surgery and recurrent cases are rare. This study retrospectively investigated the clinical characteristics of recurrent CuTS caused by ganglion. We evaluated nine patients who were surgically treated for recurrent CuTS caused by ganglion. Age distribution at recurrence ranged from 43 to 79 years. The initial surgery for CuTS had been performed using various methods. The asymptomatic period from initial surgery to recurrence ranged from 22 to 252 months. Clinical, diagnostic imaging, and operative findings during the second surgery were analyzed. All patients were treated by anterior subcutaneous ulnar nerve transposition with ganglion resection and later examined directly within a mean of 71 months after the second surgery. The interval from recurrence to consultation was shorter than two months for eight cases. Chief complaints included numbness with or without pain in the ring and little fingers in all patients and resting pain in the medial elbow in five patients. Elbow osteoarthritis was present in all cases. Although four of 10 ganglia were palpable, ultrasonography and magnetic resonance imaging could identify all ganglia preoperatively. The ulnar nerve typically had become entrapped by the ganglion posteriorly and by fascia, scar tissue, and/or muscle anteriorly. Chief complaints and ulnar nerve function were improved in all patients following revision surgery. The acute onset of numbness with or without intolerable pain in the ring and little fingers after a long-term remission period following initial surgery for CuTS in patients with elbow osteoarthritis appears to be the characteristic clinical profile of recurrent CuTS caused by ganglion. As ganglia are often not palpable, ultrasonography and magnetic resonance imaging are recommended for accurate diagnosis.

  11. The fungus Trichophyton redellii sp. nov. causes skin infections that resemble white-nose syndrome of hibernating bats

    Jeffrey M. Lorch; Andrew M. Minnis; Carol U. Meteyer; Jennifer A. Redell; J. Paul White; Heather M. Kaarakka; Laura K. Muller; Daniel L. Lindner; Michelle L. Verant; Valerie Shearn-Bochsler; David S. Blehert

    2015-01-01

    Before the discovery of white-nose syndrome (WNS), a fungal disease caused by Pseudogymnoascus destructans, there were no reports of fungal skin infections in bats during hibernation. In 2011, bats with grossly visible fungal skin infections similar in appearance to WNS were reported from multiple sites in Wisconsin, US, a state outside the known...

  12. Molecular characterization of a heterothallic mating system in Pseudogymnoascus destructans, the fungus causing white-nose syndrome of bats

    Jonathan M. Palmer; Alena Kubatova; Alena Novakova; Andrew M. Minnis; Miroslav Kolarik; Daniel L. Lindner

    2014-01-01

    White-nose syndrome (WNS) of bats has devastated bat populations in eastern North America since its discovery in 2006. WNS, caused by the fungus Pseudogymnoascus destructans, has spread quickly in North America and has become one of the most severe wildlife epidemics of our time. While P. destructans is spreading rapidly in North...

  13. Germline Mutations in BMPR1A/ALK3 Cause a Subset of Cases of Juvenile Polyposis Syndrome and of Cowden and Bannayan-Riley-Ruvalcaba Syndromes*

    PubMed Central

    Zhou, Xiao-Ping; Woodford-Richens, Kelly; Lehtonen, Rainer; Kurose, Keisuke; Aldred, Micheala; Hampel, Heather; Launonen, Virpi; Virta, Sanno; Pilarski, Robert; Salovaara, Reijo; Bodmer, Walter F.; Conrad, Beth A.; Dunlop, Malcolm; Hodgson, Shirley V.; Iwama, Takeo; Järvinen, Heikki; Kellokumpu, Ilmo; Kim, J. C.; Leggett, Barbara; Markie, David; Mecklin, Jukka-Pekka; Neale, Kay; Phillips, Robin; Piris, Juan; Rozen, Paul; Houlston, Richard S.; Aaltonen, Lauri A.; Tomlinson, Ian P. M.; Eng, Charis

    2001-01-01

    Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor β–receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype. PMID:11536076

  14. Invasive liver abscess syndrome caused by Klebsiella pneumoniae with definite K2 serotyping in Japan: a case report.

    PubMed

    Seo, Ryota; Kudo, Daisuke; Gu, Yoshiaki; Yano, Hisakazu; Aoyagi, Tetsuji; Omura, Taku; Irino, Shigemi; Kaku, Mitsuo; Kushimoto, Shigeki

    2016-12-01

    Klebsiella pneumonia is a well-known human pathogen, and recently, a distinct invasive syndrome caused by K. pneumoniae serotypes K1 and K2 has been recognized in Southeast Asia. This syndrome is characterized by primary liver abscess and extrahepatic complications resulting from bacteremic dissemination. We report the first adult case of primary liver abscess caused by the definite K2 serotyped pathogen, with endogenous endophthalmitis in Japan. A 64-year-old woman was admitted to a nearby hospital for a high fever and diarrhea. She had visual loss of her right eye, renal dysfunction, and thrombocytopenia within 24 h from admission. She was transferred to our institution. On admission, she had no alteration of mental status and normal vital signs; however, she had almost complete ablepsia of the right eye. Laboratory data showed severe inflammation, liver dysfunction, thrombocytopenia, an increased serum creatinine level, and coagulopathy. Computed tomography showed a low density area in the right lobe of the liver. Invasive liver abscess syndrome probably caused by K. pneumonia was highly suspected and immediately administered broad-spectrum antibiotics for severe sepsis. Concurrently, endogenous endophthalmitis was diagnosed, and we performed vitrectomy on the day of admission. The blood culture showed K. pneumoniae infection. Percutaneous drainage of the liver abscess was also performed. Although she was discharged in a good general condition on day 22, she had complete ablepsia of the right eye. The K2A gene was detected by polymerase chain reaction (PCR), which is consistent with the K2 serotype. PCR was also positive for the virulence-associated gene rmpA. Final diagnosis was invasive liver abscess syndrome caused by K2 serotype K. pneumonia. Although the primary liver abscess caused by K. pneumoniae with a hypermucoviscous phenotype is infrequently reported outside Southeast Asia, physicians should recognize this syndrome, and appropriate diagnosis and

  15. Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

    PubMed Central

    Tucci, Valter; Kleefstra, Tjitske; Hardy, Andrea; Heise, Ines; Maggi, Silvia; Willemsen, Marjolein H.; Hilton, Helen; Esapa, Chris; Simon, Michelle; Buenavista, Maria-Teresa; McGuffin, Liam J.; Vizor, Lucie; Dodero, Luca; Tsaftaris, Sotirios; Romero, Rosario; Nillesen, Willy N.; Vissers, Lisenka E.L.M.; Kempers, Marlies J.; Vulto-van Silfhout, Anneke T.; Iqbal, Zafar; Orlando, Marta; Maccione, Alessandro; Lassi, Glenda; Farisello, Pasqualina; Contestabile, Andrea; Tinarelli, Federico; Nieus, Thierry; Raimondi, Andrea; Greco, Barbara; Cantatore, Daniela; Gasparini, Laura; Berdondini, Luca; Bifone, Angelo; Gozzi, Alessandro; Wells, Sara; Nolan, Patrick M.

    2014-01-01

    The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults. PMID:24614104

  16. Scalp eschar and neck lymphadenopathy after tick bite: an emerging syndrome with multiple causes.

    PubMed

    Dubourg, G; Socolovschi, C; Del Giudice, P; Fournier, P E; Raoult, D

    2014-08-01

    The clinical and epidemiological features of 56 patients with scalp eschar associated with neck lymphadenopathy after a tick bite (SENLAT) syndrome were evaluated at the National French Rickettsial Center. Eschar swabs, crusts, and biopsies as well as ticks and blood samples were acquired for molecular and serological assays. SENLAT predominantly affects children (p < 0.05), followed by 40- to 70-year-olds, and it is found mostly in women (p < 0.05). The seasonal distribution has two peaks: one in the spring (55%) and one in the autumn (30%). The etiological agent was identified in 18 cases, which include Rickettsia slovaca in 13 cases with incidences of two co-infections with Rickettsia raoultii and one case caused by Rickettsia sibirica mongolitimonae. Other possible agents that were found in attached ticks were Candidatus R. rioja, Coxiella burnetii, and Borrelia burgdorferi. The tick vector was Dermacentor marginatus in almost all cases, with the exception of one case, in which Ixodes ricinus was identified as the vector. Our findings show that SENLAT is a clinical entity characterized as a local infection controlled by the immune system and is neither pathogen- nor vector-specific.

  17. Translational read-through of a nonsense mutation causing Bartter syndrome.

    PubMed

    Cho, Hee Yeon; Lee, Beom Hee; Cheong, Hae Il

    2013-06-01

    Bartter syndrome (BS) is classified into 5 genotypes according to underlying mutant genes and BS III is caused by loss-of-function mutations in the CLCNKB gene encoding for basolateral ClC-Kb. BS III is the most common genotype in Korean patients with BS and W610X is the most common CLCNKB mutation in Korean BS III. In this study, we tested the hypothesis that the CLCNKB W610X mutation can be rescued in vitro using aminoglycoside antibiotics, which are known to induce translational read-through of a nonsense mutation. The CLCNKB cDNA was cloned into a eukaryotic expression vector and the W610X nonsense mutation was generated by site-directed mutagenesis. Cultured polarized MDCK cells were transfected with the vectors, and the read-through was induced using an aminoglycoside derivative, G418. Cellular expression of the target protein was monitored via immunohistochemistry. While cells transfected with the mutant CLCNKB failed to express ClC-Kb, G418 treatment of the cells induced the full-length protein expression, which was localized to the basolateral plasma membranes. It is demonstrated that the W610X mutation in CLCNKB can be a good candidate for trial of translational read-through induction as a therapeutic modality.

  18. Temperature-dependent growth of Geomyces destructans, the fungus that causes bat white-nose syndrome

    Verant, Michelle L.; Boyles, Justin G.; Waldrep, William; Wibbelt, Gudrun; Blehert, David S.

    2012-01-01

    White-nose syndrome (WNS) is an emergent disease estimated to have killed over five million North American bats. Caused by the psychrophilic fungus Geomyces destructans, WNS specifically affects bats during hibernation. We describe temperature-dependent growth performance and morphology for six independent isolates of G. destructans from North America and Europe. Thermal performance curves for all isolates displayed an intermediate peak with rapid decline in performance above the peak. Optimal temperatures for growth were between 12.5 and 15.8°C, and the upper critical temperature for growth was between 19.0 and 19.8°C. Growth rates varied across isolates, irrespective of geographic origin, and above 12°C all isolates displayed atypical morphology that may have implications for proliferation of the fungus. This study demonstrates that small variations in temperature, consistent with those inherent of bat hibernacula, affect growth performance and physiology of G. destructans, which may influence temperature-dependent progression and severity of WNS in wild bats.

  19. Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.

    PubMed

    Tham, Emma; Lindstrand, Anna; Santani, Avni; Malmgren, Helena; Nesbitt, Addie; Dubbs, Holly A; Zackai, Elaine H; Parker, Michael J; Millan, Francisca; Rosenbaum, Kenneth; Wilson, Golder N; Nordgren, Ann

    2015-03-05

    Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: NM_001099412.1: c.3116_3117 delCT, p.(Ser1039∗); c.3830_3831insTT, p.(Arg1278Serfs∗17); c.3879 dupA, p.(Glu1294Argfs∗19); c.4108G>T p.(Glu1370∗) and c.4292 dupT, p.(Leu1431Phefs∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  20. Molecular pathogenesis of Spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins

    PubMed Central

    Bin, Bum-Ho; Hojyo, Shintaro; Hosaka, Toshiaki; Bhin, Jinhyuk; Kano, Hiroki; Miyai, Tomohiro; Ikeda, Mariko; Kimura-Someya, Tomomi; Shirouzu, Mikako; Cho, Eun-Gyung; Fukue, Kazuhisa; Kambe, Taiho; Ohashi, Wakana; Kim, Kyu-Han; Seo, Juyeon; Choi, Dong-Hwa; Nam, Yeon-Ju; Hwang, Daehee; Fukunaka, Ayako; Fujitani, Yoshio; Yokoyama, Shigeyuki; Superti-Furga, Andrea; Ikegawa, Shiro; Lee, Tae Ryong; Fukada, Toshiyuki

    2014-01-01

    The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13G64D, in which Gly at amino acid position 64 is replaced by Asp, and ZIP13ΔFLA, which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13G64D and ZIP13ΔFLA protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS. PMID:25007800

  1. Computer vision syndrome: a review of ocular causes and potential treatments.

    PubMed

    Rosenfield, Mark

    2011-09-01

    Computer vision syndrome (CVS) is the combination of eye and vision problems associated with the use of computers. In modern western society the use of computers for both vocational and avocational activities is almost universal. However, CVS may have a significant impact not only on visual comfort but also occupational productivity since between 64% and 90% of computer users experience visual symptoms which may include eyestrain, headaches, ocular discomfort, dry eye, diplopia and blurred vision either at near or when looking into the distance after prolonged computer use. This paper reviews the principal ocular causes for this condition, namely oculomotor anomalies and dry eye. Accommodation and vergence responses to electronic screens appear to be similar to those found when viewing printed materials, whereas the prevalence of dry eye symptoms is greater during computer operation. The latter is probably due to a decrease in blink rate and blink amplitude, as well as increased corneal exposure resulting from the monitor frequently being positioned in primary gaze. However, the efficacy of proposed treatments to reduce symptoms of CVS is unproven. A better understanding of the physiology underlying CVS is critical to allow more accurate diagnosis and treatment. This will enable practitioners to optimize visual comfort and efficiency during computer operation. Ophthalmic & Physiological Optics © 2011 The College of Optometrists.

  2. Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome.

    PubMed

    Lund, Caroline; Striano, Pasquale; Sorte, Hanne Sørmo; Parisi, Pasquale; Iacomino, Michele; Sheng, Ying; Vigeland, Magnus D; Øye, Anne-Marte; Møller, Rikke Steensbjerre; Selmer, Kaja K; Zara, Federico

    2016-09-01

    Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected.

  3. Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.

    PubMed

    Castellsagué, E; Liu, J; Volenik, A; Giroux, S; Gagné, R; Maranda, B; Roussel-Jobin, A; Latreille, J; Laframboise, R; Palma, L; Kasprzak, L; Marcus, V A; Breguet, M; Nolet, S; El-Haffaf, Z; Australie, K; Gologan, A; Aleynikova, O; Oros-Klein, K; Greenwood, C; Mes-Masson, A M; Provencher, D; Tischkowitz, M; Chong, G; Rousseau, F; Foulkes, W D

    2015-06-01

    We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome.

    PubMed

    Bacrot, Séverine; Doyard, Mathilde; Huber, Céline; Alibeu, Olivier; Feldhahn, Niklas; Lehalle, Daphné; Lacombe, Didier; Marlin, Sandrine; Nitschke, Patrick; Petit, Florence; Vazquez, Marie-Paule; Munnich, Arnold; Cormier-Daire, Valérie

    2015-02-01

    Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene. This gene includes three transcripts, namely transcripts 1 and 2, encoding components of the core spliceosomal machinery (SmB' and SmB) and transcript 3 undergoing nonsense-mediated mRNA decay. All variants were located in the premature termination codon (PTC)-introducing alternative exon of transcript 3. Quantitative RT-PCR analysis revealed a significant increase in transcript 3 levels in leukocytes of CCMS individuals compared to controls. We conclude that CCMS is due to heterozygous mutations in SNRPB, enhancing inclusion of a SNRPB PTC-introducing alternative exon, and show that this developmental disease is caused by defects in the splicing machinery. Our finding confirms the report of SNRPB mutations in CCMS patients by Lynch et al. (2014) and further extends the clinical and molecular observations. © 2014 WILEY PERIODICALS, INC.

  5. Chronic food protein-induced enterocolitis syndrome caused by cow's milk proteins passed through breast milk.

    PubMed

    Miceli Sopo, Stefano; Monaco, Serena; Greco, Monica; Scala, Guglielmo

    2014-01-01

    We describe 2 cases of food protein-induced enterocolitis syndrome (FPIES) caused by cow's milk (CM) passed through breast milk. The onset in both cases was characterized by chronic symptoms (regurgitation, colic, diarrhea, failure to thrive); in one patient, two acute episodes due to the direct consumption of CM formula by the infant were also reported. The diagnosis of FPIES through breast milk can be easily overlooked, especially in milder cases. We also discuss some important issues concerning the general management of the disease. In conclusion, (1) the diagnosis of chronic FPIES should be taken into account even in exclusively breast-fed infants who present suggestive symptoms such as persistent regurgitation, small amounts of vomiting, lethargy, failure to thrive, dehydration, diarrhea (sometimes bloody) and abdominal distention. A 2-week maternal elimination diet should be considered even in apparently mild cases. (2) CM seems to be the most frequently reported culprit food. (3) In those cases in which acute FPIES is elicited by the direct consumption of the culprit food in breast-fed infants, maternal diet may be unrestricted. © 2014 S. Karger AG, Basel.

  6. Cryopyrin-associated Periodic Syndrome Caused by a Myeloid-Restricted Somatic NLRP3 Mutation

    PubMed Central

    Zhou, Qing; Aksentijevich, Ivona; Wood, Geryl M.; Walts, Avram D.; Hoffmann, Patrycja; Remmers, Elaine F.; Kastner, Daniel L.; Ombrello, Amanda K.

    2015-01-01

    Objective To identify the cause of disease in an adult patient presenting with recent onset fevers, chills, urticaria, fatigue, and profound myalgia, who was negative for cryopyrin-associated periodic syndrome (CAPS) NLRP3 mutations by conventional Sanger DNA sequencing. Methods We performed whole-exome sequencing and targeted deep sequencing using DNA from the patient’s whole blood to identify a possible NLRP3 somatic mutation. We then screened for this mutation in subcloned NLRP3 amplicons from fibroblasts, buccal cells, granulocytes, negatively-selected monocytes, and T and B lymphocytes and further confirmed the somatic mutation by targeted sequencing of exon 3. Results We identified a previously reported CAPS-associated mutation, p.Tyr570Cys, with a mutant allele frequency of 15% based on exome data. Targeted sequencing and subcloning of NLRP3 amplicons confirmed the presence of the somatic mutation in whole blood at a ratio similar to the exome data. The mutant allele frequency was in the range of 13.3%–16.8% in monocytes and 15.2%–18% in granulocytes; Notably, this mutation was either absent or present at a very low frequency in B and T lymphocytes, buccal cells, and in the patient’s cultured fibroblasts. Conclusion These data document the possibility of myeloid-restricted somatic mosaicism in the pathogenesis of CAPS, underscoring the emerging role of massively-parallel sequencing in clinical diagnosis. PMID:25988971

  7. Growth without growth hormone in combined pituitary hormone deficiency caused by pituitary stalk interruption syndrome

    PubMed Central

    Lee, Sang Soo; Han, A-Leum; Ahn, Moon Bae; Kim, Shin Hee; Cho, Kyoung Soon; Park, So Hyun; Jung, Min Ho; Suh, Byung-Kyu

    2017-01-01

    Growth hormone (GH) is an essential element for normal growth. However, reports of normal growth without GH have been made in patients who have undergone brain surgery for craniopharyngioma. Normal growth without GH can be explained by hyperinsulinemia, hyperprolactinemia, elevated leptin levels, and GH variants; however, its exact mechanism has not been elucidated yet. We diagnosed a female patient aged 13 with combined pituitary hormone deficiency (CPHD) caused by pituitary stalk interruption syndrome (PSIS). The patient has experienced recurrent hypoglycemic seizures since birth, but reached the height of 160 cm at the age of 13, showing normal growth. She grew another 8 cm for 3 years after the diagnosis, and she reached her final adult height of 168 cm which was greater than the midparental height, at the age of 16. The patient's blood GH and insulin-like growth factor-I levels were consistently subnormal, although her insulin levels were normal. Her physical examination conducted at the age of 15 showed truncal obesity, dyslipidemia, and osteoporosis, which are metabolic features of GH deficiency (GHD). Herein, we report a case in which a PSIS-induced CPHD patient attained her final height above mid parental height despite a severe GHD. PMID:28443260

  8. Growth without growth hormone in combined pituitary hormone deficiency caused by pituitary stalk interruption syndrome.

    PubMed

    Lee, Sang Soo; Han, A-Leum; Ahn, Moon Bae; Kim, Shin Hee; Cho, Won Kyoung; Cho, Kyoung Soon; Park, So Hyun; Jung, Min Ho; Suh, Byung-Kyu

    2017-03-01

    Growth hormone (GH) is an essential element for normal growth. However, reports of normal growth without GH have been made in patients who have undergone brain surgery for craniopharyngioma. Normal growth without GH can be explained by hyperinsulinemia, hyperprolactinemia, elevated leptin levels, and GH variants; however, its exact mechanism has not been elucidated yet. We diagnosed a female patient aged 13 with combined pituitary hormone deficiency (CPHD) caused by pituitary stalk interruption syndrome (PSIS). The patient has experienced recurrent hypoglycemic seizures since birth, but reached the height of 160 cm at the age of 13, showing normal growth. She grew another 8 cm for 3 years after the diagnosis, and she reached her final adult height of 168 cm which was greater than the midparental height, at the age of 16. The patient's blood GH and insulin-like growth factor-I levels were consistently subnormal, although her insulin levels were normal. Her physical examination conducted at the age of 15 showed truncal obesity, dyslipidemia, and osteoporosis, which are metabolic features of GH deficiency (GHD). Herein, we report a case in which a PSIS-induced CPHD patient attained her final height above mid parental height despite a severe GHD.

  9. Muenke Syndrome Mutation, FgfR3P244R, Causes TMJ Defects

    PubMed Central

    Yasuda, T.; Nah, H.D.; Laurita, J.; Kinumatsu, T.; Shibukawa, Y.; Shibutani, T.; Minugh-Purvis, N.; Pacifici, M.; Koyama, E.

    2012-01-01

    Muenke syndrome is characterized by various craniofacial deformities and is caused by an autosomal-dominant activating mutation in fibroblast growth factor receptor 3 (FGFR3P250R). Here, using mice carrying a corresponding mutation (FgfR3P244R), we determined whether the mutation affects temporomandibular joint (TMJ) development and growth. In situ hybridization showed that FgfR3 was expressed in condylar chondroprogenitors and maturing chondrocytes that also expressed the Indian hedgehog (Ihh) receptor and transcriptional target Patched 1(Ptch1). In FgfR3P244R mutants, the condyles displayed reduced levels of Ihh expression, H4C-positive proliferating chondroprogenitors, and collagen type II- and type X-expressing chondrocytes. Primary bone spongiosa formation was also disturbed and was accompanied by increased osteoclastic activity and reduced trabecular bone formation. Treatment of wild-type condylar explants with recombinant FGF2/FGF9 decreased Ptch1 and PTHrP expression in superficial/polymorphic layers and proliferation in chondroprogenitors. We also observed early degenerative changes of condylar articular cartilage, abnormal development of the articular eminence/glenoid fossa in the TMJ, and fusion of the articular disc. Analysis of our data indicates that the activating FgfR3P244R mutation disturbs TMJ developmental processes, likely by reducing hedgehog signaling and endochondral ossification. We suggest that a balance between FGF and hedgehog signaling pathways is critical for the integrity of TMJ development and for the maintenance of cellular organization. PMID:22622662

  10. MASA syndrome is caused by mutations in the neural cell adhesion gene, L1CAM

    SciT

    Schwartz, C.E.; Wang, Y.; Schroer, R.J.

    1994-09-01

    The MASA syndrome is a recessive X-linked disorder characterized by Mental retardation, Adducted thumbs, Shuffling gait and Aphasia. Recently we found that MASA in one family was likely caused by a point mutation in exon 6 of the L1CAM gene. This gene has also been shown to be involved in X-linked hydrocephalus (HSAS). We have screened 60 patients with either sporadic HSAS or MASA as well as two additional families with MASA. For the screening, we initially utilized 3 cDNA probes for the L1CAM gene. In one of the MASA families, K8310, two affected males were found to have anmore » altered BglII band. The band was present in their carrier mother but not in their normal brothers. This band was detected by the entire cDNA probe as well as the cDNA probe for 3{prime} end of the gene. Analysis of the L1CAM sequence indicated the altered BglII site is distal to the exon 28 but proximal to the punative poly A signal site. It is hypothesized that this point mutation alters the stability of the L1CAM mRNA. This is being tested using cell lines established from the two affected males.« less

  11. Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency.

    PubMed

    Mellor, Russell H; Tate, Naomi; Stanton, Anthony W B; Hubert, Charlotte; Mäkinen, Taija; Smith, Alberto; Burnand, Kevin G; Jeffery, Steve; Levick, J Rodney; Mortimer, Peter S

    2011-01-01

    Human lymphoedema distichiasis syndrome (LDS) results from germline mutations in transcription factor FOXC2. In a mouse model, lack of lymphatic and venous valves is observed plus abnormal smooth muscle cell recruitment to initial lymphatics. We investigated the mechanism of lymphoedema in humans with FOXC2 mutations, specifically the effect of gravitational forces on dermal lymphatic function. We performed (1) quantitative fluorescence microlymphangiography (FML) on the skin of the forearm (non-swollen region) at heart level, and the foot (swollen region) below heart level (dependent) and then at heart level, and (2) immunohistochemical staining of microlymphatics in forearm and foot skin biopsies, using antibodies to podoplanin, LYVE-1 and smooth muscle actin. FML revealed a marked reduction in fluid uptake by initial lymphatics in the LDS foot during dependency, yet normal uptake (similar to controls) in the same foot at heart level and in LDS forearms. In control subjects, dependency did not impair initial lymphatic filling. Immunohistochemical microlymphatic density in forearm and foot did not differ between LDS and controls. FOXC2 mutations cause a functional failure of dermal initial lymphatics during gravitational stress (dependency), but not hypoplasia. The results reveal a pathophysiological mechanism contributing to swelling in LDS. Copyright © 2011 S. Karger AG, Basel.

  12. Chronic Pain Syndrome Caused by a Bird's Nest Filter: First Case Report

    SciT

    Al-Basheer, Mamoun Ahmad, E-mail: drbasheer30@yahoo.co; Hamilton, Mark; Holdaway, Chris

    2008-07-15

    AimTo report the first case of a Bird's Nest IVC filter causing a chronic pain syndrome lasting 13 years through IVC wall penetration and subsequent break off of one of the filter struts.Materials and ResultsA 43-year-old female presented with a 13-year history of abdominal pain following uneventful insertion of a Bird's Nest vena cava filter through a right internal jugular percutanous approach. A year following the procedure, CT scan revealed one arm of the filter to be outside IVC borders. Nine years from the date of insertion the nature of the pain changed acutely following a five feet jump tomore » more localized RUQ pain worse with twisting movements. A CT scan showed the strut to have pierced the IVC wall and penetrated the Unicate process of pancreas. Plain x-rays taken at different times in February 2006 showed one of the struts to be free floating in the peritoneal cavity. The floating strut was removed surgically from the wall of the Ileum. Postoperative recovery was uneventful and the patient was discharged pain free three days later.ConclusionChronic pain is an added complication of BNF devices. Although rare, it further emphasizes the need for long-term follow up of patients with IVC filters.« less

  13. Causes of Cancer Death Among First-Degree Relatives in Japanese Families with Lynch Syndrome.

    PubMed

    Tanakaya, Kohji; Yamaguchi, Tatsuro; Ishikawa, Hideki; Hinoi, Takao; Furukawa, Yoichi; Hirata, Keiji; Saida, Yoshihisa; Shimokawa, Mototsugu; Arai, Masami; Matsubara, Nagahide; Tomita, Naohiro; Tamura, Kazuo; Sugano, Kokichi; Ishioka, Chikashi; Yoshida, Teruhiko; Ishida, Hideyuki; Watanabe, Toshiaki; Sugihara, Kenichi

    2016-04-01

    To elucidate the causes of cancer death in Japanese families with Lynch syndrome (LS). The distributions of cancer deaths in 485 individuals from 67 families with LS (35, 30, and two families with MutL homologue 1 (MLH1), MSH2, and MSH6 gene mutations, respectively), obtained from the Registry of the Japanese Society for Cancer of the Colon and Rectum were analyzed. Among 98 cancer deaths of first-degree relatives of unknown mutation status, 53%, 19%, 13% (among females), 7% (among females) and 5% were due to colorectal, gastric, uterine, ovarian, and hepatobiliary cancer, respectively. The proportion of deaths from extra-colonic cancer was significantly higher in families with MSH2 mutation than in those with MLH1 mutation (p=0.003). In addition to colonic and uterine cancer, management and surveillance targeting gastric, ovarian and hepatobiliary cancer are considered important for Japanese families with LS. Extra-colonic cancer in families with MSH2 mutation might require for more intensive surveillance. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome

    PubMed Central

    Deng, Zhong; Glousker, Galina; Molczan, Aliah; Fox, Alan J.; Lamm, Noa; Dheekollu, Jayaraju; Weizman, Orr-El; Schertzer, Michael; Wang, Zhuo; Vladimirova, Olga; Schug, Jonathan; Aker, Memet; Londoño-Vallejo, Arturo; Kaestner, Klaus H.; Lieberman, Paul M.; Tzfati, Yehuda

    2013-01-01

    Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal–Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres. PMID:23959892

  15. Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome.

    PubMed

    Deng, Zhong; Glousker, Galina; Molczan, Aliah; Fox, Alan J; Lamm, Noa; Dheekollu, Jayaraju; Weizman, Orr-El; Schertzer, Michael; Wang, Zhuo; Vladimirova, Olga; Schug, Jonathan; Aker, Memet; Londoño-Vallejo, Arturo; Kaestner, Klaus H; Lieberman, Paul M; Tzfati, Yehuda

    2013-09-03

    Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres.

  16. Three siblings with Prader-Willi syndrome caused by imprinting center microdeletions and review.

    PubMed

    Hartin, Samantha N; Hossain, Waheeda A; Weisensel, Nicolette; Butler, Merlin G

    2018-04-01

    Prader-Willi syndrome (PWS) is a complex genetic imprinting disorder characterized by childhood obesity, short stature, hypogonadism/hypogenitalism, hypotonia, cognitive impairment, and behavioral problems. Usually PWS occurs sporadically due to the loss of paternally expressed genes on chromosome 15 with the majority of individuals having the 15q11-q13 region deleted. Examples of familial PWS have been reported but rarely. To date 13 families have been reported with more than one child with PWS and without a 15q11-q13 deletion secondary to a chromosome 15 translocation, inversion, or uniparental maternal disomy 15. Ten of those 13 families were shown to carry microdeletions in the PWS imprinting center. The microdeletions were found to be of paternal origin in nine of the ten cases in which family studies were carried out. Using a variety of techniques, the microdeletions were identified in regions within the complex SNRPN gene locus encompassing the PWS imprinting center. Here, we report the clinical and genetic findings in three adult siblings with PWS caused by a microdeletion in the chromosome 15 imprinting center inherited from an unaffected father that controls the activity of genes in the 15q11-q13 region and summarize the 13 reported cases in the literature. © 2018 Wiley Periodicals, Inc.

  17. A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3.

    PubMed

    Chao, Hsiao-Tuan; Davids, Mariska; Burke, Elizabeth; Pappas, John G; Rosenfeld, Jill A; McCarty, Alexandra J; Davis, Taylor; Wolfe, Lynne; Toro, Camilo; Tifft, Cynthia; Xia, Fan; Stong, Nicholas; Johnson, Travis K; Warr, Coral G; Yamamoto, Shinya; Adams, David R; Markello, Thomas C; Gahl, William A; Bellen, Hugo J; Wangler, Michael F; Malicdan, May Christine V

    2017-01-05

    Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  18. Glucose ingestion causes cardiac repolarization disturbances in type 1 long QT syndrome patients and healthy subjects.

    PubMed

    Hyltén-Cavallius, Louise; Iepsen, Eva W; Christiansen, Michael; Graff, Claus; Linneberg, Allan; Pedersen, Oluf; Holst, Jens J; Hansen, Torben; Torekov, Signe S; Kanters, Jørgen K

    2017-08-01

    Both hypoglycemia and severe hyperglycemia constitute known risk factors for cardiac repolarization changes potentially leading to malignant arrhythmias. Patients with loss of function mutations in KCNQ1 are characterized by long QT syndrome (LQTS) and may be at increased risk for glucose-induced repolarization disturbances. The purpose of this study was to test the hypothesis that KCNQ1 LQTS patients are at particular risk for cardiac repolarization changes during the relative hyperglycemia that occurs after an oral glucose load. Fourteen KCNQ1 LQTS patients and 28 control participants matched for gender, body mass index, and age underwent a 3-hour oral 75-g glucose tolerance test with ECGs obtained at 7 time points. Fridericia corrected QT interval (QTcF), Bazett corrected QT interval (QTcB), and the Morphology Combination Score (MCS) were calculated. QTc and MCS increased in both groups. MCS remained elevated until 150 minutes after glucose ingestion, and the maximal change from baseline was larger among KCNQ1 LQTS patients compared with control subjects (0.28 ± 0.27 vs 0.15 ± 0.13; P <.05). Relative hyperglycemia induced by ingestion of 75-g glucose caused cardiac repolarization disturbances that were more severe in KCNQ1 LQTS patients compared with control subjects. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  19. Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

    PubMed

    Fergelot, Patricia; Van Belzen, Martine; Van Gils, Julien; Afenjar, Alexandra; Armour, Christine M; Arveiler, Benoit; Beets, Lex; Burglen, Lydie; Busa, Tiffany; Collet, Marie; Deforges, Julie; de Vries, Bert B A; Dominguez Garrido, Elena; Dorison, Nathalie; Dupont, Juliette; Francannet, Christine; Garciá-Minaúr, Sixto; Gabau Vila, Elisabeth; Gebre-Medhin, Samuel; Gener Querol, Blanca; Geneviève, David; Gérard, Marion; Gervasini, Cristina Giovanna; Goldenberg, Alice; Josifova, Dragana; Lachlan, Katherine; Maas, Saskia; Maranda, Bruno; Moilanen, Jukka S; Nordgren, Ann; Parent, Philippe; Rankin, Julia; Reardon, Willie; Rio, Marlène; Roume, Joëlle; Shaw, Adam; Smigiel, Robert; Sojo, Amaia; Solomon, Benjamin; Stembalska, Agnieszka; Stumpel, Constance; Suarez, Francisco; Terhal, Paulien; Thomas, Simon; Touraine, Renaud; Verloes, Alain; Vincent-Delorme, Catherine; Wincent, Josephine; Peters, Dorien J M; Bartsch, Oliver; Larizza, Lidia; Lacombe, Didier; Hennekam, Raoul C

    2016-12-01

    Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Major outbreak of toxic shock-like syndrome caused by Streptococcus mitis.

    PubMed

    Lu, Hong-Zhou; Weng, Xin-Hua; Zhu, Bai; Li, Haijing; Yin, You-Kuan; Zhang, Yong-Xin; Haas, David W; Tang, Yi-Wei

    2003-07-01

    Severe illness caused by viridans streptococci rarely occurs in immunocompetent hosts. Between December 1990 and May 1991, thousands of patients in the YangZi River Delta area of Jiangsu Province, China, suffered from scarlet fever-like pharyngitis. Fewer cases occurred in subsequent years with the same seasonality. Approximately half of the cases developed complications characteristic of streptococcal toxic shock-like syndrome (TSLS). Throat cultures yielded predominant growth of alpha-hemolytic streptococci. All cases admitted to Haian People's Hospital were investigated. Clinical specimens were collected, medical records were reviewed, and bacterial isolates were identified phenotypically and analyzed by 16S rRNA gene sequencing and pulsed-field gel electrophoresis (PFGE). Proteins were purified from culture supernatants by extraction, ammonium sulfate precipitation, and fast-protein liquid chromatography. Biological activities of protein components were determined by subcutaneous inoculation into rabbits. A total of 178 cases of non-beta-hemolytic streptococcal scarlet fever-like pharyngitis were studied. In 88 (79.3%) of 111 patients, oropharyngeal swab cultures grew morphologically identical alpha-hemolytic streptococci. A protein in culture supernatants was pyrogenic in rabbits, was mitogenic for splenocytes, and enhanced rabbit susceptibility to endotoxin challenge. The N-terminal amino acid sequence of this 34-kDa protein showed no homology with known Streptococcus pyrogenic exotoxins. The organism was identified as Streptococcus mitis based on biochemical and 16S rRNA sequence analyses. Representative outbreak isolates from 1990 to 1995 displayed identical PFGE patterns. This TSLS outbreak in southeastern China was caused by a toxigenic clone of S. mitis. An apparently novel toxin may explain the unusual virulence of this organism.

  1. Clinical Characteristics and Prognosis of Pulmonary Embolism Caused by Economy Class Syndrome.

    PubMed

    Abellás, María; Menéndez, Ana; Morillo, Raquel; Jara-Palomares, Luis; Barrios, Deisy; Nieto, Rosa; Barbero, Esther; Corres, Jesús; Ruiz-Artacho, Pedro; Jiménez, David

    2017-09-01

    Clinical presentation and short-term prognosis of patients with travel-associated acute pulmonary embolism (PE) (i.e., economy class syndrome [ECS]) is not well understood. In this retrospective cohort study of patients with acute PE identified from a single center registry, we assessed the clinical presentation and the association between ECS and the outcomes of all-cause mortality, PE-related mortality, nonfatal venous thromboembolism and nonfatal major bleeding rates through 30days after initiation of PE treatment. Of the 2,333 patients with acute symptomatic PE, 124 (5.3%; 95% confidence interval, 4.4-6.3%) had ECS. Patients with ECS were younger and had fewer comorbid diseases (recent bleeding, chronic obstructive pulmonary disease, congestive heart failure), but they presented with more signs of clinical severity (syncope [48% vs. 14%; P<.001], tachycardia [37% vs. 21%; P<.001], right ventricular dysfunction [31% vs. 19%; P<.01] and myocardial injury [57% vs. 28%; P<.001]) compared to those without ECS. Regression analyses showed a significantly lower risk of all-cause mortality for patients with ECS compared to patients without ECS (1.6% vs. 9.6%; P<.01). We did not detect a difference in PE-related mortality at 30days between those with and those without ECS (0.8% vs. 3.1%; P=.18). PE patients with ECS are younger and have fewer comorbid diseases compared to those without ECS. Though they present with more signs of clinical severity, their short-term prognosis is excellent. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome

    PubMed Central

    Garone, Caterina; D’Souza, Aaron R; Dallabona, Cristina; Lodi, Tiziana; Rebelo-Guiomar, Pedro; Rorbach, Joanna; Donati, Maria Alice; Procopio, Elena; Montomoli, Martino; Guerrini, Renzo; Zeviani, Massimo; Calvo, Sarah E; Mootha, Vamsi K; DiMauro, Salvatore; Ferrero, Ileana; Minczuk, Michal

    2017-01-01

    Abstract Defects in nuclear-encoded proteins of the mitochondrial translation machinery cause early-onset and tissue-specific deficiency of one or more OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encephalomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreased mtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was excluded. Targeted exome sequencing of genes encoding the mitochondrial proteome identified a damaging mutation, c.567 G > A, affecting a highly conserved amino acid residue (p.Gly189Arg) of the MRM2 protein. MRM2 has never before been linked to a human disease and encodes an enzyme responsible for 2’-O-methyl modification at position U1369 in the human mitochondrial 16S rRNA. We generated a knockout yeast model for the orthologous gene that showed a defect in respiration and the reduction of the 2’-O-methyl modification at the equivalent position (U2791) in the yeast mitochondrial 21S rRNA. Complementation with the mrm2 allele carrying the equivalent yeast mutation failed to rescue the respiratory phenotype, which was instead completely rescued by expressing the wild-type allele. Our findings establish that defective MRM2 causes a MELAS-like phenotype, and suggests the genetic screening of the MRM2 gene in patients with a m.3243 A > G negative MELAS-like presentation. PMID:28973171

  3. Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome.

    PubMed

    Garone, Caterina; D'Souza, Aaron R; Dallabona, Cristina; Lodi, Tiziana; Rebelo-Guiomar, Pedro; Rorbach, Joanna; Donati, Maria Alice; Procopio, Elena; Montomoli, Martino; Guerrini, Renzo; Zeviani, Massimo; Calvo, Sarah E; Mootha, Vamsi K; DiMauro, Salvatore; Ferrero, Ileana; Minczuk, Michal

    2017-11-01

    Defects in nuclear-encoded proteins of the mitochondrial translation machinery cause early-onset and tissue-specific deficiency of one or more OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encephalomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreased mtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was excluded. Targeted exome sequencing of genes encoding the mitochondrial proteome identified a damaging mutation, c.567 G > A, affecting a highly conserved amino acid residue (p.Gly189Arg) of the MRM2 protein. MRM2 has never before been linked to a human disease and encodes an enzyme responsible for 2'-O-methyl modification at position U1369 in the human mitochondrial 16S rRNA. We generated a knockout yeast model for the orthologous gene that showed a defect in respiration and the reduction of the 2'-O-methyl modification at the equivalent position (U2791) in the yeast mitochondrial 21S rRNA. Complementation with the mrm2 allele carrying the equivalent yeast mutation failed to rescue the respiratory phenotype, which was instead completely rescued by expressing the wild-type allele. Our findings establish that defective MRM2 causes a MELAS-like phenotype, and suggests the genetic screening of the MRM2 gene in patients with a m.3243 A > G negative MELAS-like presentation. © The Author 2017. Published by Oxford University Press.

  4. Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome

    PubMed Central

    Jacobs, Damon T.; Silva, Luciane M.; Allard, Bailey A.; Schonfeld, Michael P.; Chatterjee, Anindita; Talbott, George C.

    2016-01-01

    ABSTRACT Primary cilia extend from the plasma membrane of most vertebrate cells and mediate signaling pathways. Ciliary dysfunction underlies ciliopathies, which are genetic syndromes that manifest multiple clinical features, including renal cystic disease and obesity. THM1 (also termed TTC21B or IFT139) encodes a component of the intraflagellar transport-A complex and mutations in THM1 have been identified in 5% of individuals with ciliopathies. Consistent with this, deletion of murine Thm1 during late embryonic development results in cystic kidney disease. Here, we report that deletion of murine Thm1 during adulthood results in obesity, diabetes, hypertension and fatty liver disease, with gender differences in susceptibility to weight gain and metabolic dysfunction. Pair-feeding of Thm1 conditional knock-out mice relative to control littermates prevented the obesity and related disorders, indicating that hyperphagia caused the obese phenotype. Thm1 ablation resulted in increased localization of adenylyl cyclase III in primary cilia that were shortened, with bulbous distal tips on neurons of the hypothalamic arcuate nucleus, an integrative center for signals that regulate feeding and activity. In pre-obese Thm1 conditional knock-out mice, expression of anorexogenic pro-opiomelanocortin (Pomc) was decreased by 50% in the arcuate nucleus, which likely caused the hyperphagia. Fasting of Thm1 conditional knock-out mice did not alter Pomc nor orexogenic agouti-related neuropeptide (Agrp) expression, suggesting impaired sensing of changes in peripheral signals. Together, these data indicate that the Thm1-mutant ciliary defect diminishes sensitivity to feeding signals, which alters appetite regulation and leads to hyperphagia, obesity and metabolic disease. PMID:27482817

  5. Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome.

    PubMed

    Jacobs, Damon T; Silva, Luciane M; Allard, Bailey A; Schonfeld, Michael P; Chatterjee, Anindita; Talbott, George C; Beier, David R; Tran, Pamela V

    2016-07-01

    Primary cilia extend from the plasma membrane of most vertebrate cells and mediate signaling pathways. Ciliary dysfunction underlies ciliopathies, which are genetic syndromes that manifest multiple clinical features, including renal cystic disease and obesity. THM1 (also termed TTC21B or IFT139) encodes a component of the intraflagellar transport-A complex and mutations in THM1 have been identified in 5% of individuals with ciliopathies. Consistent with this, deletion of murine Thm1 during late embryonic development results in cystic kidney disease. Here, we report that deletion of murine Thm1 during adulthood results in obesity, diabetes, hypertension and fatty liver disease, with gender differences in susceptibility to weight gain and metabolic dysfunction. Pair-feeding of Thm1 conditional knock-out mice relative to control littermates prevented the obesity and related disorders, indicating that hyperphagia caused the obese phenotype. Thm1 ablation resulted in increased localization of adenylyl cyclase III in primary cilia that were shortened, with bulbous distal tips on neurons of the hypothalamic arcuate nucleus, an integrative center for signals that regulate feeding and activity. In pre-obese Thm1 conditional knock-out mice, expression of anorexogenic pro-opiomelanocortin (Pomc) was decreased by 50% in the arcuate nucleus, which likely caused the hyperphagia. Fasting of Thm1 conditional knock-out mice did not alter Pomc nor orexogenic agouti-related neuropeptide (Agrp) expression, suggesting impaired sensing of changes in peripheral signals. Together, these data indicate that the Thm1-mutant ciliary defect diminishes sensitivity to feeding signals, which alters appetite regulation and leads to hyperphagia, obesity and metabolic disease. © 2016. Published by The Company of Biologists Ltd.

  6. [Neurological syndromes linked with the intake of plants and fungi containing a toxic component (I). Neurotoxic syndromes caused by the ingestion of plants, seeds and fruits].

    PubMed

    Carod-Artal, F J

    A wide range of plants, seeds and fruits used for nutritional and medicinal purposes can give rise to neurotoxic symptoms. We review the neurological pathology associated with the acute or chronic consumption of plants, seeds and fruits in human beings and in animals. Of the plants that can trigger acute neurotoxic syndromes in humans, some of the most notable include Mandragora officinalis, Datura stramonium, Conium maculatum (hemlock), Coriaria myrtifolia (redoul), Ricinus communis, Gloriosa superba, Catharanthus roseus, Karwinskia humboldtiana and Podophyllum pelatum. We also survey different neurological syndromes linked with the ingestion of vegetable foodstuffs that are rich in cyanogenic glycosides, Jamaican vomiting sickness caused by Blighia sapida, Parkinson dementia ALS of Guam island and exposition to Cycas circinalis, Guadeloupean parkinsonism and exposition to Annonaceae, konzo caused by ingestion of wild manioc and neurolathyrism from ingestion of Lathyrus sativus, the last two being models of motor neurone disease. Locoism is a chronic disease that develops in livestock feeding on plants belonging to Astragalus and Oxytropis sp., Sida carpinifolia and Ipomea carnea, which are rich in swainsonine, a toxin that inhibits the enzyme alpha mannosidase and induces a cerebellar syndrome. The ingestion of neurotoxic seeds, fruits and plants included in the diet and acute poisoning by certain plants can give rise to different neurological syndromes, some of which are irreversible.

  7. Recurrent menstrual toxic shock syndrome despite discontinuation of tampon use: is menstrual toxic shock syndrome really caused by tampons?

    PubMed

    Dixit, Shreya; Fischer, Gayle; Wittekind, Carola

    2013-11-01

    Menstrual toxic shock syndrome (MTSS) is a rare and potentially life-threatening illness. We present a case of recurrent MTSS initially associated with tampon use that continued to recur when tampons were discontinued, which was successfully treated with rifampicin and clindamycin. © 2012 The Authors Australasian Journal of Dermatology © 2012 The Australasian College of Dermatologists.

  8. Moyamoya disease associated with asymptomatic mosaic Turner syndrome: a rare cause of hemorrhagic stroke.

    PubMed

    Manjila, Sunil; Miller, Benjamin R; Rao-Frisch, Anitha; Otvos, Balint; Mitchell, Anna; Bambakidis, Nicholas C; De Georgia, Michael A

    2014-01-01

    Moyamoya disease is a rare cerebrovascular anomaly involving the intracranial carotid arteries that can present clinically with either ischemic or hemorrhagic disease. Moyamoya syndrome, indistinguishable from moyamoya disease at presentation, is associated with multiple clinical conditions including neurofibromatosis type 1, autoimmune disease, prior radiation therapy, Down syndrome, and Turner syndrome. We present the first reported case of an adult patient with previously unrecognized mosaic Turner syndrome with acute subarachnoid and intracerebral hemorrhage as the initial manifestation of moyamoya syndrome. A 52-year-old woman was admitted with a subarachnoid hemorrhage with associated flame-shaped intracerebral hemorrhage in the left frontal lobe. Physical examination revealed short stature, pectus excavatum, small fingers, micrognathia, and mild facial dysmorphism. Cerebral angiography showed features consistent with bilateral moyamoya disease, aberrant intrathoracic vessels, and an unruptured 4-mm right superior hypophyseal aneurysm. Genetic analysis confirmed a diagnosis of mosaic Turner syndrome. Our case report is the first documented presentation of adult moyamoya syndrome with subarachnoid and intracerebral hemorrhage as the initial presentation of mosaic Turner syndrome. It illustrates the utility of genetic evaluation in patients with cerebrovascular disease and dysmorphism. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  9. [Graft-versus-host disease as the cause of symptoms mimicking Sjögren's syndrome].

    PubMed

    Tuchocka-Piotrowska, Aleksandra; Puszczewicz, Mariusz; Kołczewska, Aleksandra; Majewski, Dominik

    2006-01-01

    A case of chronic graft-versus-host disease (chronic GvHD) mimicking symptoms associated with idiopathic Sjögren's syndrome is presented. Hypotheses on the pathophysiological origin of clinical syndromes associated with graft-versus-host disease are discussed.

  10. Acute Compartment Syndrome Which Causes Rhabdomyolysis by Carbon Monoxide Poisoning and Sciatic Nerve Injury Associated with It: A Case Report.

    PubMed

    Ji, Jung-Woo

    2017-09-01

    Rhabdomyolysis is most frequently caused by soft tissue injury with trauma to the extremities. Non-traumatic rhabdomyolysis may be caused by alcohol or drug abuse, infection, collagen disease, or intensive exercise, but incidence is low. In particular, rhabdomyolysis resulting from carbon monoxide poisoning is especially rare. If caught before death, carbon monoxide poisoning has been shown to cause severe muscle necrosis and severe muscle damage leading to acute renal failure. In cases of carbon-monoxide-induced rhabdomyolsis leading to acute compartment syndrome in the buttocks and sciatic nerve injury are rare. We have experience treating patients with acute compartment syndrome due to rhabdomyolysis following carbon monoxide poisoning. We report the characteristic features of muscle necrosis observed during a decompression operation and magnetic resonance imaging findings with a one-year follow-up in addition to a review of the literature.

  11. [From gene to disease; genetic causes of hearing loss and visual impairment sometimes accompanied by vestibular problems (Usher syndrome)].

    PubMed

    Pennings, R J E; Kremer, H; Deutman, A F; Kimberling, W J; Cremers, C W R J

    2002-12-07

    Usher syndrome is an autosomal recessively inherited disease, characterised by sensorineural hearing loss, tapetoretinal degeneration and in some cases vestibular problems. Based on the clinical heterogeneity, the disease can be classified into three clinical types (I, II and III), which have their own genetic subtypes (Usher 1A-Usher IG, Usher 2A-Usher 2C and Usher 3). The majority of the Usher type I cases are caused by mutations in the MYO7A gene (Usher 1B) while mutations in the USH2A gene (Usher 2A) are the cause of most cases of type II. Usher syndrome type III, caused by mutations in the USH3 gene, is frequently seen only in Finland.

  12. A rare cause of acute abdominal pain: Herlyn-Werner-Wunderlich syndrome.

    PubMed

    Aydin, Ramazan; Ozdemir, Ayse Zehra; Ozturk, Bahadir; Bilgici, Meltem Ceyhan; Tosun, Migraci

    2014-01-01

    Herlyn-Werner-Wunderlich (HWW) syndrome is a rare müllerian duct anomaly with uterus didelphys, unilateral obstructed hemivagina, and ipsilateral renal agenesis. Patients with this syndrome generally present after menarche with pelvic pain and mass and, rarely, primary infertility in later years. Strong suspicion and knowledge of this syndrome are mandatory for an accurate diagnosis. A 14-year-old female patient presented with acute retention of urine and abdominopelvic pain. Her condition was diagnosed with the use ultrasonography and magnetic resonance imaging as a case of HWW syndrome. She was treated with vaginal hemiseptal resection. The HWW syndrome should be considered among the differential diagnoses in girls with renal anomalies presenting with pelvic mass, symptoms of acute abdominal pain, and acute urinary retention.

  13. Enterohemorrhagic Escherichia coli as Causes of Hemolytic Uremic Syndrome in the Czech Republic

    PubMed Central

    Marejková, Monika; Bláhová, Květa; Janda, Jan; Fruth, Angelika; Petráš, Petr

    2013-01-01

    Background Enterohemorrhagic Escherichia coli (EHEC) cause diarrhea-associated hemolytic uremic syndrome (D+ HUS) worldwide, but no systematic study of EHEC as the causative agents of HUS was performed in the Czech Republic. We analyzed stools of all patients with D+ HUS in the Czech Republic between 1998 and 2012 for evidence of EHEC infection. We determined virulence profiles, phenotypes, antimicrobial susceptibilities and phylogeny of the EHEC isolates. Methodology/Principal Findings Virulence loci were identified using PCR, phenotypes and antimicrobial susceptibilities were determined using standard procedures, and phylogeny was assessed using multilocus sequence typing. During the 15-year period, EHEC were isolated from stools of 39 (69.4%) of 56 patients. The strains belonged to serotypes [fliC types] O157:H7/NM[fliC H7] (50% of which were sorbitol-fermenting; SF), O26:H11/NM[fliC H11], O55:NM[fliC H7], O111:NM[fliC H8], O145:H28[fliC H28], O172:NM[fliC H25], and Orough:NM[fliC H25]. O26:H11/NM[fliC H11] was the most common serotype associated with HUS (41% isolates). Five stx genotypes were identified, the most frequent being stx 2a (71.1% isolates). Most strains contained EHEC-hlyA encoding EHEC hemolysin, and a subset (all SF O157:NM and one O157:H7) harbored cdt-V encoding cytolethal distending toxin. espPα encoding serine protease EspPα was found in EHEC O157:H7, O26:H11/NM, and O145:H28, whereas O172:NM and Orough:NM strains contained espPγ. All isolates contained eae encoding adhesin intimin, which belonged to subtypes β (O26), γ (O55, O145, O157), γ2/θ (O111), and ε (O172, Orough). Loci encoding other adhesins (efa1, lpfA O26, lpfA O157OI-141, lpfA O157OI-154, iha) were usually associated with particular serotypes. Phylogenetic analysis demonstrated nine sequence types (STs) which correlated with serotypes. Of these, two STs (ST660 and ST1595) were not found in HUS-associated EHEC before. Conclusions/Significance EHEC strains, including O157:H

  14. Antiphospholipid Syndrome with Antiβ2glicoprotein-1 Antibodies as the Cause of Recurrent Tibial Vein Thrombosis in SAPHO syndrome.

    PubMed

    Przepiera-Będzak, Hanna; Brzosko, Marek

    2016-12-01

    thrombosis in this syndrome, but the patient with multiple venous thrombosis presented in his case report was negative for aCL antibodies; however, he was not tested for anti-β2G-1 antibodies. There was a paper demonstrating increased level of aCL antibodies in 5 of 12 patients with SAPHO syndrome (11). In our observations of 17 patients with SAPHO syndrome, only 1 had increased level of aCL antibodies without symptoms of thrombosis (12). That patient was negative for aCL antibodies, aPT antibodies, aPS antibodies, and antiphosphatidylserine antibodies, but she was positive twice for anti-β2G-1 antibodies. The presence of anti-β2G-1antibodies may be caused by an infectious agent, but in our case bacteria culture of the discharge from pustules was negative. One year after the first episode of deep vein thrombosis, our patient met the criteria of antiphospholipid syndrome. We conclude that antiphospholipid syndrome, especially the presence of anti-β2G-1 antibodies, could be the cause of increased risk of vein thrombosis in SAPHO syndrome.

  15. Whole Exome Sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome

    PubMed Central

    Martinez, Fernando; Lee, Jeong Ho; Lee, Ji Eun; Blanco, Sandra; Nickerson, Elizabeth; Gabriel, Stacey; Frye, Michaela; Al-Gazali, Lihadh; Gleeson, Joseph G.

    2016-01-01

    Dubowitz Syndrome is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies, but causes are still unknown. We studied a multiplex consanguineous family with many features of Dubowitz syndrome using whole exome sequencing and identified a splice mutation in NSUN2, encoding a conserved RNA methyltransferase. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentations that can include chromosomal instability and immunological defects. Patient cells displayed loss of NSUN2-specific methylation at two residues of the aspartate tRNA. Our findings establish NSUN2 as the first causal gene with relationship to the Dubowitz syndrome spectrum phenotype. PMID:22577224

  16. Leigh syndrome caused by a novel m.4296G>A mutation in mitochondrial tRNA isoleucine.

    PubMed

    Cox, Rachel; Platt, Julia; Chen, Li Chieh; Tang, Sha; Wong, Lee-Jun; Enns, Gregory M

    2012-03-01

    Leigh syndrome is a severe neurodegenerative disease with heterogeneous genetic etiology. We report a novel m.4296G>A variant in the mitochondrial tRNA isoleucine gene in a child with Leigh syndrome, mitochondrial proliferation, lactic acidosis, and abnormal respiratory chain enzymology. The variant is present at >75% heteroplasmy in blood and cultured fibroblasts from the proband, <5% in asymptomatic maternal relatives, and is absent in 3000 controls. It is located in the highly conserved anticodon region of tRNA(Ile) where three other pathogenic changes have been described. We conclude that there is strong evidence to classify m.4296G>A as a pathogenic mutation causing Leigh syndrome. Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  17. Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome Caused by Crystal-Induced Arthritis of the Wrist: A Case Report

    PubMed Central

    Hakozaki, Michiyuki; Fukuda, Hironari; Tajino, Takahiro; Kikuchi, Shinichi; Abe, Satoshi; Konno, Shinichi

    2013-01-01

    Objective To describe a rare case of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome caused by gouty arthritis. Clinical Presentation and Intervention A 76-year-old man presented with swelling and pain in the dorsum of feet and hands bilaterally. From the laboratory and radiologic findings, the diagnosis of gout-induced RS3PE syndrome was made. Conservative therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular corticosteroid injection in the wrist joint completely and rapidly resolved all symptoms. The patient was successfully treated with oral administration of NSAIDs and a one-time intra-articular corticosteroid injection in the left wrist joint. Conclusion This case demonstrated the importance of considering the possibility of crystal-induced arthritis such as gout and pseudogout, as well as malignant disease, when diagnosing the primary disease responsible for RS3PE syndrome. PMID:23006891

  18. Obstructive sleep apnea syndrome in Prader-Willi Syndrome: an unrecognized and untreated cause of cognitive and behavioral deficits?

    PubMed

    Camfferman, Danny; Lushington, Kurt; O'Donoghue, Fergal; Doug McEvoy, R

    2006-09-01

    Prader-Willi Syndrome (PWS) is a rare genetic disorder characterized by a range of physical, psychological, and physiological abnormalities. It is also distinguished by the high prevalence of obstructive sleep apnea syndrome (OSAS), i.e., repetitive upper airway collapse during sleep resulting in hypoxia and sleep fragmentation. In non-PWS populations, OSAS is associated with a range of neurocognitive and psychosocial deficits. Importantly, these deficits are at least partly reversible following treatment. Given the findings in non-PWS populations, it is possible that OSAS may contribute to neurocognitive and psychosocial deficits in PWS. The present review examines this possibility. While acknowledging a primary contribution from the primary genetic abnormality to central neural dysfunction in PWS, we conclude that OSAS may be an important secondary contributing factor to reduced neurocognitive and psychosocial performance. Treatment of OSAS may have potential benefits in improving neurocognitive performance and behavior in PWS, but this awaits confirmatory investigation.

  19. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)

    PubMed Central

    Doherty, D; Parisi, M A; Finn, L S; Gunay-Aygun, M; Al-Mateen, M; Bates, D; Clericuzio, C; Demir, H; Dorschner, M; van Essen, A J; Gahl, W A; Gentile, M; Gorden, N T; Hikida, A; Knutzen, D; Özyurek, H; Phelps, I; Rosenthal, P; Verloes, A; Weigand, H; Chance, P F; Dobyns, W B; Glass, I A

    2011-01-01

    Objective To identify genetic causes of COACH syndrome Background COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). Methods In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. Results 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). Conclusions Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L. PMID:19574260

  20. Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes.

    PubMed

    Schultz, Julie M; Bhatti, Rashid; Madeo, Anne C; Turriff, Amy; Muskett, Julie A; Zalewski, Christopher K; King, Kelly A; Ahmed, Zubair M; Riazuddin, Saima; Ahmad, Nazir; Hussain, Zawar; Qasim, Muhammad; Kahn, Shaheen N; Meltzer, Meira R; Liu, Xue Z; Munisamy, Murali; Ghosh, Manju; Rehm, Heidi L; Tsilou, Ekaterini T; Griffith, Andrew J; Zein, Wadih M; Brewer, Carmen C; Riazuddin, Sheikh; Friedman, Thomas B

    2011-11-01

    Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth. To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele. One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.

  1. Is disomic homozygosity at the APECED locus the cause of increased autoimmunity in Down's syndrome?

    PubMed Central

    Shield, J.; Wadsworth, E.; Hassold, T.; Judis, L. A.; Jacobs, P.

    1999-01-01

    AIMS—To examine the age of onset of insulin dependent diabetes mellitus (IDDM) in children with Down's syndrome compared with non-trisomic individuals, and to assess whether differences might be related to disomic homozygosity at the autoimmune polyglandular disease type 1 (APECED) gene locus.
METHODS—Children with Down's syndrome and IDDM were identified through the Down's syndrome association newsletter and from paediatricians. DNA was extracted from mouthbrush preparations provided by the parents and patients using standard techniques. Mapping techniques were then used to identify areas of reduction to homozygosity, including a marker that overlaps the locus for APECED. The frequency of disomic homozygosity for all markers (n = 18) was compared with a control group of 99 patients with Down's syndrome and their parents. The families also answered a questionnaire concerning diabetes and related autoimmune conditions in the family. Details were compared with the British Paediatric Surveillance Group 1988diabetes study.
RESULTS—Children with Down's syndrome and IDDM were diagnosed significantly earlier than the general population (6.7 v 8.0 years) with a far higher proportion diagnosed in the first 2 years of life (22% v 7%). There was no evidence of increased disomic homozygosity in the region of the APECED locus in Down's syndrome patients with IDDM compared with simple Down's syndrome.
CONCLUSIONS—The natural history of IDDM in Down's syndrome is different from that of the general population. Although children with Down's syndrome have features similar to cases of APECED, disomic homozygosity in this region does not explain the predilection for autoimmune disease.

 PMID:10490523

  2. Inability to have children caused by recurrent HELLP syndrome in early pregnancies - implications for a review of literature.

    PubMed

    Pawelec, Małgorzata; Karmowski, Andrzej; Karmowski, Mikołaj; Krzemieniewska, Joanna; Kulczycka, Aleksandra; Gabryś, Marian Stanisław; Koryś, Jerzy; Gworys, Bohdan

    2013-01-01

    This review is inspired by a case of two pregnancies of the same patient complicated by HELLP syndrome, which suggests that there is a predisposition for the occurrence of preeclampsia and HELLP syndrome in early pregnancy. HELLP syndrome, uncommon below the 20th week and rarer still in two consecutive pregnancies, appeared in two pregnancies of the same woman. The aim of our work is to try to understand the cause of heterogeneity of HELLP syndrome and help find a way of prolonging such pregnancies. Recurrent HELLP syndrome in early pregnancy is a form of severe, fulminant preeclampsia. The preceding symptom is a surge in blood pressure. The hypertension becomes resistant to antihypertensive drugs, which indicates that preexisting hypertension is later accompanied by other factors contributing to the rise in blood pressure. Different effects of high dosage of corticosteroids on liver and platelets show that there are different factors responsible for liver damage and for thrombocytopenia. It seems that the symptoms have various origins, so the therapy with one drug only is not sufficiently effective. Nicotine analogues or a plant extract (from rootstock of Eriosema kraussianum) used by South African traditional healers for erectile dysfunction seem to give a chance of prolonging pregnancy and, consequently, having children.

  3. Noonan Syndrome: An Underestimated Cause of Severe to Profound Sensorineural Hearing Impairment. Which Clues to Suspect the Diagnosis?

    PubMed

    Ziegler, Alban; Loundon, Natalie; Jonard, Laurence; Cavé, Hélène; Baujat, Geneviève; Gherbi, Souad; Couloigner, Vincent; Marlin, Sandrine

    2017-09-01

    To highlight Noonan syndrome as a clinically recognizable cause of severe to profound sensorineural hearing impairment. New clinical cases and review. Patients evaluated for etiological diagnosis by a medical geneticist in a reference center for hearing impairment. Five patients presenting with confirmed Noonan syndrome and profound sensorineural hearing impairment. Diagnostic and review of the literature. Five patients presented with profound sensorineural hearing impairment and molecularly confirmed Noonan syndrome. Sensorineural hearing impairment has been progressive for three patients. Cardiac echography identified pulmonary stenosis in two patients and was normal for the three other patients. Short stature was found in two patients. Mild intellectual disability was found in one patient. Inconspicuous clinical features as facial dysmorphism, cryptorchidism, or easy bruising were of peculiar interest to reach the diagnosis of Noonan syndrome. Profound sensorineural hearing impairment can be the main feature of Noonan syndrome. Associated features are highly variable; thus, detailed medical history and careful physical examination are mandatory to consider the diagnosis in case of a sensorineural hearing impairment.

  4. Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation.

    PubMed

    Schüle, Birgitt; Oviedo, Angelica; Johnston, Kathreen; Pai, Shashidhar; Francke, Uta

    2005-12-01

    The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency. SC phocomelia (SC) has a milder phenotype, with a lesser degree of limb reduction and with survival to adulthood. Since heterochromatin repulsion (HR) is characteristic for both disorders and is not complemented in somatic-cell hybrids, it has been hypothesized that the disorders are allelic. Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS. To determine whether ESCO2 mutations are also responsible for SC, we studied three families with SC and two families in which variable degrees of limb and craniofacial abnormalities, detected by fetal ultrasound, led to pregnancy terminations. All cases were positive for HR. We identified seven novel mutations in exons 3-8 of ESCO2. In two families, affected individuals were homozygous--for a 5-nucleotide deletion in one family and a splice-site mutation in the other. In three nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice-site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype. Having established that RBS and SC are caused by mutations in the same gene, we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR.

  5. Inactivating Mutations in ESCO2 Cause SC Phocomelia and Roberts Syndrome: No Phenotype-Genotype Correlation

    PubMed Central

    Schüle, Birgitt; Oviedo, Angelica; Johnston, Kathreen; Pai, Shashidhar; Francke, Uta

    2005-01-01

    The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency. SC phocomelia (SC) has a milder phenotype, with a lesser degree of limb reduction and with survival to adulthood. Since heterochromatin repulsion (HR) is characteristic for both disorders and is not complemented in somatic-cell hybrids, it has been hypothesized that the disorders are allelic. Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS. To determine whether ESCO2 mutations are also responsible for SC, we studied three families with SC and two families in which variable degrees of limb and craniofacial abnormalities, detected by fetal ultrasound, led to pregnancy terminations. All cases were positive for HR. We identified seven novel mutations in exons 3–8 of ESCO2. In two families, affected individuals were homozygous—for a 5-nucleotide deletion in one family and a splice-site mutation in the other. In three nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice-site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype. Having established that RBS and SC are caused by mutations in the same gene, we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR. PMID:16380922

  6. Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)

    PubMed Central

    Heon, Elise; Kim, Gunhee; Qin, Sophie; Garrison, Janelle E.; Tavares, Erika; Vincent, Ajoy; Nuangchamnong, Nina; Scott, C. Anthony; Slusarski, Diane C.; Sheffield, Val C.

    2016-01-01

    Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17-year-old female affected with BBS did not identify any mutation in the known BBS genes. Whole-genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) in C8ORF37, a gene coding for a cilia protein. The proband was overweight (body mass index 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, three limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus and elevated liver enzymes. Mutations in C8ORF37 were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role of C8ORF37 in a vertebrate system, we performed gene knockdown in Danio rerio and assessed the cardinal features of BBS and visual function. Knockdown of c8orf37 resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer’s vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association of C8ORF37 mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show that C8ORF37 variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration. PMID:27008867

  7. Defective membrane expression of human growth hormone (GH) receptor causes Laron-type GH insensitivity syndrome.

    PubMed Central

    Duquesnoy, P; Sobrier, M L; Amselem, S; Goossens, M

    1991-01-01

    Mutations in the growth hormone receptor (GHR) gene can cause growth hormone (GH) resistance. Given the sequence homology between the extracellular domain of the GHR and a soluble GH-binding protein (GH-BP), it is remarkable that GH-BP binding activity is absent from the serum of patients with Laron-type GH insensitivity, a hereditary form of severe dwarfism. We have previously identified a mutation within the extracellular domain of this receptor, replacing phenylalanine by serine at position 96 of the mature protein, in a patient with Laron syndrome. We have now investigated the effect of this Phe----Ser substitution on hormone binding activity by expressing the total human GHR cDNA and mutant form in eukaryotic cells. The wild-type protein expressed was able to bind GH but no plasma membrane binding was detectable on cells transfected with the mutant cDNA; this was also the case of cells transfected with a Phe96----Ala mutant cDNA, suggesting that the lack of binding activity is not due to a posttranslational modification of serine. Examination of the variant proteins in subcellular fractions revealed the presence of specific GH binding activity in the lysosomal fraction, whereas immunofluorescence studies located mutant proteins in the cytosol. Our findings suggest that these mutant GHRs fail to follow the correct intracellular transport pathway and underline the potential importance of this phenylalanine residue, which is conserved among the GH, prolactin, and erythropoietin receptors that belong to the same cytokine receptor superfamily. Images PMID:1719554

  8. A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma

    PubMed Central

    Micheal, Shazia; Villanueva-Mendoza, Cristina; Cortés-González, Vianney; Khan, Muhammad Imran; den Hollander, Anneke I.

    2016-01-01

    Background Anterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders. Methods We studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes. Results Mutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma. Conclusions Our study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development. PMID:27463523

  9. A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma.

    PubMed

    Micheal, Shazia; Siddiqui, Sorath Noorani; Zafar, Saemah Nuzhat; Villanueva-Mendoza, Cristina; Cortés-González, Vianney; Khan, Muhammad Imran; den Hollander, Anneke I

    2016-01-01

    Anterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders. We studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes. Mutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma. Our study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development.

  10. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

    PubMed

    Lal, Dennis; Reinthaler, Eva M; Dejanovic, Borislav; May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M Arfan; van Duijn, Cornelia M; Uitterlinden, Andre G; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G; Cilio, Maria Roberta; Kunz, Wolfram S; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A

    2016-01-01

    The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

  11. Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype.

    PubMed

    Yao, Likun; Chen, Jing; Wu, Xiaotong; Jia, Shunji; Meng, Anming

    2017-11-01

    Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients. © The Author 2017. Published by Oxford University Press.

  12. Homozygous SALL1 Mutation Causes a Novel Multiple Congenital Anomaly—Mental Retardation Syndrome

    PubMed Central

    Vodopiutz, Julia; Zoller, Heinz; Fenwick, Aimée L.; Arnhold, Richard; Schmid, Max; Prayer, Daniela; Müller, Thomas; Repa, Andreas; Pollak, Arnold; Aufricht, Christoph; Wilkie, Andrew O.M.; Janecke, Andreas R.

    2013-01-01

    Objective To delineate a novel autosomal recessive multiple congenital anomaly-mental retardation (MCA-MR) syndrome in 2 female siblings of a consanguineous pedigree and to identify the disease-causing mutation. Study design Both siblings were clinically characterized and homozygosity mapping and sequencing of candidate genes were applied. The contribution of nonsense-mediated messenger RNA (mRNA) decay to the expression of mutant mRNA in fibroblasts of a healthy carrier and a control was studied by pyrosequencing. Results We identified the first homozygous SALL1 mutation, c.3160C > T (p.R1054*), in 2 female siblings presenting with multiple congenital anomalies, central nervous system defects, cortical blindness, and absence of psychomotor development (ie, a novel recognizable, autosomal recessive MCA-MR). The mutant SALL1 transcript partially undergoes nonsense-mediated mRNA decay and is present at 43% of the normal transcript level in the fibroblasts of a healthy carrier. Conclusion Previously heterozygous SALL1 mutations and deletions have been associated with dominantly inherited anal-renal-radial-ear developmental anomalies. We identified an allelic recessive SALL1-related MCA-MR. Our findings imply that quantity and quality of SALL1 transcript are important for SALL1 function and determine phenotype, and mode of inheritance, of allelic SALL1-related disorders. This novel MCA-MR emphasizes SALL1 function as critical for normal central nervous system development and warrants a detailed neurologic investigation in all individuals with SALL1 mutations. PMID:23069192

  13. Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype

    PubMed Central

    Yao, Likun; Chen, Jing; Wu, Xiaotong; Jia, Shunji; Meng, Anming

    2017-01-01

    Abstract Cell Division Cycle 6 (Cdc6) is a component of pre-replicative complex (preRC) forming on DNA replication origins in eukaryotes. Recessive mutations in ORC1, ORC4, ORC6, CDT1 or CDC6 of the preRC in human cause Meier-Gorlin syndrome (MGS) that is characterized by impaired post-natal growth, short stature and microcephaly. However, vertebrate models of MGS have not been reported. Through N-ethyl-N-nitrosourea mutagenesis and Cas9 knockout, we generate several cdc6 mutant lines in zebrafish. Loss-of-function mutations of cdc6, as manifested by cdc6tsu4305 and cdc6tsu7cd mutants, lead to embryonic lethality due to cell cycle arrest at the S phase and extensive apoptosis. Embryos homozygous for a cdc6 hypomorphic mutation, cdc6tsu21cd, develop normally during embryogenesis. Later on, compared with their wild-type (WT) siblings, cdc6tsu21cd mutant fish show growth retardation, and their body weight and length in adulthood are greatly reduced, which resemble human MGS. Surprisingly, cdc6tsu21cd mutant fish become males with a short life and fail to mate with WT females, suggesting defective reproduction. Overexpression of Cdc6 mutant forms, which mimic human CDC6(T323R) mutation found in a MGS patient, in zebrafish cdc6tsu4305 mutant embryos partially represses cell death phenotype, suggesting that the human CDC6(T323R) mutation is a hypomorph. cdc6tsu21cd mutant fish will be useful to detect more tissue defects and develop medical treatment strategies for MGS patients. PMID:28985365

  14. Identification of novel genetic causes of Rett syndrome-like phenotypes.

    PubMed

    Lopes, Fátima; Barbosa, Mafalda; Ameur, Adam; Soares, Gabriela; de Sá, Joaquim; Dias, Ana Isabel; Oliveira, Guiomar; Cabral, Pedro; Temudo, Teresa; Calado, Eulália; Cruz, Isabel Fineza; Vieira, José Pedro; Oliveira, Renata; Esteves, Sofia; Sauer, Sascha; Jonasson, Inger; Syvänen, Ann-Christine; Gyllensten, Ulf; Pinto, Dalila; Maciel, Patrícia

    2016-03-01

    The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  15. A comprehensive review on experimental and clinical findings in intermediate syndrome caused by organophosphate poisoning

    SciT

    Abdollahi, Mohammad, E-mail: mohammad.abdollahi@utoronto.ca; Karami-Mohajeri, Somayyeh

    2012-02-01

    Acute organophosphate (OP) intoxication is important because of its high morbidity and mortality and occurrence of muscular paralysis associated by inhibition of acetylcholinesterase (AChE) activity at the neuromuscular junction. Cholinergic crisis, intermediate syndrome (IMS), and OP-induced delayed neuropathy (OPIDN) are the evidences that can be observed in OP intoxication. The main cause of morbidity due to OP poisoning is IMS that occurs 24–96 h after poisoning. Mechanisms underlying the IMS are not fully known. Although the electrophysiological aspects of delayed neuropathy are best characterized, the IMS remain very little studied. The aim of this study was to revisit current knowledgemore » related to OP and the IMS. For this purpose, a systematic review without date limitation was performed. A total of 599 relevant articles were found and reviewed. Data were categorized according to experimental and clinical studies. Occurrences of persistent AChE inhibition, electromyography changes, muscle cell injury, and oxidative stress are the most important pieces of evidence for involvement of IMS in OP toxicity. Delayed AChE inhibition, muscle necrosis, down regulation or desensitization of postsynaptic ACh receptors, failure of postsynaptic ACh release, and oxidative stress-related myopathy are involved in IMS. Toxicokinetic factors, such as a high lipid-solubility, duration of AChE inhibition and metabolite excretion, evolution of alterations on repetitive nerve stimulation (RNS), type and frequency of muscle lesions can estimate the probability of the IMS. Plasma AChE of less than 200 units is a predictor and the 30 Hz RNS decremental response could be a useful marker for the IMS.« less

  16. Novel PAX3 mutations causing Waardenburg syndrome type 1 in Tunisian patients.

    PubMed

    Trabelsi, Mediha; Nouira, Malek; Maazoul, Faouzi; Kraoua, Lilia; Meddeb, Rim; Ouertani, Ines; Chelly, Imen; Benoit, Valérie; Besbes, Ghazi; Mrad, Ridha

    2017-12-01

    Waardenburg syndrome (WS) is an auditory-pigmentary disease characterized by a clinical and genetic variability. WS is classified into four types depending on the presence or absence of additional symptoms: WS1, WS2, WS3 and WS4. Type 1 and 3 are mostly caused by PAX3 mutations, while type 2 and type 4 are genetically heterogeneous. The aims of this study are to confirm the diagnostic of WS1 by the sequencing of PAX3 gene and to evaluate the genotype phenotype correlation. A clinical classification was established for 14 patients WS, as proposed by the Waardenburg Consortium, and noted a predominance of type 1 and type 2 with 6 patients WS1, 7 patients WS2 and 1 patient WS3. A significant inter and intra-familial clinical heterogeneity was also observed. A sequencing of PAX3 gene in the 6 patients WS1 confirmed the diagnosis in 4 of them by revealing three novel mutations that modify two functional domains of the protein: the c.942delC; the c.933_936dupTTAC and the c.164delTCCGCCACA. These three variations are most likely responsible for the phenotype, however their pathogenic effects need to be confirmed by functional studies. The MLPA analysis of the 2 patients who were sequence negative for PAX3 gene revealed, in one of them, a heterozygous deletion of exons 5 to 9 confirming the WS1 diagnosis. Both clinical and molecular approaches led to the conclusion that there is a lack of genotype-phenotype correlation in WS1, an element that must be taken into account in genetic counseling. The absence of PAX3 mutation in one patient WS1 highlights the fact that the clinical classification is sometimes insufficient to distinguish WS1 from other types WS hence the interest of sequencing the other WS genes in this patient. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility.

    PubMed

    Chen, Tailai; Bian, Yuehong; Liu, Xiaoman; Zhao, Shigang; Wu, Keliang; Yan, Lei; Li, Mei; Yang, Zhenglin; Liu, Hongbin; Zhao, Han; Chen, Zi-Jiang

    2017-09-07

    Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyses and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 (ZP3). The same mutation was identified in an unrelated EFS pedigree. Haplotype analysis revealed that the disease allele of these two families came from different origins. Furthermore, in a cohort of 21 cases of EFS, two were also found to have the ZP3 c.400 G>A mutation. Immunofluorescence and histological analysis indicated that the oocytes of the EFS female had degenerated and lacked the zona pellucida (ZP). ZP3 is a major component of the ZP filament. When mutant ZP3 was co-expressed with wild-type ZP3, the interaction between wild-type ZP3 and ZP2 was markedly decreased as a result of the binding of wild-type ZP3 and mutant ZP3, via dominant negative inhibition. As a result, the assembly of ZP was impeded and the communication between cumulus cells and the oocyte was prevented, resulting in oocyte degeneration. These results identified a genetic basis for EFS and oocyte degeneration and, moreover, might pave the way for genetic diagnosis of infertile females with this phenotype. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  18. Primary Cytomegalovirus Infection Causing Guillain-Barré Syndrome in a Living Renal Allograft Recipient

    PubMed Central

    Israel, Ezra

    2017-01-01

    Guillain-Barré Syndrome (GBS) is a common acute autoimmune polyneuropathy in adults. There have been few reported cases of Guillain-Barré Syndrome associated with active cytomegalovirus (CMV) infection in renal transplant recipients. Here we present a case of active CMV viremia inducing Guillain-Barré Syndrome in a renal transplant recipient. We discuss the treatment regimen utilized. Furthermore, we performed a review of the literature and discuss the cases of CMV induced GBS in renal transplant recipients. PMID:29348962

  19. Kindler surprise: mutations in a novel actin-associated protein cause Kindler syndrome.

    PubMed

    White, Sharon J; McLean, W H Irwin

    2005-06-01

    Kindler syndrome is an autosomal recessive genodermatosis characterized by acral blistering in neonates and diffuse, progressive poikiloderma in later life. Other clinical features include photosensitivity, premature skin ageing and severe periodontal disease. Two groups have recently shown that the molecular basis of Kindler syndrome is loss of a novel epidermal protein, kindlin-1, encoded by the gene KIND1. Two additional kindlin proteins, kindlin-2 and kindlin-3, have also been described. Kindlin-1 is considered to be a component in the linkage of the actin cytoskeleton to the extracellular matrix and as such is proposed to have both structural and cell-signalling functions. Kindler syndrome is therefore the first skin fragility syndrome due to disruption of the actin-extracellular matrix system.

  20. Refeeding syndrome as an iatrogenic cause of delirium: a retrospective pilot study.

    PubMed

    Caplan, Jason P; Chang, Grace

    2010-01-01

    Refeeding syndrome describes a pattern of electrolyte disturbances occurring after the reintroduction of nutrition to the malnourished patient; it is often associated with delirium. The authors investigated whether hospitalized elderly patients who develop delirium are more likely to have laboratory findings consistent with refeeding syndrome. The authors conducted a retrospective chart review of 100 patients over age 60. Charts were examined for indications of delirium and refeeding syndrome. Significantly lower serum levels of magnesium and phosphate were found in patients with delirium. Delirium was not associated with any significant difference in levels of potassium. This study supports an association between delirium in elderly patients and electrolyte changes consistent with those seen in refeeding syndrome.

  1. Febuxostat hypersensitivity: another cause of DRESS syndrome in chronic kidney disease?

    PubMed

    Paschou, E; Gavriilaki, E; Papaioannou, G; Tsompanakou, A; Kalaitzoglou, A; Sabanis, N

    2016-11-01

    Febuxostat is a xanthine oxidase inhibitor that during the last years has successfully replaced allopurinol treatment in patients with chronic kidney disease (CKD) and hyperuricemia. Several adverse events have been observed during therapy with febuxostat. DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome induced by febuxostat has been poorly described, mainly in patient with CKD who previously developed allopurinol hypersensitivity syndrome. DRESS syndrome is characterized by manifold cutaneous reactions and systemic disorders with potential devastating consequences. The underlying pathogenetic mechanisms remain unidentified, though immune responses are often complicated. P-i concept can partially explain the phenomenon. The role of renal insufficiency appears to be crucial and further investigation is required. The present article describes the case of a CKD patient that developed febuxostat-related DRESS syndrome.

  2. Is obstructive sleep apnoea syndrome really one of the causes of secondary polycythaemia?

    PubMed

    Solmaz, Soner; Duksal, Faysal; Ganidağlı, Sencer

    2015-03-01

    It is widely believed that sleep apnoea syndrome leads to polycythaemia, but the evidence is largely anecdotal. We believe that polycythaemia is not commonly seen in patients with sleep apnoea syndrome. Therefore, we aimed to determine the relationship between polycythaemia and sleep apnoea syndrome. The study included 335 patients diagnosed with obstructive sleep apnoea (OSA) syndrome, all of whom underwent standard nocturnal polysomnography. There were no significant differences in haemoglobin levels or haematocrit (P > 0.05) between the OSA groups in all patients. Of the 335 patients, only 1 male patient with severe OSA (0.3%) had clinically significant polycythaemia. According to regression analysis, there was a weak linear correlation between haemoglobin levels and lowest oxygen saturation levels in female patients (r = -0.242, P = 0.021). We think that OSA is very rarely the reason for secondary polycythaemia.

  3. [Leigh syndrome caused by the mitochondrial DNA G14459A mutation in a Mexican family].

    PubMed

    Gutiérrez, A; Saldaña-Martínez, A; García-Ramírez, R; Rayo-Mares, D; Carreras, M; López-Pérez, M J; Ruiz-Pesini, E; Montoya, J; Montiel-Sosa, J F

    Leigh syndrome is a neurodegenerative and progressive disease that appears usually in childhood due to defects in nuclear or mitochondrial genome. The mutation G14459A in mitochondrial DNA has been associated previously to Leber hereditary optic neuropathy and recently to Leigh syndrome. A 10 months-old Mexican girl diagnosed of Leigh syndrome. Molecular-genetic studies detected the mutation G14459A in a percentage close to homoplasmy and in low heteroplasmy in her mother. The rest of the maternally related family members analyzed were negative. The G14459A mutation, although not very frequently associated to Leigh syndrome, should be analyzed in patients that do not present the most common point mutations.

  4. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

    PubMed Central

    Cullup, Thomas; Kho, Ay L.; Dionisi-Vici, Carlo; Brandmeier, Birgit; Smith, Frances; Urry, Zoe; Simpson, Michael A.; Yau, Shu; Bertini, Enrico; McClelland, Verity; Al-Owain, Mohammed; Koelker, Stefan; Koerner, Christian; Hoffmann, Georg F.; Wijburg, Frits A.; Hoedt, Amber E. ten; Rogers, Curtis; Manchester, David; Miyata, Rie; Hayashi, Masaharu; Said, Elizabeth; Soler, Doriette; Kroisel, Peter M.; Windpassinger, Christian; Filloux, Francis M.; Al-Kaabi, Salwa; Hertecant, Jozef; Del Campo, Miguel; Buk, Stefan; Bodi, Istvan; Goebel, Hans-Hilmar; Sewry, Caroline A.; Abbs, Stephen; Mohammed, Shehla; Josifova, Dragana; Gautel, Mathias; Jungbluth, Heinz

    2012-01-01

    Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 patients. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homologue of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies demonstrated a severe block of autophagosomal clearance in muscle and fibroblasts from EPG5 mutant patients, resulting in autophagic cargo accumulation in autophagosomes. These findings indicate Vici syndrome as a paradigm of a human multisystem disorder associated with defective autophagy, and suggest a fundamental role of the autophagy pathway in the anatomical and functional formation of organs such as the brain, the heart and the immune system. PMID:23222957

  5. A non-urologic cause of nocturia and enuresis--obstructive sleep apnea syndrome (OSAS).

    PubMed

    Ulfberg, J; Thuman, R

    1996-04-01

    Three case reports describe nocturia and enuresis as complications of the obstructive sleep apnea syndrome (OSAS). It is important to recognize the causal relationship since these troublesome symptoms are easily treated by treating the sleep apnea.

  6. Bardet-Biedl syndrome: A rare cause of end stage renal disease.

    PubMed

    Hemachandar, R

    2015-01-01

    Bardet-Biedl syndrome is a rare autosomal recessive disorder, recently categorized as ciliopathy characterized by dysfunction of primary cilia which results in myriad manifestations in various organ systems. Though renal abnormalities can occur in this syndrome, renal failure is a rare presentation. The author reports a case of 18-year-old female who presented with polydactyly, obesity, retinitis pigmentosa, learning disability and renal failure.

  7. Acute coronary syndrome caused by coronary vasospasms associated with Churg-Strauss syndrome: effects of betamethasone therapy.

    PubMed

    Suzuki, Yuji; Nishiyama, Osamu; Sakai, Toshiaki; Niiyama, Masanobu; Itoh, Tomonori; Nakamura, Motoyuki

    2014-01-01

    A 42-year-old woman with a history of aspirin-induced asthma was admitted with severe chest pain. Emergency coronary angiography revealed coronary artery spasms. The administration of vasodilators did not suppress the anginal symptoms, and the differential white blood cell count continued to show eosinophilia. The patient's symptoms of aspirin-induced asthma, eosinophilia and other allergic states led to the diagnosis of Churg-Strauss syndrome (CSS). After starting betamethasone therapy, the eosinophilia and cardiac symptoms rapidly disappeared. Although coronary vasospasms related to CSS are rare, the present case suggests that a differential white blood cell count should be obtained in patients with refractory coronary vasospasms.

  8. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome.

    PubMed

    Sousa, Sérgio B; Jenkins, Dagan; Chanudet, Estelle; Tasseva, Guergana; Ishida, Miho; Anderson, Glenn; Docker, James; Ryten, Mina; Sa, Joaquim; Saraiva, Jorge M; Barnicoat, Angela; Scott, Richard; Calder, Alistair; Wattanasirichaigoon, Duangrurdee; Chrzanowska, Krystyna; Simandlová, Martina; Van Maldergem, Lionel; Stanier, Philip; Beales, Philip L; Vance, Jean E; Moore, Gudrun E

    2014-01-01

    Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

  9. Treacher Collins syndrome with craniosynostosis, choanal atresia, and esophageal regurgitation caused by a novel nonsense mutation in TCOF1.

    PubMed

    Horiuchi, Katsumi; Ariga, Tadashi; Fujioka, Hirotaka; Kawashima, Kunihiro; Yamamoto, Yuhei; Igawa, Hiroharu; Sakiyama, Yukio; Sugihara, Tsuneki

    2004-07-15

    Treacher Collins syndrome (TCS) is caused by mutations in TCOF1 of the nonsense, small deletion, and small insertion types, which most likely result in haploinsufficiency. We report a novel de novo nonsense mutation 2731C --> T, resulting in Arg911Stop, which truncates the protein. Our patient had the classic findings of TCS, but with documented craniosynostosis, choanal atresia, and esophageal regurgitation. Copyright 2004 Wiley-Liss, Inc.

  10. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes–Brocks Syndrome

    PubMed Central

    Webb, Bryn D.; Metikala, Sanjeeva; Wheeler, Patricia G.; Sherpa, Mingma D.; Houten, Sander M.; Horb, Marko E.; Schadt, Eric E.

    2017-01-01

    A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419* variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419* protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes–Brocks syndrome. PMID:28054444

  11. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome.

    PubMed

    Webb, Bryn D; Metikala, Sanjeeva; Wheeler, Patricia G; Sherpa, Mingma D; Houten, Sander M; Horb, Marko E; Schadt, Eric E

    2017-04-01

    A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419 * variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419 * protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome. © 2017 WILEY PERIODICALS, INC.

  12. MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.

    PubMed

    Brancati, Francesco; Iannicelli, Miriam; Travaglini, Lorena; Mazzotta, Annalisa; Bertini, Enrico; Boltshauser, Eugen; D'Arrigo, Stefano; Emma, Francesco; Fazzi, Elisa; Gallizzi, Romina; Gentile, Mattia; Loncarevic, Damir; Mejaski-Bosnjak, Vlatka; Pantaleoni, Chiara; Rigoli, Luciana; Salpietro, Carmelo D; Signorini, Sabrina; Stringini, Gilda Rita; Verloes, Alain; Zabloka, Dominika; Dallapiccola, Bruno; Gleeson, Joseph G; Valente, Enza Maria

    2009-02-01

    The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs. (c) 2008 Wiley-Liss, Inc.

  13. MKS3/TMEM67 Mutations Are a Major Cause of COACH Syndrome, a Joubert Syndrome Related Disorder with Liver Involvement

    PubMed Central

    Brancati, Francesco; Iannicelli, Miriam; Travaglini, Lorena; Mazzotta, Annalisa; Bertini, Enrico; Boltshauser, Eugen; D’Arrigo, Stefano; Emma, Francesco; Fazzi, Elisa; Gallizzi, Romina; Gentile, Mattia; Loncarevic, Damir; Mejaski-Bosnjak, Vlatka; Pantaleoni, Chiara; Rigoli, Luciana; Salpietro, Carmelo D.; Signorini, Sabrina; Stringini, Gilda Rita; Verloes, Alain; Zabloka, Dominika; Dallapiccola, Bruno; Gleeson, Joseph G.; Valente, Enza Maria

    2008-01-01

    The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs. PMID:19058225

  14. Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome.

    PubMed

    Lin, Angela E; Michot, Caroline; Cormier-Daire, Valerie; L'Ecuyer, Thomas J; Matherne, G Paul; Barnes, Barrett H; Humberson, Jennifer B; Edmondson, Andrew C; Zackai, Elaine; O'Connor, Matthew J; Kaplan, Julie D; Ebeid, Makram R; Krier, Joel; Krieg, Elizabeth; Ghoshhajra, Brian; Lindsay, Mark E

    2016-10-01

    Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF-β signaling cascade (Marfan, Loeys-Dietz, or Shprintzen-Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF-β, BMP, and Activin signaling. The co-occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley

  15. A thymic neuroendocrine tumour in a young female: a rare cause of relapsing and remitting Cushing's syndrome.

    PubMed

    Trott, M J; Farah, G; Stokes, V J; Wang, L M; Grossman, A B

    2016-01-01

    We present a case of a young female patient with a rare cause of relapsing and remitting Cushing's syndrome due to ectopic ACTH secretion from a thymic neuroendocrine tumour. A 34-year-old female presented with a constellation of symptoms of Cushing's syndrome, including facial swelling, muscle weakness and cognitive impairment. We use the terms 'relapsing and remitting' in this case report, given the unpredictable time course of symptoms, which led to a delay of 2 years before the correct diagnosis of hypercortisolaemia. Diagnostic workup confirmed ectopic ACTH secretion, and a thymic mass was seen on mediastinal imaging. The patient subsequently underwent thymectomy with complete resolution of her symptoms. Several case series have documented the association of Cushing's syndrome with thymic neuroendocrine tumours (NETs), although to our knowledge there are a few published cases of patients with relapsing and remitting symptoms. This case is also notable for the absence of features of the MEN-1 syndrome, along with the female gender of our patient and her history of non-smoking. Ectopic corticotrophin (ACTH) secretion should always be considered in the diagnostic workup of young patients with Cushing's syndromeThere is a small but growing body of literature describing the correlation between ectopic ACTH secretion and thymic neuroendocrine tumours (NETs)The possibility of a MEN-1 syndrome should be considered in all patients with thymic NETs, and we note the observational association with male gender and cigarette smoking in this cohortAn exception to these associations is the finding of relatively high incidence of thymic NETs among female non-smoking MEN-1 patients in the Japanese compared with Western populationsThe relapsing and remitting course of our patient's symptoms is noteworthy, given the paucity of this finding among other published cases.

  16. Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

    PubMed Central

    Hoornaert, Kristien P; Vereecke, Inge; Dewinter, Chantal; Rosenberg, Thomas; Beemer, Frits A; Leroy, Jules G; Bendix, Laila; Björck, Erik; Bonduelle, Maryse; Boute, Odile; Cormier-Daire, Valerie; De Die-Smulders, Christine; Dieux-Coeslier, Anne; Dollfus, Hélène; Elting, Mariet; Green, Andrew; Guerci, Veronica I; Hennekam, Raoul C M; Hilhorts-Hofstee, Yvonne; Holder, Muriel; Hoyng, Carel; Jones, Kristi J; Josifova, Dragana; Kaitila, Ilkka; Kjaergaard, Suzanne; Kroes, Yolande H; Lagerstedt, Kristina; Lees, Melissa; LeMerrer, Martine; Magnani, Cinzia; Marcelis, Carlo; Martorell, Loreto; Mathieu, Michèle; McEntagart, Meriel; Mendicino, Angela; Morton, Jenny; Orazio, Gabrielli; Paquis, Véronique; Reish, Orit; Simola, Kalle O J; Smithson, Sarah F; Temple, Karen I; Van Aken, Elisabeth; Van Bever, Yolande; van den Ende, Jenneke; Van Hagen, Johanna M; Zelante, Leopoldo; Zordania, Riina; De Paepe, Anne; Leroy, Bart P; De Buyzere, Marc; Coucke, Paul J; Mortier, Geert R

    2010-01-01

    Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome. PMID:20179744

  17. Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.

    PubMed

    Simon, Mariella; Richard, Elodie M; Wang, Xinjian; Shahzad, Mohsin; Huang, Vincent H; Qaiser, Tanveer A; Potluri, Prasanth; Mahl, Sarah E; Davila, Antonio; Nazli, Sabiha; Hancock, Saege; Yu, Margret; Gargus, Jay; Chang, Richard; Al-Sheqaih, Nada; Newman, William G; Abdenur, Jose; Starr, Arnold; Hegde, Rashmi; Dorn, Thomas; Busch, Anke; Park, Eddie; Wu, Jie; Schwenzer, Hagen; Flierl, Adrian; Florentz, Catherine; Sissler, Marie; Khan, Shaheen N; Li, Ronghua; Guan, Min-Xin; Friedman, Thomas B; Wu, Doris K; Procaccio, Vincent; Riazuddin, Sheikh; Wallace, Douglas C; Ahmed, Zubair M; Huang, Taosheng; Riazuddin, Saima

    2015-03-01

    Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

  18. Neurogenic Thoracic Outlet Syndrome Caused by Vascular Compression of the Brachial Plexus: A Report of Two Cases

    PubMed Central

    Hanna, Amgad; Bodden, Larry O'Neil; Siebiger, Gabriel R. L.

    2018-01-01

    Thoracic outlet syndrome (TOS) is caused by compression of the brachial plexus and/or subclavian vessels as they pass through the cervicothoracobrachial region, exiting the chest. There are three main types of TOS: neurogenic TOS, arterial TOS, and venous TOS. Neurogenic TOS accounts for approximately 95% of all cases, and it is usually caused by physical trauma (posttraumatic etiology), chronic repetitive motion (functional etiology), or bone or muscle anomalies (congenital etiology). We present two cases in which neurogenic TOS was elicited by vascular compression of the inferior portion of the brachial plexus. PMID:29497457

  19. A fatal case of streptococcal toxic shock syndrome due to Streptococcus dysgalactiae subsp. equisimilis possibly caused by an intramuscular injection.

    PubMed

    Hagiya, Hideharu; Okita, Shunji; Kuroe, Yasutoshi; Nojima, Hiroyoshi; Otani, Shinkichi; Sugiyama, Junichi; Naito, Hiromichi; Kawanishi, Susumu; Hagioka, Shingo; Morimoto, Naoki

    2013-01-01

    An 88-year-old man died of streptococcal toxic shock syndrome due to a group G streptococcus infection that was possibly caused by an intramuscular injection given 30 hours earlier in his right deltoid muscle. The causative pathogen was later identified to be Streptococcus dysgalactiae subsp. equisimilis (stG485). Although providing intramuscular injections is an essential skill of health care workers that is performed daily worldwide, it may constitute a port of entry for pathogens via skin breaches that can cause life-threatening infections. All invasive procedures should be carefully performed, especially when immunologically compromised patients are involved.

  20. Mutations in the TGF-β Repressor SKI Cause Shprintzen-Goldberg Syndrome with Aortic Aneurysm

    PubMed Central

    Doyle, Alexander J.; Doyle, Jefferson J.; Bessling, Seneca L.; Maragh, Samantha; Lindsay, Mark E.; Schepers, Dorien; Gillis, Elisabeth; Mortier, Geert; Homfray, Tessa; Sauls, Kimberly; Norris, Russell A.; Huso, Nicholas D.; Leahy, Dan; Mohr, David W.; Caulfield, Mark J.; Scott, Alan F.; Destrée, Anne; Hennekam, Raoul C.; Arn, Pamela H.; Curry, Cynthia J.; Van Laer, Lut; McCallion, Andrew S.; Loeys, Bart L.; Dietz, Harry C.

    2012-01-01

    Increased transforming growth factor beta (TGF-β) signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS)1-4. However, the location and character of many of the causal mutations in LDS would intuitively infer diminished TGF-β signaling5. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm6-8. We identified causative variation in 10 patients with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity9,10. Cultured patient dermal fibroblasts showed enhanced activation of TGF-β signaling cascades and increased expression of TGF-β responsive genes. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in SGS patients. These data support the conclusion that increased TGF-β signaling is the mechanism underlying SGS and contributes to multiple syndromic presentations of aortic aneurysm. PMID:23023332

  1. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

    PubMed Central

    May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M. Arfan; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G.; Cilio, Maria Roberta; Kunz, Wolfram S.; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R.; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A.

    2016-01-01

    Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10−4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions. PMID:26990884

  2. Obstructive sleep apnoea syndrome as a cause of road traffic accidents.

    PubMed

    Aguiar, M; Valença, J; Felizardo, M; Caeiro, F; Moreira, S; Staats, R; Bugalho de Almeida, A A

    2009-01-01

    Several studies have demonstrated that obstructive sleep apnoea syndrome (OSAS) patients have a higher rate of road traffic accidents. Our study aimed to analyse any differences in OSAS patients between those who reported having had road traffic accidents and/or near misses and those who did not. We studied 163 patients with OSAS (apnoea- hypopnoea index (AHI)>10/h) diagnosed using nocturnal polysomnography (NPSG), all drivers, 18.4% of whom drove for a living. Patients were asked at their first clinical interview to self-report road traffic accidents and/or near misses over the past 3 years which had been caused by abnormal daytime drowsiness. This allowed patients to be divided into two groups, those who had had road traffic accidents and/or near misses and those who had not. Both were compared as to age, body mass index (BMI), Epworth Sleepiness Scale (ESS), daytime PaO2 and PaCO2, Functional Outcomes of Sleep Questionnaire (FOSQ) test and NPSG data. This latter was total sleep time (TTS), sleep efficiency, sleep stages, arousal index (ARI), AHI, minimal and average SaO2, % of time with SaO2 < 90% (T90), desaturation index (ODI), total duration of apnoea-hypopnoea (TDAH) (T test). Group I (no road traffic accidents) No=89 patients; group II (road traffic accidents) No=74 patients. Age (years) was 57.6+/-11.8 vs. 54.7+/-10.9 (ns); male gender, 75% vs. 78.4%; ESS, 12.3+/-5.4 vs. 17.6+/-4.3 (p<0.001); BMI, (Kg/m2) 36.2+/-8.1 vs. 35.6+/-6.3 (ns); PaO2 (mmHg), 76.1+/-11.4 vs. 78.5+/-12.6 (ns); PaCO2 (mmHg), 42.6+/-5.1 vs. 42.2+/-4.7 (ns); FOSQ, 15.1+/-3.1 vs. 12.9+/-3.4 (p<0.001). NPSG data revealed differences only in AHI: 45.0+/-21.6 vs. 56.2+/-29.7 (p=0.01) and in TDAH (minutes), 98.5+/-63.7 vs. 133.3+/-83.2 (p=0,005). In our experience patients who had road traffic accidents and/or near misses had a more severe OSAS, with higher AHI, excessive daytime sleepiness and lower quality of life.

  3. An unusual cause of recurrent spontaneous pneumothorax: the Mounier-Kuhn syndrome.

    PubMed

    Unlu, Elif Nisa; Annakkaya, Ali Nihat; Balbay, Ege Gulec; Aydın, Leyla Yilmaz; Safcı, Sinem; Boran, Mertay; Guclu, Derya

    2016-01-01

    We present a case of 63-year-old man who was referred to the emergency department with a right-sided pneumothorax. He had a history of spontaneous pneumothorax for 2 times. The chest computed tomographic scan showed tracheobronchomegaly with an increase in the diameter of the trachea and right and left main bronchus. Fiberoptic bronchoscopy revealed enlarged trachea and both main bronchus with diverticulas. These findings are consistent with a diagnosis of Mounier-Kuhn syndrome. Mounier-Kuhn syndrome is a rare clinical and radiologic condition. It is characterized by a tracheal and bronchial dilation. Diagnosis is made by computed tomography and bronchoscopy. Mounier-Kuhn syndrome should be kept in mind in the differential diagnosis of recurrent spontaneous pneumothorax.

  4. Early spinal cord and brainstem involvement in infantile Leigh syndrome possibly caused by a novel variant.

    PubMed

    Tenney, Jeffrey R; Prada, Carlos E; Hopkin, Robert J; Hallinan, Barbara E

    2013-12-01

    Leigh syndrome, due to a dysfunction of mitochondrial energy metabolism, is a genetically heterogeneous and progressive neurologic disorder that usually occurs in infancy and childhood. Its clinical presentation and neuroimaging findings can be variable, especially early in the course of the disease. This report presents a patient with infantile Leigh syndrome who had atypical radiologic findings on serial neuroimaging studies with early and severe involvement of the cervical spinal cord and brainstem and injury to the thalami and basal ganglia occurring only late in the clinical course. Postmortem microscopic examination supported this timing of injury within the central nervous system. In addition, mitochondrial deoxyribonucleic acid sequencing showed a novel homoplasmic variant that could be responsible for this unique lethal form of Leigh syndrome.

  5. Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.

    PubMed

    Warejko, Jillian K; Schueler, Markus; Vivante, Asaf; Tan, Weizhen; Daga, Ankana; Lawson, Jennifer A; Braun, Daniela A; Shril, Shirlee; Amann, Kassaundra; Somers, Michael J G; Rodig, Nancy M; Baum, Michelle A; Daouk, Ghaleb; Traum, Avram Z; Kim, Heung Bae; Vakili, Khashayar; Porras, Diego; Lock, James; Rivkin, Michael J; Chaudry, Gulraiz; Smoot, Leslie B; Singh, Michael N; Smith, Edward R; Mane, Shrikant M; Lifton, Richard P; Stein, Deborah R; Ferguson, Michael A; Hildebrandt, Friedhelm

    2018-04-01

    Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease ( NF1 , JAG1 , ELN , GATA6 , and RNF213 ). Ten of the 15 mutations have not previously been reported. This is the first report of ELN , RNF213 , or GATA6 mutations in individuals with MAS. Mutations were detected in NF1 (6/15 families), JAG1 (4/15 families), ELN (3/15 families), and one family each for GATA6 and RNF213 Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS. © 2018 American Heart Association, Inc.

  6. A patient with Dent disease and features of Bartter syndrome caused by a novel mutation of CLCN5.

    PubMed

    Okamoto, Takayuki; Tajima, Toshihiro; Hirayama, Tomoya; Sasaki, Satoshi

    2012-02-01

    Dent disease is an X-linked tubulopathy mainly caused by inactivating mutations of CLCN5. Features of Bartter syndrome such as hypokalemic metabolic alkalosis are rarely observed in patients with Dent disease. We report a Japanese male patient with Dent disease who also manifested features of Bartter syndrome. At the age of 3 years, he was diagnosed with Dent disease based on low molecular weight proteinuria and hypercalciuria. One year later, he was found to have features of Bartter syndrome, i.e., hypokalemia and metabolic alkalosis, and high levels of plasma renin activity and aldosterone with a normal blood pressure. Despite medical interventions, he developed chronic kidney disease stage 3 at the age of 21 years. To investigate the molecular basis of his disease, CLCN5, KCNJ1, SLC12A1, and CLCkb were analyzed and a novel mutation (Y567X) in CLCN5 was identified. Hypokalemic metabolic alkalosis is a rare manifestation in Dent disease. It is speculated that Dent patients with features of Bartter syndrome are susceptible to progression to renal failure. To study this hypothesis, additional observations and long-term follow-up of such patients are necessary.

  7. The Loss of Vacuolar Protein Sorting 11 (vps11) Causes Retinal Pathogenesis in a Vertebrate Model of Syndromic Albinism

    PubMed Central

    Thomas, Jennifer L.; Vihtelic, Thomas S.; denDekker, Aaron D.; Willer, Gregory; Luo, Xixia; Murphy, Taylor R.; Gregg, Ronald G.; Hyde, David R.

    2011-01-01

    Purpose. To establish the zebrafish platinum mutant as a model for studying vision defects caused by syndromic albinism diseases such as Chediak-Higashi syndrome, Griscelli syndrome, and Hermansky-Pudlak syndrome (HPS). Methods. Bulked segregant analysis and candidate gene sequencing revealed that the zebrafish platinum mutation is a single-nucleotide insertion in the vps11 (vacuolar protein sorting 11) gene. Expression of vps11 was determined by RT-PCR and in situ hybridization. Mutants were analyzed for pigmentation defects and retinal disease by histology, immunohistochemistry, and transmission electron microscopy. Results. Phenocopy and rescue experiments determined that a loss of Vps11 results in the platinum phenotype. Expression of vps11 appeared ubiquitous during zebrafish development, with stronger expression in the developing retina and retinal pigmented epithelium (RPE). Zebrafish platinum mutants exhibited reduced pigmentation in the body and RPE; however, melanophore development, migration, and dispersion occurred normally. RPE, photoreceptors, and inner retinal neurons formed normally in zebrafish platinum mutants. However, a gradual loss of RPE, an absence of mature melanosomes, and the subsequent degradation of RPE/photoreceptor interdigitation was observed. Conclusions. These data show that Vps11 is not necessary for normal retinal development or initiation of melanin biosynthesis, but is essential for melanosome maturation and healthy maintenance of the RPE and photoreceptors. PMID:21330665

  8. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.

    PubMed

    McGregor, Lesley; Makela, Ville; Darling, Susan M; Vrontou, Sofia; Chalepakis, Georges; Roberts, Catherine; Smart, Nicola; Rutland, Paul; Prescott, Natalie; Hopkins, Jason; Bentley, Elizabeth; Shaw, Alison; Roberts, Emma; Mueller, Robert; Jadeja, Shalini; Philip, Nicole; Nelson, John; Francannet, Christine; Perez-Aytes, Antonio; Megarbane, Andre; Kerr, Bronwyn; Wainwright, Brandon; Woolf, Adrian S; Winter, Robin M; Scambler, Peter J

    2003-06-01

    Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.

  9. Upper Extremity Compartment Syndrome in a Patient with Acute Gout Attack but without Trauma or Other Typical Causes.

    PubMed

    Skedros, John G; Smith, James S; Henrie, Marshall K; Finlinson, Ethan D; Trachtenberg, Joel D

    2018-01-01

    We report the case of a 30-year-old Polynesian male with a severe gout flare of multiple joints and simultaneous acute compartment syndrome (ACS) of his right forearm and hand without trauma or other typical causes. He had a long history of gout flares, but none were known to be associated with compartment syndrome. He also had concurrent infections in his right elbow joint and olecranon bursa. A few days prior to this episode of ACS, high pain and swelling occurred in his right upper extremity after a minimal workout with light weights. A similar episode occurred seven months prior and was attributed to a gout flare. Unlike past flares that resolved with colchicine and/or anti-inflammatory medications, his current upper extremity pain/swelling worsened and became severe. Hand and forearm fasciotomies were performed. Workup included general medicine, rheumatology and infectious disease consultations, myriad blood tests, and imaging studies including Doppler ultrasound and CT angiography. Additional clinical history suggested that he had previously unrecognized recurrent exertional compartment syndrome that led to the episode of ACS reported here. Chronic exertional compartment syndrome (CECS) presents a difficult diagnosis when presented with multiple symptoms concurrently. This case provides an example of one such diagnosis.

  10. Upper Extremity Compartment Syndrome in a Patient with Acute Gout Attack but without Trauma or Other Typical Causes

    PubMed Central

    Smith, James S.; Henrie, Marshall K.; Finlinson, Ethan D.; Trachtenberg, Joel D.

    2018-01-01

    We report the case of a 30-year-old Polynesian male with a severe gout flare of multiple joints and simultaneous acute compartment syndrome (ACS) of his right forearm and hand without trauma or other typical causes. He had a long history of gout flares, but none were known to be associated with compartment syndrome. He also had concurrent infections in his right elbow joint and olecranon bursa. A few days prior to this episode of ACS, high pain and swelling occurred in his right upper extremity after a minimal workout with light weights. A similar episode occurred seven months prior and was attributed to a gout flare. Unlike past flares that resolved with colchicine and/or anti-inflammatory medications, his current upper extremity pain/swelling worsened and became severe. Hand and forearm fasciotomies were performed. Workup included general medicine, rheumatology and infectious disease consultations, myriad blood tests, and imaging studies including Doppler ultrasound and CT angiography. Additional clinical history suggested that he had previously unrecognized recurrent exertional compartment syndrome that led to the episode of ACS reported here. Chronic exertional compartment syndrome (CECS) presents a difficult diagnosis when presented with multiple symptoms concurrently. This case provides an example of one such diagnosis. PMID:29796328

  11. Xeroderma pigmentosum is a definite cause of Huntington's disease-like syndrome.

    PubMed

    Garcia-Moreno, Hector; Fassihi, Hiva; Sarkany, Robert P E; Phukan, Julie; Warner, Thomas; Lehmann, Alan R; Giunti, Paola

    2018-01-01

    Xeroderma pigmentosum is characterized by cutaneous, ophthalmological, and neurological features. Although it is typical of childhood, late presentations can mimic different neurodegenerative conditions. We report two families presenting as Huntington's disease-like syndromes. The first case (group G) presented with neuropsychiatric features, cognitive decline and chorea. Typical lentigines were only noticed after the neurological disease started. The second case (group B) presented adult-onset chorea and neuropsychiatric symptoms after an aggressive ocular melanoma. Xeroderma pigmentosum can manifest as a Huntington's Disease-like syndrome. Classic dermatological and oncological features have to be investigated in choreic patients with negative genetic tests for Huntington's disease-like phenotypes.

  12. Adder bite: an uncommon cause of compartment syndrome in northern hemisphere

    PubMed Central

    2010-01-01

    Snakebite envenomation is an uncommon condition in the northern hemisphere, but requires high vigilance with regard to both the systemic effects of the venom and the locoregional impact on the soft tissues. Bites from the adder, Vipera Berus, may have serious clinical consequences due to systemic effects. A case of a 44-year-old man is reported. The patient was bitten in the right hand. He developed fasciotomy-requiring compartment syndrome of the upper limb. Recognition of this most seldom complication of an adder bite is vital to save the limb. We recommend that the classical signs and symptoms of compartment syndrome serve as indication for surgical decompression. PMID:20854675

  13. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome).

    PubMed

    Buchanan, Daniel D; Rosty, Christophe; Clendenning, Mark; Spurdle, Amanda B; Win, Aung Ko

    2014-01-01

    Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic

  14. Sheehan's Syndrome-The Most Common Cause of Panhypopituitarism at Moderate Altitude: A Sub-Himalayan Study.

    PubMed

    Mokta, Jatinder; Ranjan, Asha; Thakur, Surinder; Bhawani, Rajesh; Mokta, Kiran K; Sharma, Jai Bharat; Kumar, Manish

    2017-12-01

    Panhypopituitarism is a rare disorder with varied clinical presentation having various etiologies. Sheehan's syndrome (SS) is decreasing in frequency worldwide and is a rare cause of panhypopituitarism in developed nations. A retrospective study done between May 2011 and May 2015 in tertiary care hospital. We reviewed the records of patients with hypopituitarism. Clinical features, hormonal profile and radiological investigations noted. Total 14 patients of panhypopituitarism included with average duration of symptoms 1.93± 1.96 years. four (28.57%) were males and ten (71.43%) were females with mean age of diagnosis 37.78± 13.68 years. Sheehan's syndrome (SS) was the most common cause of panhypopituitarism in 57.14%(8 patients), followed by post surgery in 14.28% (2 patients). 80% of women had SS with a mean duration of symptoms 2.39±1.54 years. Sheehan's syndrome is not uncommon in developing countries, High degree of clinical suspicion is desired as clinical features are most often subtle.

  15. Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

    PubMed

    Deik, A; Johannes, B; Rucker, J C; Sánchez, E; Brodie, S E; Deegan, E; Landy, K; Kajiwara, Y; Scelsa, S; Saunders-Pullman, R; Paisán-Ruiz, C

    2014-12-01

    PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

  16. Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

    PubMed Central

    Konantz, Martina; Paillard, Catherine; Miao, Zhichao; Pichot, Angélique; Leduc, Magalie S.; Yang, Yaping; Bergstrom, Katie L.; Mahoney, Donald H.; Shardy, Deborah L.; Alsaleh, Ghada; Naegely, Lydie; Kolmer, Aline; Paul, Nicodème; Hanauer, Antoine; Rolli, Véronique; Müller, Joëlle S.; Alghisi, Elisa; Sauteur, Loïc; Macquin, Cécile; Morlon, Aurore; Sancho, Consuelo Sebastia; Amati-Bonneau, Patrizia; Procaccio, Vincent; Mosca-Boidron, Anne-Laure; Marle, Nathalie; Goetz, Jacky G.; Unal, Sule; Akarsu, Nurten A.; Radosavljevic, Mirjana; Chenard, Marie-Pierre; Rialland, Fanny; Grain, Audrey; Béné, Marie-Christine; Eveillard, Marion; Vincent, Marie; Guy, Julien; Faivre, Laurence; Thauvin-Robinet, Christel; Thevenon, Julien; Fleming, Mark D.; Bottollier-Lemallaz, Elodie; Westhof, Eric; Isidor, Bertrand

    2017-01-01

    Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond–like phenotype. PMID:28972538

  17. Frasier syndrome, a potential cause of end-stage renal failure in childhood.

    PubMed

    Bache, Manon; Dheu, Céline; Doray, Bérénice; Fothergill, Hélène; Soskin, Sylvie; Paris, Françoise; Sultan, Charles; Fischbach, Michel

    2010-03-01

    The diagnosis of Frasier syndrome is based on the association of male pseudohermaphroditism (as a result of gonadal dysgenesis), with steroid-resistant nephrotic syndrome due to focal and segmental glomerular sclerosis (FSGS), which progresses to end-stage renal failure (ESRF) during adolescence or adulthood. Frasier syndrome results from mutations in the Wilms' tumour suppressor gene WT1, which is responsible for alterations in male genital development and podocyte dysfunction. We describe the case of a 7-year-old girl who was referred to the paediatric emergency department with ESRF. Haemodialysis was started immediately because of severe hypertension and hyperkalaemia. In view of the fact that our patient had a past medical history of pseudohermaphroditism, we suspected that the acute presentation in ESRF may be related to a new diagnosis of Frasier syndrome. Our hypothesis was confirmed on examination of the medical records. There had been no medical follow-up for several years and, in particular, no renal imaging or functional assessment had ever been performed. This lack of surveillance explains why our patient presented with ESRF much earlier in this disease than expected and subsequently had to undergo kidney transplantation at a very young age.

  18. Hantavirus Pulmonary Syndrome Caused by Maripa Virus in French Guiana, 2008-2016.

    PubMed

    Matheus, Séverine; Kallel, Hatem; Mayence, Claire; Bremand, Laetitia; Houcke, Stéphanie; Rousset, Dominique; Lacoste, Vincent; de Thoisy, Benoit; Hommel, Didier; Lavergne, Anne

    2017-10-01

    We report 5 human cases of hantavirus pulmonary syndrome found during surveillance in French Guiana in 2008-2016; of the 5 patients, 4 died. This pathogen should continue to be monitored in humans and rodents in effort to reduce the occurrence of these lethal infections in humans stemming from ecosystem disturbances.

  19. Hantavirus Pulmonary Syndrome Caused by Maripa Virus in French Guiana, 2008–2016

    PubMed Central

    Kallel, Hatem; Mayence, Claire; Bremand, Laetitia; Houcke, Stéphanie; Rousset, Dominique; Lacoste, Vincent; de Thoisy, Benoit; Hommel, Didier; Lavergne, Anne

    2017-01-01

    We report 5 human cases of hantavirus pulmonary syndrome found during surveillance in French Guiana in 2008–2016; of the 5 patients, 4 died. This pathogen should continue to be monitored in humans and rodents in effort to reduce the occurrence of these lethal infections in humans stemming from ecosystem disturbances. PMID:28930019

  20. Herpes zoster ophthalmicus and strabismus: a unique cause of secondary Brown syndrome.

    PubMed

    Broderick, Kevin M; Raymond, William R; Boden, John H

    2017-08-01

    Herpes zoster ophthalmicus can be associated with a variety of ocular and visual sequelae, including isolated or even multiple cranial neuropathies, potentially affecting the oculomotor, trochlear, or abducens nerves. We report a case of a secondary Brown syndrome following resolution of a unilateral isolated trochlear nerve palsy associated with herpes zoster ophthalmicus in an immunocompetent 57-year-old man. Published by Elsevier Inc.

  1. An Exploration of Causes of Non-Literal Language Problems in Individuals with Asperger Syndrome

    ERIC Educational Resources Information Center

    Martin, Ingerith; McDonald, Skye

    2004-01-01

    Individuals with Asperger Syndrome (AS), a high functioning variant of Autism, are often noted to possess intact language ability, yet fail to use this language capacity to engage in interactive communication. This difficulty using language in a social context has been referred to as a deficit in pragmatic language. In particular, difficulty…

  2. Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.

    PubMed

    Brancati, Francesco; Camerota, Letizia; Colao, Emma; Vega-Warner, Virginia; Zhao, Xiangzhong; Zhang, Ruixiao; Bottillo, Irene; Castori, Marco; Caglioti, Alfredo; Sangiuolo, Federica; Novelli, Giuseppe; Perrotti, Nicola; Otto, Edgar A

    2018-06-11

    A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.

  3. Giant pseudomeningocele causing urinary obstruction in a patient with Marfan syndrome.

    PubMed

    Stone, Jeremy G; Bergmann, Liisa L; Takamori, Ryan; Donovan, Daniel J

    2015-07-01

    Defective collagen biosynthesis in Marfan syndrome predisposes to dural defects such as dural ectasia, meningocele, and pseudomeningocele; thus, an increased index of suspicion for these conditions should be present in the clinical setting of Marfan syndrome. The authors describe a young woman with Marfan syndrome who was being treated with anticoagulants for a prosthetic heart valve and who presented with a spontaneous retroperitoneal hemorrhage requiring surgical evacuation. No CSF leak was encountered at surgery, but she developed progressively more severe positional headaches over the following year. She then experienced the sudden onset of acute urinary obstruction, at which time CT revealed a 17 × 15 × 13-cm presacral pseudomeningocele communicating with the thecal sac through a sacral bone defect. An anterior surgical approach was used for drainage of the pseudomeningocele as well as for primary closure of the dural defect with a bovine pericardial patch and autologous subcutaneous fat graft. After a short period of lumbar subarachnoid drainage of the CSF, the patient was able to resume normal activity without recurrent symptoms. To the authors' knowledge, such a pseudomeningocele in a patient with Marfan syndrome has been reported only twice, and this case features the largest pseudomeningocele to date. They also review the pertinent literature regarding presentation, diagnosis, and management of these lesions.

  4. Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.

    PubMed

    Carapito, Raphael; Konantz, Martina; Paillard, Catherine; Miao, Zhichao; Pichot, Angélique; Leduc, Magalie S; Yang, Yaping; Bergstrom, Katie L; Mahoney, Donald H; Shardy, Deborah L; Alsaleh, Ghada; Naegely, Lydie; Kolmer, Aline; Paul, Nicodème; Hanauer, Antoine; Rolli, Véronique; Müller, Joëlle S; Alghisi, Elisa; Sauteur, Loïc; Macquin, Cécile; Morlon, Aurore; Sancho, Consuelo Sebastia; Amati-Bonneau, Patrizia; Procaccio, Vincent; Mosca-Boidron, Anne-Laure; Marle, Nathalie; Osmani, Naël; Lefebvre, Olivier; Goetz, Jacky G; Unal, Sule; Akarsu, Nurten A; Radosavljevic, Mirjana; Chenard, Marie-Pierre; Rialland, Fanny; Grain, Audrey; Béné, Marie-Christine; Eveillard, Marion; Vincent, Marie; Guy, Julien; Faivre, Laurence; Thauvin-Robinet, Christel; Thevenon, Julien; Myers, Kasiani; Fleming, Mark D; Shimamura, Akiko; Bottollier-Lemallaz, Elodie; Westhof, Eric; Lengerke, Claudia; Isidor, Bertrand; Bahram, Seiamak

    2017-11-01

    Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.

  5. Judgments of Cause and Blame: Sensitivity to Intentionality in Asperger's Syndrome

    ERIC Educational Resources Information Center

    Channon, Shelley; Lagnado, David; Fitzpatrick, Sian; Drury, Helena; Taylor, Isabelle

    2011-01-01

    Sensitivity to intentionality in people with Asperger's syndrome (AS) and matched controls was investigated using two scenario-based tasks. The first compared intentional and unintentional human actions and physical events leading to the same negative outcomes. The second compared intentional actions that varied in their subjective and objective…

  6. Dominant missense mutations in ABCC9 cause Cantú syndrome.

    PubMed

    Harakalova, Magdalena; van Harssel, Jeske J T; Terhal, Paulien A; van Lieshout, Stef; Duran, Karen; Renkens, Ivo; Amor, David J; Wilson, Louise C; Kirk, Edwin P; Turner, Claire L S; Shears, Debbie; Garcia-Minaur, Sixto; Lees, Melissa M; Ross, Alison; Venselaar, Hanka; Vriend, Gert; Takanari, Hiroki; Rook, Martin B; van der Heyden, Marcel A G; Asselbergs, Folkert W; Breur, Hans M; Swinkels, Marielle E; Scurr, Ingrid J; Smithson, Sarah F; Knoers, Nine V; van der Smagt, Jasper J; Nijman, Isaac J; Kloosterman, Wigard P; van Haelst, Mieke M; van Haaften, Gijs; Cuppen, Edwin

    2012-05-18

    Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.

  7. Insulin resistance in obesity as the underlying cause for the metabolic syndrome.

    PubMed

    Gallagher, Emily J; Leroith, Derek; Karnieli, Eddy

    2010-01-01

    The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and β cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic

  8. Budd-Chiari Syndrome Due to Protein C Deficiency: A Rare Disorder to cause Chronic Liver Disease.

    PubMed

    Begum, Rukshana; Mahtab, Mamun Al; Mamun, Ayub Al; Moben, Ahmed Lutful; Hossain, Sharker Mohammad Shahadat; Das, Dulal Chandra; Malakar, Debraj; Or Rashid, Harun; Roy, Partho Protim; Rahman, Salimur

    2016-01-01

    The Budd-Chiari syndrome (BCS) is a rare disorder due to chronic liver disease (CLD), which is caused by the obstruction of hepatic venous outflow that can be located at any place from the small hepatic venules up to the entrance of the inferior vena cava (IVC) into the right atrium. Among the causes of BCS, the rarer one is coagulation factor deficiencies. Here, we report a case of BCS associated with deficiency of protein C resulting in thrombus in IVC. The patient was a 50-year-old male, who had been suffering from recurrent abdominal and leg swelling for a long period of 7 years. He was evaluated thoroughly, and other causes of liver cirrhosis were excluded. Begum R, Al Mahtab M, Al Mamun A, Moben AL, Hossain SMS, Das DC, Malakar D, Rashid HO, Roy PP, Rahman S. Budd-Chiari Syndrome Due to Protein C Deficiency: A Rare Disorder to cause Chronic Liver Disease. Euroasian J Hepato-Gastroenterol 2016;6(2):194-197.

  9. Severe manifestation of Bartter syndrome Type IV caused by a novel insertion mutation in the BSND gene.

    PubMed

    de Pablos, Augusto Luque; García-Nieto, Victor; López-Menchero, Jesús C; Ramos-Trujillo, Elena; González-Acosta, Hilaria; Claverie-Martín, Félix

    2014-05-01

    Bartter syndrome Type IV is a rare subtype of the Bartter syndromes that leads to both severe renal salt wasting and sensorineural deafness. This autosomal recessive disease is caused by mutations in the gene encoding barttin, BSND, an essential subunit of the ClC-K chloride channels expressed in renal and inner ear epithelia. Patients differ in the severity of renal symptoms, which appears to depend on the modification of channel function by the mutant barttin. To date, only a few BSND mutations have been reported, most of which are missense or nonsense mutations. In this study, we report the identification of the first insertion mutation, p.W102Vfs*7, in the BSND gene of a newborn girl with acute clinical symptoms including early-onset chronic renal failure. The results support previous data indicating that mutations that are predicted to abolish barttin expression are associated with a severe phenotype and early onset renal failure.

  10. Pneumocystis Pneumonia Concomitant with Ectopic ACTH Syndrome Caused by a Large Cell Neuroendocrine Carcinoma of the Thymus.

    PubMed

    Oda, Naohiro; Miyahara, Nobuaki; Tabata, Masahiro; Minami, Daisuke; Ninomiya, Kiichiro; Kanehiro, Arihiko; Komatsubara, Motoshi; Inagaki, Kenichi; Tanimoto, Mitsune; Kiura, Katsuyuki

    2017-01-01

    We herein report the case of a 44-year-old man who was diagnosed with pneumocystis pneumonia (PCP) concomitant with ectopic adrenocorticotropic hormone (ACTH) syndrome, which had been caused by a large cell neuroendocrine carcinoma of the thymus. Chest computed tomography revealed ground-glass opacities in the lungs. PCP was diagnosed by a polymerase chain reaction with bronchoalveolar lavage. The levels of cortisol were slowly corrected with an adrenal enzyme inhibitor, and the exacerbation of PCP was successfully avoided. Our case indicates that in addition to prophylaxis, the early diagnosis of PCP and the slow correction of hypercortisolemia should be considered in order to prevent an exacerbation due to the reconstitution of the immune function in patients with ectopic ACTH syndrome.

  11. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy.

    PubMed

    Vaché, Christel; Besnard, Thomas; le Berre, Pauline; García-García, Gema; Baux, David; Larrieu, Lise; Abadie, Caroline; Blanchet, Catherine; Bolz, Hanno Jörn; Millan, Jose; Hamel, Christian; Malcolm, Sue; Claustres, Mireille; Roux, Anne-Françoise

    2012-01-01

    USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs). © 2011 Wiley Periodicals, Inc.

  12. Acute encephalopathy with biphasic seizures and late reduced diffusion associated with staphylococcal toxic shock syndrome caused by burns.

    PubMed

    Yokochi, Takaoki; Sakanishi, Shinpei; Ishidou, Yuuki; Kawano, Go; Matsuishi, Toyojiro; Akita, Yukihiro; Obu, Keizo

    2016-10-01

    We report a case of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) associated with toxic shock syndrome caused by burns. A one-year-old girl was admitted to our hospital for treatment of severe burns. On day 3, she exhibited a fever, generalized rash and multiple organ failure. She was diagnosed with toxic shock syndrome after burns. She had seizures with fever twice on the same day, followed by secondary seizures on day 8 and transient deterioration of the gross motor functions involved in sitting alone and rolling over. On day 9, MRI diffusion-weighted images showed bright tree appearance (BTA). We conclude that she developed AESD. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  13. Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3.

    PubMed

    Shalev, Stavit Allon; Khayat, Morad; Etty, Daniel-Spiegl; Elpeleg, Orly

    2015-03-01

    Mutations in genes encoding the origin recognition complex subunits cause Meier-Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation. © 2015 Wiley Periodicals, Inc.

  14. An atypical case of fragile X syndrome caused by a deletion that includes the FMR1 gene.

    PubMed Central

    Quan, F; Zonana, J; Gunter, K; Peterson, K L; Magenis, R E; Popovich, B W

    1995-01-01

    Fragile X syndrome is the most common form of inherited mental retardation and results from the transcriptional inactivation of the FMR1 gene. In the vast majority of cases, this is caused by the expansion of an unstable CGG repeat in the first exon of the FMR1 gene. We describe here a phenotypically atypical case of fragile X syndrome, caused by a deletion that includes the entire FMR1 gene and > or = 9.0 Mb of flanking DNA. The proband, RK, was a 6-year-old mentally retarded male with obesity and anal atresia. A diagnosis of fragile X syndrome was established by the failure of RK's DNA to hybridize to a 558-bp PstI-XhoI fragment (pfxa3) specific for the 5'-end of the FMR1 gene. The analysis of flanking markers in the interval from Xq26.3-q28 indicated a deletion extending from between 160-500 kb distal and 9.0 Mb proximal to the FMR1 gene. High-resolution chromosome banding confirmed a deletion with breakpoints in Xq26.3 and Xq27.3. This deletion was maternally transmitted and arose as a new mutation on the grandpaternal X chromosome. The maternal transmission of the deletion was confirmed by FISH using a 34-kb cosmid (c31.4) containing most of the FMR1 gene. These results indicated that RK carried a deletion of the FMR1 region with the most proximal breakpoint described to date. This patient's unusual clinical presentation may indicate the presence of genes located in the deleted interval proximal to the FMR1 locus that are able to modify the fragile X syndrome phenotype. Images Figure 5 Figure 2 Figure 4 Figure 6 Figure 7 PMID:7726157

  15. Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene.

    PubMed

    Hagebeuk, Eveline E O; van den Bossche, Renilde A S; de Weerd, Al W

    2013-05-01

    In female children with drug-resistant seizures and developmental delay from birth, atypical Rett syndrome caused by mutations in the CDKL5 gene should be considered. Several clinical features resemble classic Rett syndrome. Respiratory and sleep abnormalities are frequently present in Rett syndrome, whereas little is known in patients with CDKL5 mutations. In four genetically confirmed female patients with CDKL5 mutations (age range 2-15 y), the presence of breathing and sleep abnormalities was evaluated using the validated Sleep Disturbance Scale for Children and polysomnography (PSG). The Sleep Disturbance Scale for Children indicated disorders of initiating and maintaining sleep, daytime somnolence, and sleep breathing disorders. In one patient, PSG showed central apnoeas during sleep: her total apnoea-hypopnoea index (AHI) was 4.9, of which the central AHI was 3.4/h. When awake, central apnoeas were present in two of the four female children (central AHI 28/h and 41/h respectively), all preceded by hyperventilation. PSG showed low rapid eye movement (REM) sleep (9.7-18.3%), frequent awakenings, and low sleep efficiency (range 59-78%). Episodic hyperventilation followed by central apnoeas was present while awake in two of four patients. This may indicate failure of brainstem respiratory centres. In addition, low REM sleep, frequent arousals (not caused by apnoeas/seizures), and low sleep efficiency were present. Similar to Rett syndrome, in patients with CDKL5 mutations PSG seems warranted to evaluate breathing and sleep disturbances. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

  16. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia.

    PubMed

    Cavé, Hélène; Caye, Aurélie; Ghedira, Nehla; Capri, Yline; Pouvreau, Nathalie; Fillot, Natacha; Trimouille, Aurélien; Vignal, Cédric; Fenneteau, Odile; Alembik, Yves; Alessandri, Jean-Luc; Blanchet, Patricia; Boute, Odile; Bouvagnet, Patrice; David, Albert; Dieux Coeslier, Anne; Doray, Bérénice; Dulac, Olivier; Drouin-Garraud, Valérie; Gérard, Marion; Héron, Delphine; Isidor, Bertrand; Lacombe, Didier; Lyonnet, Stanislas; Perrin, Laurence; Rio, Marlène; Roume, Joëlle; Sauvion, Sylvie; Toutain, Annick; Vincent-Delorme, Catherine; Willems, Marjorie; Baumann, Clarisse; Verloes, Alain

    2016-08-01

    Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.

  17. Lennox-Gastaut syndrome of unknown cause: phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project.

    PubMed

    Widdess-Walsh, Peter; Dlugos, Dennis; Fahlstrom, Robyn; Joshi, Sucheta; Shellhaas, Renée; Boro, Alex; Sullivan, Joseph; Geller, Eric

    2013-11-01

    Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features of LGS of unknown or genetic cause (LGS(u)). The Epilepsy Phenome/Genome Project (EPGP) aims to characterize LGS(u) by phenotypic analysis of patients with LGS(u) and their parents. One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. LGS(u) in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients with LGS(u) completed secondary school. Parents were cognitively normal. All subjects had EEG recordings with generalized epileptiform abnormalities with a spike wave frequency range of 1-5 Hz (median 2 Hz), whereas 8.1% of subjects had EEG studies with a normal posterior dominant rhythm. Almost 12% of patients evolved from West syndrome. LGS(u) has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGS(u) coupled with future genetic studies will advance our understanding of this epilepsy syndrome. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  18. Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice*

    PubMed Central

    Yang, Xiaodong; Mudgett, John; Bou-About, Ghina; Champy, Marie-France; Jacobs, Hugues; Monassier, Laurent; Pavlovic, Guillaume; Sorg, Tania; Herault, Yann; Petit-Demoulière, Benoit; Lu, Ku; Feng, Wen; Wang, Hongwu; Ma, Li-Jun; Askew, Roger; Erion, Mark D.; Kelley, David E.; Myers, Robert W.; Li, Cai

    2016-01-01

    Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2NI) and R531G (AMPKγ2RG), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2NI or AMPKγ2RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2NI or AMPKγ2RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2NI and AMPKγ2RG, respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2NI or AMPKγ2RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2WT mice, AMPKγ2NI and AMPKγ2RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2RG but not AMPKγ2NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2NI and AMPKγ2RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD. PMID:27621313

  19. Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice.

    PubMed

    Yang, Xiaodong; Mudgett, John; Bou-About, Ghina; Champy, Marie-France; Jacobs, Hugues; Monassier, Laurent; Pavlovic, Guillaume; Sorg, Tania; Herault, Yann; Petit-Demoulière, Benoit; Lu, Ku; Feng, Wen; Wang, Hongwu; Ma, Li-Jun; Askew, Roger; Erion, Mark D; Kelley, David E; Myers, Robert W; Li, Cai; Guan, Hong-Ping

    2016-11-04

    Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2 NI ) and R531G (AMPKγ2 RG ), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2 NI or AMPKγ2 RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2 NI or AMPKγ2 RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2 NI and AMPKγ2 RG , respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2 NI or AMPKγ2 RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2 WT mice, AMPKγ2 NI and AMPKγ2 RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2 RG but not AMPKγ2 NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2 NI and AMPKγ2 RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2 RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. [Sudeck syndrome (CRPS) caused by unique personality traits: myth and fiction].

    PubMed

    Lesky, J

    2010-12-01

    In analogy to the thesis of "pain-proneness", conceptualised by G. Engel more than 50 years ago, the idea of a unique structure in personality emerged, which was given a causal meaning in the development of Sudeck's Disease (now known as complex regional pain syndrome - CRPS), of which the pathogenesis is particularly unknown until today. It was supposed that certain psychological traits predispose one to develop CRPS. Predisposition in this context was apprehended as a personal susceptibility to produce and maintain an excessive reaction to nociceptive stimulations. This model has been maintained for a long time and was the subject of scientific examination just in the last two decades. Some publications reporting sporadic correlations between CRPS and certain personality traits, for example anxiety, neuroticism and depressive mood, are presented as are also 15 current empirical studies and five reviews, which deal in a more differentiated manner with the formulated question and lead to sobering results. The relevant state of research as well as the fundamental and methodical difficulties in regard to verifying a CRPS personality or pain-prone personality are discussed critically. In general, there is a lack of high-quality relevant studies. Some retrospective/cross-sectional studies yield contradictory results regarding psychological problems in patients with CRPS but the majority shows no association, and studies with higher methodological quality tend to the conclusion of no relationship between psychological factors like depression, anxiety, neuroticism, or anger and CRPS. Especially, the few prospective studies do not report such a relationship, psychological factors are not associated with CRPS onset. Compared to other patients with chronic pain there is no unique disturbed psychological profile and no higher degree of psychosocial disturbance in CRPS patients. In all, the results of research cannot confirm the hypothesis of correlations between

  1. Whole-Genome Characterization and Strain Comparison of VT2f-Producing Escherichia coli Causing Hemolytic Uremic Syndrome

    PubMed Central

    Michelacci, Valeria; Bondì, Roslen; Gigliucci, Federica; Franz, Eelco; Badouei, Mahdi Askari; Schlager, Sabine; Minelli, Fabio; Tozzoli, Rosangela; Caprioli, Alfredo; Morabito, Stefano

    2016-01-01

    Verotoxigenic Escherichia coli infections in humans cause disease ranging from uncomplicated intestinal illnesses to bloody diarrhea and systemic sequelae, such as hemolytic uremic syndrome (HUS). Previous research indicated that pigeons may be a reservoir for a population of verotoxigenic E. coli producing the VT2f variant. We used whole-genome sequencing to characterize a set of VT2f-producing E. coli strains from human patients with diarrhea or HUS and from healthy pigeons. We describe a phage conveying the vtx2f genes and provide evidence that the strains causing milder diarrheal disease may be transmitted to humans from pigeons. The strains causing HUS could derive from VT2f phage acquisition by E. coli strains with a virulence genes asset resembling that of typical HUS-associated verotoxigenic E. coli. PMID:27584691

  2. Hitch-hiker taken for a ride: an unusual cause of myocarditis, septic shock and adult respiratory distress syndrome

    PubMed Central

    Kushawaha, Anurag; Brown, Mark; Martin, Ismael; Evenhuis, Walther

    2013-01-01

    Rocky Mountain spotted fever (RMSF) is a serious tick-borne illness caused by Rickettsia rickettsii that is endemic in southeastern USA. Although RMSF has been described as causing the classic clinical triad of fever, headache and a characteristic rash, serious and potentially life-threatening manifestations can occur. Cardiopulmonary involvement, although infrequent, may occur with severe cases of RMSF. Rickettsial myocarditis is an uncommon occurrence. We present a case of a previously healthy 26-year-old man, who was hitch-hiking across the southeastern USA, with serologically proven RMSF causing adult respiratory distress syndrome, septic shock and myocarditis manifested by elevated cardiac enzymes and decrease in myocardial function. After treatment with antibiotics, the myocarditis resolved. Therefore, although unusual, clinicians should be aware of possible myocardial involvement in patients with appropriate tick-exposure histories or other clinical signs of RMSF. PMID:23314875

  3. DK phocomelia phenotype (von Voss-Cherstvoy syndrome) caused by somatic mosaicism for del(13q).

    PubMed

    Bamforth, J S; Lin, C C

    1997-12-31

    DK phocomelia (von Voss-Cherstvoy syndrome) is a rare condition characterized by radial ray defects, occipital encephalocoele, and urogenital abnormalities. Lubinsky et al. [1994: Am J Med Genet 52:272-278] pointed out similarities between this and the del(13q) syndrome. To date, all reported cases of DK phocomelia have been apparently normal chromosomally. We report on a case of DK phocomelia in which the proposita had normal lymphocyte chromosomes, but was mosaic in fibroblasts for del(13)(q12). Fibroblast chromosomes studies on other cases of DK phocomelia have not been reported: this raises the possibility that some cases of DK phocomelia may be somatic mosaics for del(13)(q12).

  4. Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F.

    PubMed

    Alagramam, K N; Yuan, H; Kuehn, M H; Murcia, C L; Wayne, S; Srisailpathy, C R; Lowry, R B; Knaus, R; Van Laer, L; Bernier, F P; Schwartz, S; Lee, C; Morton, C C; Mullins, R F; Ramesh, A; Van Camp, G; Hageman, G S; Woychik, R P; Smith, R J; Hagemen, G S

    2001-08-01

    We have determined the molecular basis for Usher syndrome type 1F (USH1F) in two families segregating for this type of syndromic deafness. By fluorescence in situ hybridization, we placed the human homolog of the mouse protocadherin Pcdh15 in the linkage interval defined by the USH1F locus. We determined the genomic structure of this novel protocadherin, and found a single-base deletion in exon 10 in one USH1F family and a nonsense mutation in exon 2 in the second. Consistent with the phenotypes observed in these families, we demonstrated expression of PCDH15 in the retina and cochlea by RT-PCR and immunohistochemistry. This report shows that protocadherins are essential for maintenance of normal retinal and cochlear function.

  5. [Seronin syndrome and cardiac arrest caused by high-dose moclobemide (case report)].

    PubMed

    Cekmen, N; Badalov, P; Erdemli, O

    2008-01-01

    Serotonin syndrome is the syndrome resulting from brain tissue serotonin accumulation and accompanying by central nervous system dysfunction and circulatory collapse, which leads to a serious mortal danger to life. A female patient aged 31 years, diagnosed as having chronic psychosis in the history, was admitted to an intensive care unit in a critical state for having taking an increased moclobemide dose. The patient developed cardiac arrest and cardiopulmonary resuscitation (CPR) was initiated. A 15-minute CPR recovered sinus rhythm and pulse on the peripheral arteries of the limbs. When consciousness and respiration improved, the patient was weaned from resuscitation and extubated on the second day. On day 4, the patient was transferred from the intensive care unit to the department of psychiatry. The authors consider that patients with overdosage of antipsychotic agents at a risk for such serious complications, such as cardiac arrest, should be necessarily monitored in the intensive care unit.

  6. Gorlin-Goltz Syndrome: An Uncommon Cause of Facial Pain and Asymmetry.

    PubMed

    Pickrell, Brent B; Nguyen, Harrison P; Buchanan, Edward P

    2015-10-01

    Gorlin-Goltz syndrome is an underdiagnosed autosomal dominant disorder with variable expressivity that is characterized by an increased predisposition to tumorigenesis of multiple types. The major clinical features include multiple basal cell carcinomas (BCCs) appearing in early childhood, palmar and plantar pits, odontogenic keratocysts of the oral cavity, skeletal defects, craniofacial dysmorphism, and ectopic intracranial calcification. The authors present the clinical course of a 12-year-old girl presenting with facial asymmetry and pain because of previously undiagnosed Gorlin-Goltz syndrome. Early diagnosis and attentive management by a multidisciplinary team are paramount to improving outcomes in patients with this disorder, and this report serves as a paradigm for maintaining a high clinical suspicion, which must be accompanied by an appropriate radiologic workup.

  7. A rare presentation of atypical demyelination: tumefactive multiple sclerosis causing Gerstmann’s syndrome

    PubMed Central

    2014-01-01

    Background Tumefactive demyelinating lesions are a rare manifestation of multiple sclerosis (MS). Differential diagnosis of such space occupying lesions may not be straightforward and sometimes necessitate brain biopsy. Impaired cognition is the second most common clinical manifestation of tumefactive MS; however complex cognitive syndromes are unusual. Case presentation We report the case of a 30 year old woman who presented with Gerstmann’s syndrome. MRI revealed a large heterogeneous contrast enhancing lesion in the left cerebral hemisphere. Intravenous corticosteroids did not stop disease progression. A tumour or cerebral lymphoma was suspected, however brain biopsy confirmed inflammatory demyelination. Following diagnosis of tumefactive MS treatment with natalizumab effectively suppressed disease activity. Conclusions The case highlights the need for clinicians, radiologists and surgeons to appreciate the heterogeneous presentation of tumefactive MS. Early brain biopsy facilitates rapid diagnosis and management. Treatment with natalizumab may be useful in cases of tumefactive demyelination where additional evidence supports a diagnosis of relapsing MS. PMID:24694183

  8. Lumbosacral transitional vertebra causing Bertolotti's syndrome: a case report and review of the literature.

    PubMed

    Paraskevas, Georgios; Tzaveas, Alexandros; Koutras, Georgios; Natsis, Konstantinos

    2009-07-06

    Lumbosacral transitional vertebra is an anatomical variation of the fifth lumbar vertebra in which an enlarged transverse process can form a joint or fusion with the sacrum or ilium. The association of that variant with low back pain and the change in the biomechanical properties of the lumbar spine is called Bertolotti's syndrome. We report a case of a 40-year-old male patient with chronic low back pain extending to the left buttock, just above the ipsilateral sacroiliac joint. Radiographic investigation revealed an anomalous enlargement of the left transverse process of the fifth lumbar vertebra forming a pseudarthrosis with the infrajacent ala of the sacrum. In young patients with back pain the possibility of Bertolotti's syndrome should always be taken in account.

  9. Lumbosacral transitional vertebra causing Bertolotti’s syndrome: a case report and review of the literature

    PubMed Central

    Koutras, Georgios; Natsis, Konstantinos

    2009-01-01

    Introduction Lumbosacral transitional vertebra is an anatomical variation of the fifth lumbar vertebra in which an enlarged transverse process can form a joint or fusion with the sacrum or ilium. The association of that variant with low back pain and the change in the biomechanical properties of the lumbar spine is called Bertolotti’s syndrome. Case presentation We report a case of a 40-year-old male patient with chronic low back pain extending to the left buttock, just above the ipsilateral sacroiliac joint. Radiographic investigation revealed an anomalous enlargement of the left transverse process of the fifth lumbar vertebra forming a pseudarthrosis with the infrajacent ala of the sacrum. Conclusion In young patients with back pain the possibility of Bertolotti’s syndrome should always be taken in account. PMID:19830065

  10. A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.

    PubMed

    Anderson, S L; Chung, W K; Frezzo, J; Papp, J C; Ekstein, J; DiMauro, S; Rubin, B Y

    2008-12-01

    Leigh syndrome is a neurodegenerative disorder of infancy or childhood generally due to mutations in nuclear or mitochondrial genes involved in mitochondrial energy metabolism. We performed linkage analysis in an Ashkenazi Jewish (AJ) family without consanguinity with three affected children. Linkage to microsatellite markers D5S1969 and D5S407 led to evaluation of the complex I gene NDUFS4, in which we identified a novel homozygous c.462delA mutation that disrupts the reading frame. The resulting protein lacks a cAMP-dependent protein kinase phosphorylation site required for activation of mitochondrial respiratory chain complex I. In a random sample of 5000 healthy AJ individuals, the carrier frequency of the NDUFS4 mutation c.462delA was 1 in 1000, suggesting that it should be considered in all AJ patients with Leigh syndrome.

  11. Thoracolumbar Junction Syndrome Causing Pain around Posterior Iliac Crest: A Case Report.

    PubMed

    Kim, Soo-Ryu; Lee, Min-Ji; Lee, Seung-Jun; Suh, Young-Sung; Kim, Dae-Hyun; Hong, Ji-Hee

    2013-03-01

    Thoracolumbar junction syndrome is characterized by referred pain which may originate at the thoracolumbar junction, which extends from 12th thoracic vertebra to 2nd lumbar vertebra, due to functional abnormalities. Clinical manifestations include back pain, pseudo-visceral pain and pseudo-pain on the posterior iliac crest, as well as irritable bowel symptoms. During clinical examination, pain can be demonstrated by applying pressure on the facet joints or to the sides of the spinous processes. Radiological studies show only mild and insignificant degenerative changes in most cases. We report a 42-year-old female patient with osteogenesis imperfecta who suffered from chronic low back pain. Under the diagnosis of thoracolumbar junction syndrome, she was treated with an epidural block and a sympathetic nerve block, which improved her symptoms.

  12. A rare cause of cystic lung disease - Birt-Hogg-Dubé syndrome.

    PubMed

    Minnis, P; Riddell, P; Keane, M P

    2016-01-01

    Birt-Hogg-Dubé syndrome, initially described in 1977, is an autosomal dominant inherited condition characterised by basal pulmonary cysts often resulting in pneumothorax, renal tumours and cutaneous involvement. Lung cysts have been described in up to 90% of patients with a corresponding risk of pneumothorax of 50 times greater than the normal population. We describe here a case of Birt-Hogg-Dubé diagnosed in the 9th decade of life and discuss the radiological findings and clinical implications.

  13. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7

    PubMed Central

    Pastor, Victor B.; Sahoo, Sushree S.; Boklan, Jessica; Schwabe, Georg C.; Saribeyoglu, Ebru; Strahm, Brigitte; Lebrecht, Dirk; Voss, Matthias; Bryceson, Yenan T.; Erlacher, Miriam; Ehninger, Gerhard; Niewisch, Marena; Schlegelberger, Brigitte; Baumann, Irith; Achermann, John C.; Shimamura, Akiko; Hochrein, Jochen; Tedgård, Ulf; Nilsson, Lars; Hasle, Henrik; Boerries, Melanie; Busch, Hauke; Niemeyer, Charlotte M.; Wlodarski, Marcin W.

    2018-01-01

    Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1–42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L-wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268. PMID:29217778

  14. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.

    PubMed

    Pastor, Victor B; Sahoo, Sushree S; Boklan, Jessica; Schwabe, Georg C; Saribeyoglu, Ebru; Strahm, Brigitte; Lebrecht, Dirk; Voss, Matthias; Bryceson, Yenan T; Erlacher, Miriam; Ehninger, Gerhard; Niewisch, Marena; Schlegelberger, Brigitte; Baumann, Irith; Achermann, John C; Shimamura, Akiko; Hochrein, Jochen; Tedgård, Ulf; Nilsson, Lars; Hasle, Henrik; Boerries, Melanie; Busch, Hauke; Niemeyer, Charlotte M; Wlodarski, Marcin W

    2018-03-01

    Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1-42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L -wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268 . Copyright© 2018 Ferrata Storti Foundation.

  15. [Sleep apnea syndrome as a cause of secondary hypertension. A case report].

    PubMed

    Poreba, Rafał; Derkacz, Arkadiusz; Andrzejak, Ryszard

    2005-11-01

    A case of a 51-year old man, suffering from drug-resistant hypertension, complaining of hypersomnia and fatigue during the day, is presented. In the course of diagnostic procedures the diagnosis of sleep apnea syndrome was established. Continuous positive airway pressure (CPAP) therapy was successfully started. Examination carried out 3 months later revealed good response to pharmacological treatment with normal levels of blood pressure.

  16. A fatal case of bone marrow embolism of unknown cause masquerading clinically as dengue shock syndrome.

    PubMed

    Selvi, Subramanian Kalaivani; Kar, Rakhee; Vadivelan, Mehalingam; Subrahmanyam, Dharanipragada Krishna Suri

    2012-01-01

    Bone marrow fat embolism usually occurs following multiple bone fractures, intraosseous surgical procedures, following vigorous cardiac resuscitation, ecclampsia, sickle cell anemia, malignancies, etc. We present a case of 70-year-old male who presented with fever, cough with expectoration, respiratory distress, altered sensorium, hypotension and thrombocytopenia, and diagnosed to have dengue shock syndrome and expired within 1 day of admission. Postmortem lung biopsy revealed bone marrow fat embolism.

  17. Bertolotti's syndrome: A commonly missed cause of back pain in young patients.

    PubMed

    Manmohan, S; Dzulkarnain, A; Nor Azlin, Z A; Fazir, M

    2015-01-01

    Bertolotti's syndrome must be considered as a differential diagnosis for lower back pain in young people. Treatment, whether conservative or operative, is still debatable. In this paper, we report a case of a 20-year-old girl presenting with lower back pain for 8 years. We administered injection with local anaesthetic and steroid injections within the pseudo-articulation; however, the pain was relieved for 3 weeks. Surgical excision of the pseudo-articulation successfully treated her back pain and the sciatica.

  18. Post-polypectomy electrocoagulation syndrome: a rare cause of acute abdominal pain

    PubMed Central

    Jehangir, Asad; Bennett, Kyle M.; Rettew, Andrew C.; Fadahunsi, Opeyemi; Shaikh, Bilal; Donato, Anthony

    2015-01-01

    While generally safe, the most feared complication of colonoscopy is perforation of the colon, occurring in nearly 1 in 1,000 procedures, and is more common when polypectomy is performed and electrocautery is used. Less commonly known is the post-polypectomy electrocoagulation syndrome, a transmural burn of the colon which mimics the signs and symptoms of perforation as well as the time course, but follows a benign course and can be treated conservatively. PMID:26486121

  19. Impingement syndrome of the ankle caused by a medial meniscoid lesion.

    PubMed

    Egol, K A; Parisien, J S

    1997-08-01

    Meniscoid lesion of the ankle is a well-described condition involving the anterolateral aspect of the ankle joint. To our knowledge, there are no reports of this condition involving the medial aspect of the ankle in the literature. We present the case of a 27-year-old man with a chronic deltoid ligament rupture who had developed anteromedial impingement syndrome of the ankle. The patient was treated with an arthroscopic debridement of the lesion and experienced a complete recovery.

  20. A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.

    PubMed

    Lange, L; Pagnamenta, A T; Lise, S; Clasper, S; Stewart, H; Akha, E S; Quaghebeur, G; Knight, S J L; Keays, D A; Taylor, J C; Kini, U

    2016-09-01

    Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome. © 2016 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Computer vision syndrome-A common cause of unexplained visual symptoms in the modern era.

    PubMed

    Munshi, Sunil; Varghese, Ashley; Dhar-Munshi, Sushma

    2017-07-01

    The aim of this study was to assess the evidence and available literature on the clinical, pathogenetic, prognostic and therapeutic aspects of Computer vision syndrome. Information was collected from Medline, Embase & National Library of Medicine over the last 30 years up to March 2016. The bibliographies of relevant articles were searched for additional references. Patients with Computer vision syndrome present to a variety of different specialists, including General Practitioners, Neurologists, Stroke physicians and Ophthalmologists. While the condition is common, there is a poor awareness in the public and among health professionals. Recognising this condition in the clinic or in emergency situations like the TIA clinic is crucial. The implications are potentially huge in view of the extensive and widespread use of computers and visual display units. Greater public awareness of Computer vision syndrome and education of health professionals is vital. Preventive strategies should form part of work place ergonomics routinely. Prompt and correct recognition is important to allow management and avoid unnecessary treatments. © 2017 John Wiley & Sons Ltd.

  2. Meier-Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication.

    PubMed

    Hossain, Manzar; Stillman, Bruce

    2012-08-15

    Like DNA replication, centrosomes are licensed to duplicate once per cell division cycle to ensure genetic stability. In addition to regulating DNA replication, the Orc1 subunit of the human origin recognition complex controls centriole and centrosome copy number. Here we report that Orc1 harbors a PACT centrosome-targeting domain and a separate domain that differentially inhibits the protein kinase activities of Cyclin E-CDK2 and Cyclin A-CDK2. A cyclin-binding motif (Cy motif) is required for Orc1 to bind Cyclin A and inhibit Cyclin A-CDK2 kinase activity but has no effect on Cyclin E-CDK2 kinase activity. In contrast, Orc1 inhibition of Cyclin E-CDK2 kinase activity occurs by a different mechanism that is affected by Orc1 mutations identified in Meier-Gorlin syndrome patients. The cyclin/CDK2 kinase inhibitory domain of Orc1, when tethered to the PACT domain, localizes to centrosomes and blocks centrosome reduplication. Meier-Gorlin syndrome mutations that disrupt Cyclin E-CDK2 kinase inhibition also allow centrosome reduplication. Thus, Orc1 contains distinct domains that control centrosome copy number and DNA replication. We suggest that the Orc1 mutations present in some Meier-Gorlin syndrome patients contribute to the pronounced microcephaly and dwarfism observed in these individuals by altering centrosome duplication in addition to DNA replication defects.

  3. Waardenburg syndrome type II in a Chinese patient caused by a novel nonsense mutation in the SOX10 gene.

    PubMed

    Ma, Jing; Zhang, Tie-Song; Lin, Ken; Sun, Hao; Jiang, Hong-Chao; Yang, Yan-Li; Low, Fan; Gao, Ying-Qin; Ruan, Biao

    2016-06-01

    Waardenburg syndrome is a congenital genetic disorder. It is the most common type of syndromic hearing impairment with highly genetic heterogeneity and proved to be related by 6 genes as follows: PAX3, MITF, SNAI2, EDN3, EDNRB and SOX10. This article aims to identify the genetic causes of a Chinese WS child patient. A Chinese WS child was collected for clinical data collection by questionnaire survey. DNA samples of proband and his parents were extracted from peripheral blood samples. Six candidate genes were sequenced by the Trusight One sequencing panel on the illumina NextSeq 500 platform. A novel nonsense heterozygous mutation was found in the coding region of exon 2 in the SOX10 gene of proband. The novel nonsense heterozygous mutation could cause the replacement of the 55th lysine codon by stop codon (484T > C, C142R) and further more possibly cause terminating the protein translation in advance. However, both proband's parents had no mutation of genes above mentioned. The gene mutation of SOX10 [NM_006941.3 c.163A > T] is a novel nonsense mutation. No record of this mutation has been found in dbSNP, HGMD, 1000 Genomes Project, ClinVar and ESP6500 databases. It meets the condition of PS2 of strong evidence in 2015 ACMG Standards and Guidelines. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Pheochromocytoma as a rare cause of hypertension in a 46 X, i(X)(q10) turner syndrome: a case report and literature review.

    PubMed

    Shin, Ji Yeon; Kim, Bo Hyun; Kim, Young Keum; Kim, Tae Hwa; Kim, Eun Heui; Lee, Min Jin; Kim, Jong Ho; Jeon, Yun Kyung; Kim, Sang Soo; Kim, In Joo

    2018-05-10

    Cardiovascular disease (CVD) presents the most serious health problems and contributes to the increased mortality in young women with Turner syndrome. Arterial hypertension in Turner syndrome patients is significantly more prevalent than that in a general age-matched control group. The aetiology of hypertension in Turner syndrome varies, even in the absence of cardiac anomalies and obvious structural renal abnormalities. Pheochromocytoma is an extremely rare cause among various etiologies for hypertension in patients with Turner syndrome. Here, we reported a pheochromocytoma as a rare cause of hypertension in Turner syndrome patient. A 21-year-old woman who has diagnosed with Turner syndrome with a karyotype of 46,X,i(X)(q10) visited for hypertension and mild headache. Transthoracic echography (TTE) showed no definite persistent ductus arteriosus shunt flow and cardiac valve abnormalities. Considering other important secondary causes like pheochromocytoma, hormonal studies were performed and the results showed increased serum norepinephrine, serum normetanephrine, and 24 h urine norepinephrine. We performed an abdominal computed tomography (CT) to confirm the location of pheochromocytoma. Abdominal CT showed a 1.9 cm right adrenal mass. I-131 meta-iodobenzylguanidine (MIBG) scintigraphy showed a right adrenal uptake. Laparoscopic adrenalectomy was performed and confirmed a pheochromocytoma. After surgery, blood pressure was within normal ranges and postoperative course was uneventful, and no recurrence developed via biochemical tests and abdominal CT until 24 months. Our case and previous literatures suggest that hypertension caused by pheochromocytoma which is a rare but important and potentially lethal cause of hypertension in Turner syndrome. This case underlines the importance of early detection of pheochromocytoma in Turner syndrome. Clinicians should keep in mind that pheochromocytoma can be a cause of hypertension in patients with Turner syndrome.

  5. Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome.

    PubMed

    Morak, Monika; Koehler, Udo; Schackert, Hans Konrad; Steinke, Verena; Royer-Pokora, Brigitte; Schulmann, Karsten; Kloor, Matthias; Höchter, Wilhelm; Weingart, Josef; Keiling, Cortina; Massdorf, Trisari; Holinski-Feder, Elke

    2011-08-01

    A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2. A single-nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients.

  6. Treatment with 17-allylamino-17-demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type IV caused by mutated Bsnd in mice.

    PubMed

    Nomura, Naohiro; Kamiya, Kazusaku; Ikeda, Katsuhisa; Yui, Naofumi; Chiga, Motoko; Sohara, Eisei; Rai, Tatemitu; Sakaki, Sei; Uchida, Shinich

    2013-11-22

    Mutations of BSND, which encodes barttin, cause Bartter syndrome type IV. This disease is characterized by salt and fluid loss, hypokalemia, metabolic alkalosis, and sensorineural hearing impairment. Barttin is the β-subunit of the ClC-K chloride channel, which recruits it to the plasma membranes, and the ClC-K/barttin complex contributes to transepithelial chloride transport in the kidney and inner ear. The retention of mutant forms of barttin in the endoplasmic reticulum (ER) is etiologically linked to Bartter syndrome type IV. Here, we report that treatment with 17-allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, enhanced the plasma membrane expression of mutant barttins (R8L and G47R) in Madin-Darby canine kidney cells. Administration of 17-AAG to Bsnd(R8L/R8L) knock-in mice elevated the plasma membrane expression of R8L in the kidney and inner ear, thereby mitigating hypokalemia, metabolic alkalosis, and hearing loss. These results suggest that drugs that rescue ER-retained mutant barttin may be useful for treating patients with Bartter syndrome type IV. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

    PubMed

    Webb, B D; Brandt, T; Liu, L; Jalas, C; Liao, J; Fedick, A; Linderman, M D; Diaz, G A; Kornreich, R; Trachtman, H; Mehta, L; Edelmann, L

    2014-08-01

    Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. The mitochondrial DNA 10197 G > A mutation causes MELAS/Leigh overlap syndrome presenting with acute auditory agnosia.

    PubMed

    Leng, Yinglin; Liu, Yuhe; Fang, Xiaojing; Li, Yao; Yu, Lei; Yuan, Yun; Wang, Zhaoxia

    2015-04-01

    Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes/Leigh (MELAS/LS) overlap syndrome is a mitochondrial disorder subtype with clinical and magnetic resonance imaging (MRI) features that are characteristic of both MELAS and Leigh syndrome (LS). Here, we report an MELAS/LS case presenting with cortical deafness and seizures. Cranial MRI revealed multiple lesions involving bilateral temporal lobes, the basal ganglia and the brainstem, which conformed to neuroimaging features of both MELAS and LS. Whole mitochondrial DNA (mtDNA) sequencing and PCR-RFLP revealed a de novo heteroplasmic m.10197 G > A mutation in the NADH dehydrogenase subunit 3 gene (ND3), which was predicted to cause an alanine to threonine substitution at amino acid 47. Although the mtDNA m.10197 G > A mutation has been reported in association with LS, Leber hereditary optic neuropathy and dystonia, it has never been linked with MELAS/LS overlap syndrome. Our patient therefore expands the phenotypic spectrum of the mtDNA m.10197 G > A mutation.

  9. [Imaging manifestations and pathologic basis for hepatic capsular retraction syndrome caused by benign and malignant liver tumors].

    PubMed

    Ou, Youkuan; Xiao, Enhua; Shang, Quanliang; Chen, Juan

    2015-10-01

    To investigate the imaging manifestations of CT, MRI and pathological basis for hepatic capsular retraction syndrome caused by benign and malignant liver tumors.
 CT or MRI images and pathological features for hepatic capsular retraction syndrome were retrospectively analyzed in 50 patients with benign and malignant liver tumors. Picture archive and communication system (PACS) was used to observe and compare the morphology, size, width, depth, edge of the capsular retraction and the status of liquid under the liver capsule. The structure, differentiation and proliferation of the tumor were analyzed under the microscope.
 There were malignant liver tumors in 44 patients and benign tumor in 6 patients. The smooth or rough for the edge of capsular retraction was significant difference between the benign tumors and the malignant tumors with three differentiated grades (all P<0.05). There were significant difference in the width and depth for capsule retraction with different amount of fibrous tissues (all P<0.05). The width and depth of capsule retraction were positively correlated to the size of the tumors (r=0.557, 0.309 respectively, both P<0.05).
 Benign and malignant hepatic tumors may appear capsule retraction syndrome, but there are morphological differences between them. The differences are closely related with the lesion size, differentiated degree of tumor and fibrous tissue proliferation.

  10. Hepatopulmonary syndrome caused by hypothalamic obesity and nonalcoholic fatty liver disease after surgery for craniopharyngioma: a case report.

    PubMed

    Jung, Dai; Seo, Go Hun; Kim, Yoon-Myung; Choi, Jin-Ho; Yoo, Han-Wook

    2018-03-01

    Hypothalamic obesity is often complicated in patients with craniopharyngioma due to hypothalamic damage by the tumor itself, treatment modalities, and associated multiple pituitary hormone deficiency. Hypothalamic obesity causes secondary diseases such as nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM). We report a 19-year-old female who was diagnosed with craniopharyngioma, developed hypothalamic obesity after tumor resection, and progressed to hepatopulmonary syndrome. She manifested NAFLD 1 year after tumor resection. Two years later, the craniopharyngioma recurred, and she underwent a second resection. Three years after her second operation, she was diagnosed with type 2 DM, after which she did not visit the outpatient clinic for 2 years and then suddenly reappeared with a weight loss of 25.8 kg that had occurred over 21 months. One month later, she presented to the Emergency Department with dyspnea. Laboratory findings revealed liver dysfunction and hypoxia with increased alveolar artery oxygen gradient. Liver biopsy showed portal hypertension and micronodular cirrhosis. Echocardiography and a lung perfusion scan demonstrated a right to left shunt. She was finally diagnosed with hepatopulmonary syndrome and is currently awaiting a donor for liver transplantation. Patients surviving craniopharyngioma need to be followed up carefully to detect signs of hypothalamic obesity and monitored for the development of other comorbidities such as DM, NAFLD, and hepatopulmonary syndrome.

  11. TBX15 mutations cause craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature in Cousin syndrome.

    PubMed

    Lausch, Ekkehart; Hermanns, Pia; Farin, Henner F; Alanay, Yasemin; Unger, Sheila; Nikkel, Sarah; Steinwender, Christoph; Scherer, Gerd; Spranger, Jürgen; Zabel, Bernhard; Kispert, Andreas; Superti-Furga, Andrea

    2008-11-01

    Members of the evolutionarily conserved T-box family of transcription factors are important players in developmental processes that include mesoderm formation and patterning and organogenesis both in vertebrates and invertebrates. The importance of T-box genes for human development is illustrated by the association between mutations in several of the 17 human family members and congenital errors of morphogenesis that include cardiac, craniofacial, and limb malformations. We identified two unrelated individuals with a complex cranial, cervical, auricular, and skeletal malformation syndrome with scapular and pelvic hypoplasia (Cousin syndrome) that recapitulates the dysmorphic phenotype seen in the Tbx15-deficient mice, droopy ear. Both affected individuals were homozygous for genomic TBX15 mutations that resulted in truncation of the protein and addition of a stretch of missense amino acids. Although the mutant proteins had an intact T-box and were able to bind to their target DNA sequence in vitro, the missense amino acid sequence directed them to early degradation, and cellular levels were markedly reduced. We conclude that Cousin syndrome is caused by TBX15 insufficiency and is thus the human counterpart of the droopy ear mouse.

  12. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.

    PubMed

    Marchegiani, Shannon; Davis, Taylor; Tessadori, Federico; van Haaften, Gijs; Brancati, Francesco; Hoischen, Alexander; Huang, Haigen; Valkanas, Elise; Pusey, Barbara; Schanze, Denny; Venselaar, Hanka; Vulto-van Silfhout, Anneke T; Wolfe, Lynne A; Tifft, Cynthia J; Zerfas, Patricia M; Zambruno, Giovanna; Kariminejad, Ariana; Sabbagh-Kermani, Farahnaz; Lee, Janice; Tsokos, Maria G; Lee, Chyi-Chia R; Ferraz, Victor; da Silva, Eduarda Morgana; Stevens, Cathy A; Roche, Nathalie; Bartsch, Oliver; Farndon, Peter; Bermejo-Sanchez, Eva; Brooks, Brian P; Maduro, Valerie; Dallapiccola, Bruno; Ramos, Feliciano J; Chung, Hon-Yin Brian; Le Caignec, Cédric; Martins, Fabiana; Jacyk, Witold K; Mazzanti, Laura; Brunner, Han G; Bakkers, Jeroen; Lin, Shuo; Malicdan, May Christine V; Boerkoel, Cornelius F; Gahl, William A; de Vries, Bert B A; van Haelst, Mieke M; Zenker, Martin; Markello, Thomas C

    2015-07-02

    Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  13. "Candy cane syndrome:" an underappreciated cause of abdominal pain and nausea after Roux-en-Y gastric bypass surgery.

    PubMed

    Aryaie, Amir H; Fayezizadeh, Mojtaba; Wen, Yuxiang; Alshehri, Mohammed; Abbas, Mujjahid; Khaitan, Leena

    2017-09-01

    "Candy cane" syndrome (a blind afferent Roux limb at the gastrojejunostomy) has been implicated as a cause of abdominal pain, nausea, and emesis after Roux-n-Y gastric bypass (RYGB) but remains poorly described. To report that "candy cane" syndrome is real and can be treated effectively with revisional bariatric surgery SETTING: All patients underwent "candy cane" resection at University Hospitals of Cleveland. All patients who underwent resection of the "candy cane" between January 2011 and July 2015 were included. All had preoperative workup to identify "candy cane" syndrome. Demographic data; pre-, peri-, and postoperative symptoms; data regarding hospitalization; and postoperative weight loss were assessed through retrospective chart review. Data were analyzed using Student's t test and χ 2 analysis where appropriate. Nineteen patients had resection of the "candy cane" (94% female, mean age 50±11 yr), within 3 to 11 years after initial RYGB. Primary presenting symptoms were epigastric abdominal pain (68%) and nausea/vomiting (32%), particularly with fibrous foods and meats. On upper gastrointestinal study and endoscopy, the afferent blind limb was the most direct outlet from the gastrojejunostomy. Only patients with these preoperative findings were deemed to have "candy cane" syndrome. Eighteen (94%) cases were completed laparoscopically. Length of the "candy cane" ranged from 3 to 22 cm. Median length of stay was 1 day. After resection, 18 (94%) patients had complete resolution of their symptoms (P<.001). Mean body mass index decreased from 33.9±6.1 kg/m 2 preoperatively to 31.7±5.6 kg/m 2 at 6 months (17.4% excess weight loss) and 30.5±6.9 kg/m 2 at 1 year (25.7% excess weight loss). The average length of latest follow-up was 20.7 months. "Candy cane" syndrome is a real phenomenon that can be managed safely with excellent outcomes with resection of the blind afferent limb. A thorough diagnostic workup is paramount to proper identification of this

  14. The Use of Tissue Plasminogen Activator in the Treatment of Wallenberg Syndrome Caused by Vertebral Artery Dissection.

    PubMed

    Salerno, Alexis; Cotter, Bradford V; Winters, Michael E

    2017-05-01

    Acute cerebrovascular accident (CVA) is a devastating cause of patient morbidity and mortality. Up to 10% of acute CVAs in young patients are caused by dissection of the vertebral or carotid artery. Wallenberg syndrome results from a CVA in the vertebral or posterior inferior artery of the cerebellum and manifests as various degrees of cerebellar dysfunction. The administration of a thrombolytic medication has been recommended in the treatment of patients with stroke caused by cervical artery dissection. Surprisingly, there is scant literature on the use of this medication in the treatment of this condition. We describe a 42-year-old man with the sudden onset of headache, left-sided neck pain, vomiting, nystagmus, and ataxia 1 h after completing a weightlifting routine. Computed tomography angiography revealed a grade IV left vertebral artery injury with a dissection flap extending distally and resulting in complete occlusion. Subsequent magnetic resonance imaging and angiography demonstrated acute left cerebellar and lateral medullary infarcts, consistent with Wallenberg syndrome. The patient was treated with tissue plasminogen activator, which failed to resolve his symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians frequently manage patients with acute CVAs. For select patients, the administration of tissue plasminogen activator can improve outcomes. However, the risk of major hemorrhage with this medication is significant. Cervical artery dissection is an important cause of acute stroke in young patients and is often missed on initial presentation. It is imperative for the emergency physician to consider acute cervical artery dissection as a cause of stroke and to be knowledgeable regarding the efficacy of thrombolytic medications for this condition. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. COL4A4 gene study of a European population: description of new mutations causing autosomal dominant Alport syndrome.

    PubMed

    Rosado, Consolación; Bueno, Elena; Felipe, Carmen; González-Sarmiento, Rogelio

    2014-01-01

    Autosomal forms of Alport syndrome represent 20% of all patients (15% recessive and 5% dominant). They are caused by mutations in the COL4A3 and COL4A4 genes, which encode a-3 and a-4 collagen IV chains of the glomerular basement membrane, cochlea and eye. Thin basement membrane nephropathy may affect up to 1% of the population. The pattern of inheritance in the 40% of cases is the same as autosomal dominant Alport syndrome: heterozygous mutations in these genes. The aim of this study is to detect new pathogenic mutations in the COL4A4 gene in the patients previously diagnosed with autosomal Alport syndrome and thin basement membrane nephropathy in our hospital. We conducted a clinical and genetic study in eleven patients belonging to six unrelated families with aforementioned clinical symptoms and a negative study of COL4A3 gene. The molecular study was made by conformation of sensitive gel electrophoresis (CSGE) and direct sequencing of the fragments that show an altered electrophoretic migration pattern. We found two pathogenic mutations, not yet described: IVS3 + 1G > C is a replacement of Guanine to Cytosine in position +1 of intron 3, in the splicing region, which leads to a pathogenic mutation. c.4267C > T; p.P1423S is a missense mutation, also considered pathogenic. We also found seven new polymorphisms. We describe two new pathogenic mutations, responsible for autosomal dominant Alport syndrome. The other families of the study were undiagnosed owing to problems in the method employed and the possibility of mutations in other genes, giving rise to other diseases with similar symptoms.

  16. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome.

    PubMed

    Brioude, F; Oliver-Petit, I; Blaise, A; Praz, F; Rossignol, S; Le Jule, M; Thibaud, N; Faussat, A-M; Tauber, M; Le Bouc, Y; Netchine, I

    2013-12-01

    Russell Silver syndrome (RSS) leads to prenatal and postnatal growth retardation. About 55% of RSS patients present a loss-of-methylation of the paternal ICR1 domain on chromosome 11p15. CDKN1C is a cell proliferation inhibitor encoded by an imprinted gene in the 11p15 ICR2 domain. CDKN1C mutations lead to Beckwith Wiedemann syndrome (BWS, overgrowth syndrome) and in IMAGe syndrome which associates growth retardation and adrenal insufficiency. We searched for CDKN1C mutations in a cohort of clinically diagnosed RSS patients with no molecular anomaly. The coding sequence and intron-exon boundaries of CDKN1C were analysed in 97 RSS patients. The impact of CDKN1C variants on the cell cycle in vitro were determined by flow cytometry. Stability of CDKN1C was studied by western immunoblotting after inhibition of translation with cycloheximide. We identified the novel c.836G>[G;T] (p.Arg279Leu) mutation in a familial case of intrauterine growth retardation (IUGR) with RSS phenotype and no evidence of IMAGe. All the RSS patients inherited this mutation from their mothers (consistent with monoallelic expression from the maternal allele of the gene). A mutation of this amino acid (p.Arg279Pro) has been reported in cases of IMAGe. Functional analysis showed that Arg279Leu (RSS) did not affect the cell cycle, whereas the Arg279Pro mutation (IMAGe) led to a gain of function. Arg279Leu (RSS) led to an increased stability which could explain an increased activity of CDKN1C. CDKN1C mutations cause dominant maternally transmitted RSS, completing the molecular mirror with BWS. CDKN1C should be investigated in cases with family history of RSS.

  17. A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis.

    PubMed

    Yamaguchi, Shintaro; Maruyama, Tatsuya; Wakino, Shu; Tokuyama, Hirobumi; Hashiguchi, Akinori; Tada, Shinichiro; Homma, Koichiro; Monkawa, Toshiaki; Thomas, James; Miyashita, Kazutoshi; Kurihara, Isao; Yoshida, Tadashi; Konishi, Konosuke; Hayashi, Koichi; Hayashi, Matsuhiko; Itoh, Hiroshi

    2015-11-11

    Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not