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Sample records for ichthyosis

  1. Ichthyosis uteri with leiomyoma.

    PubMed

    Kanno, Kiyoshi; Kusakabe, Takashi; Takata, Megumi; Suzuki, Kazuo; Oowada, Makoto; Suzuki, Hiroshi

    2016-11-01

    A 58-year-old, postmenopausal, multiparous woman presented with a chief complaint of abnormal vaginal bleeding. Endometrial cytology was evaluated twice, revealing only squamous epithelial cells both times. Degenerated leiomyoma or uterine sarcoma was suspected from imaging findings, and total abdominal hysterectomy and bilateral salpingo-oophorectomy were therefore performed. However, histopathological examination revealed no signs of malignancy, and the patient was diagnosed as having ichthyosis uteri with uterine leiomyoma. No koilocytosis was evident, and immunostaining for p16 was also negative. Ichthyosis uteri is an extremely rare disease of unknown origin in which squamous metaplasia of the endometrium occurs across a wide area. Although regarded as a benign condition, cases have been reported in which the underlying condition was squamous cell carcinoma or endometrial adenocarcinoma. If ichthyosis uteri is present, a comprehensive approach is required, and the possibility of uterine malignancy should be considered. However, there may be no direct association between the malignant lesions and ichthyosis uteri. © 2016 Japan Society of Obstetrics and Gynecology.

  2. Whole-exome sequencing for diagnosis of hereditary ichthyosis.

    PubMed

    Sitek, J C; Kulseth, M A; Rypdal, K B; Skodje, T; Sheng, Y; Retterstøl, L

    2018-02-14

    Hereditary ichthyosis constitutes a diverse group of cornification disorders. Identification of the molecular cause facilitates optimal patient care. We wanted to estimate the diagnostic yield of applying whole-exome sequencing (WES) in the routine genetic workup of inherited ichthyosis. During a 3-year-period, all ichthyosis patients, except X-linked and mild vulgar ichthyosis, consecutively admitted to a university hospital clinic were offered WES with subsequent analysis of ichthyosis-related genes as a first-line genetic investigation. Clinical and molecular data have been collected retrospectively. Genetic variants causative for the ichthyosis were identified in 27 of 34 investigated patients (79.4%). In all, 31 causative mutations across 13 genes were disclosed, including 12 novel variants. TGM1 was the most frequently mutated gene, accounting for 43.7% of patients suffering from autosomal recessive congenital ichthyosis (ARCI). Whole-exome sequencing appears an effective tool in disclosing the molecular cause of patients with hereditary ichthyosis seen in clinical practice and should be considered a first-tier genetic test in these patients. © 2018 European Academy of Dermatology and Venereology.

  3. Short stature with congenital ichthyosis.

    PubMed

    Lakhani, Som J; Lakhani, Om J

    2015-12-09

    PIBIDS syndrome (photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature) is a variant of trichothiodystrophy. It is a rare form of autosomal recessive congenital ichthyosis. Short stature is a vital component of PIBIDS syndrome. We present the cases of two siblings in whom we diagnosed PIBIDS syndrome. On evaluation for short stature, they were found to have severe vitamin D deficiency, which on correction led to the patients having considerable gain in stature. With this case, we would also like to propose that vitamin D deficiency could be one of the treatable causes of short stature in PIBIDS syndrome. 2015 BMJ Publishing Group Ltd.

  4. Ichthyosis vulgaris: the filaggrin mutation disease.

    PubMed

    Thyssen, J P; Godoy-Gijon, E; Elias, P M

    2013-06-01

    Ichthyosis vulgaris is caused by loss-of-function mutations in the filaggrin gene (FLG) and is characterized clinically by xerosis, scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. According to the published studies presented in this review article, FLG mutations are observed in approximately 7·7% of Europeans and 3·0% of Asians, but appear to be infrequent in darker-skinned populations. This clinical review article provides an overview of ichthyosis vulgaris epidemiology, related disorders and pathomechanisms. Not only does ichthyosis vulgaris possess a wide clinical spectrum, recent studies suggest that carriers of FLG mutations may have a generally altered risk of developing common diseases, even beyond atopic disorders. Mechanistic studies have shown increased penetration of allergens and chemicals in filaggrin-deficient skin, and epidemiological studies have found higher levels of hand eczema, irritant contact dermatitis, nickel sensitization and serum vitamin D levels. When relevant, individuals should be informed about an increased risk of developing dermatitis when repeatedly or continuously exposed to nickel or irritants. Moreover, with our current knowledge, individuals with ichthyosis vulgaris should be protected against neonatal exposure to cats to prevent atopic dermatitis and should abstain from smoking to prevent asthma. Finally, they should be advised against excessive exposure to factors that decrease skin barrier functions and increase the risk of atopic dermatitis. © 2013 The Authors. BJD © 2013 British Association of Dermatologists.

  5. [Ichthyosis and social stigma in Burkina Faso].

    PubMed

    Korsaga/Somé, N; Salissou, L; Tapsoba, G P; Ouédraogo, M S; Traoré, F; Doulla, M; Barro/Traoré, F; Niamba, P; Traoré, A

    2016-01-01

    Through the story of two families presenting ichthyosis, we report the support and social integration difficulties inherent in these genetic diseases. Family No. 1: a 38-year-old shepherd and his wife of 25 years both had lamellar ichthyosis that had been present continually since childhood. They had had 2 stillborn infants as well as a live newborn that were all presenting lamellar ichthyosis. Family No. 2: a 45-year-old housewife was seen at our consultation with her 3 youngest children aged 8 years, 6 years and 18 months. According to the mother, at birth, all 3 children were covered with a membrane resembling plastic that crackled during movement, and they had red eyes. Examination of the 3 children revealed a clinical picture of lamellar ichthyosis with ectropion, malformed ears and brachydactyly. Although they presented delayed growth and weight development, psychomotor development was normal. There was no consanguinity between the parents. In both families, the visible nature of the dermatosis resulted in discrimination and ostracism. The precarious living conditions of the parents and the high cost of treatment in an African setting resulted in degradation of quality of life with exacerbation of the difficulties of social integration, resulting in a lack of schooling and a bleak future for these children. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. A Unique Preparation and Delivery Method for Acitretin for Neonatal Harlequin Ichthyosis

    PubMed Central

    Damodaran, Kriti; Bhutada, Alok

    2018-01-01

    Harlequin ichthyosis is a rare form of congenital ichthyosis with a distinct phenotypic appearance. We describe a case of a newborn baby with harlequin ichthyosis who was treated with an oral formulation of acitretin. The treatment resulted in a satisfactory improvement in the skin condition of the patient. The tolerance to the drug was good with no side effects in the patient. The aim of this case report is to highlight an extemporaneous preparation of acitretin from the commonly available capsule form, which is effective for use in neonates with harlequin ichthyosis. It also highlights the risk of exposure to health care providers to acitretin. PMID:29720920

  7. Otologic Manifestations of Autosomal Recessive Congenital Ichthyosis in Children.

    PubMed

    Martín-Santiago, A; Rodríguez-Pascual, M; Knöpfel, N; Hernández-Martín, Á

    2015-11-01

    Few studies have investigated ear involvement in nonsyndromic autosomal recessive congenital ichthyosis (ARCI). To assess the type and frequency of otologic manifestations of ARCI in patients under follow-up at the pediatric dermatology department of our hospital. We prospectively studied the presence of ear pain, ear itching, tinnitus, otitis, cerumen impaction, accumulation of epithelial debris, and hearing loss. Daily hygiene measures, topical treatments, medical-surgical interventions, and frequency of visits to an ear, nose, and throat (ENT) specialist were noted in the patients' medical records. Ear examination and hearing tests were performed in all cases. Ten patients were studied: 2 had a self-healing collodion baby phenotype and 8 had ichthyosis. There was mention of otologic manifestations in the records of all 8 patients with ichthyosis (100%); 6 of these patients (75%) had abnormalities in the external auditory canal examination and 2 (25%) had conductive hearing loss. Our findings are limited by the small number of patients studied, all of whom were younger than 19 years. The involvement of both dermatologists and ENT specialists in the management of patients with ichthyosis is crucial to ensure the application of the best therapeutic and preventive measures. More studies are needed to assess the prevalence and impact on quality of life of ear involvement in patients with ichthyosis and to determine the optimal interval between ENT visits for these patients. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

  8. [A case of skin autograft for skin ulcers in ichthyosis].

    PubMed

    Li, Shiwei; Yang, Xiaodong; Liu, Lijun; Tang, Xueyang

    2017-10-28

    Ichthyosis refers to a group of skin diseases characterized by abnormal keratinization of the epidermis, resulting in dryness, roughness and scale of the skin. A girl with ichthyosis, who presented with skin ulcers and infection of the right dorsal foot, was admitted to our department. An autologous razor-thin skin grafting procedure was performed to repair the skin ulcers after debridement and vacuum sealing drain. After 8 months of follow-up, both the donor and recipient site healed well and there were no newly formed ulcers or infections. Although the skin quality of ichthyosis is poor, the lesion area can still be used as donor or recipient cite.

  9. Genetics Home Reference: lamellar ichthyosis

    MedlinePlus

    ... 1 mutations in patients affected by lamellar ichthyosis. Cell Death Dis. 2012 Oct 25;3:e416. doi: 10.1038/cddis.2012.152. ... are genome editing and CRISPR-Cas9? What is precision medicine? What is newborn ...

  10. Oral Manifestation of Autosomal Recessive Congenital Ichthyosis in a 2-Year-Old Patient

    PubMed Central

    Ramar, Kavitha; Annamalai, Sankar; Hariharavel, V. P.; Aravindhan, R.; Ganesh, C.; Ieshwaryah, K.

    2014-01-01

    Ichthyosis is a heterogeneous family of hereditary keratinisation disorders mostly characterized by variable erythema of the whole body and different scaling patterns. Although these disorders affect tissues of epidermal origin, there is little evidence regarding the oral and dental manifestations of Lamellar Ichthyosis. A case report of early childhood caries in lamellar ichthyosis is presented and the dental consideration and management is discussed in this paper. PMID:24995134

  11. Generalized morphea in a child with harlequin ichthyosis: a rare association.

    PubMed

    Giacomin, Maria F A; França, Camila M P; Oliveira, Zilda N P; Machado, Maria C R; Sallum, Adriana M E; Silva, Clovis A

    2016-01-01

    Harlequin ichthyosis (HI) is a severe and rare hereditary congenital skin disorder characterized by excessive dryness, ectropion and eclabion. The association of ichthyosis with systemic sclerosis has been described in only three children. No patient with generalized morphea (GM) associated with harlequin ichthyosis was described. A 4-years and 6-months girl, diagnosed with harlequin ichthyosis based on diffuse cutaneous thickening, scaling, erythema, ectropion and eclabium since the first hours of birth was described. She was treated with acitretin (1.0mg/kg/day) and emollient cream. At 3 years and 9 months, she developed muscle contractures with pain on motion and limitation in elbows and knees, and diffuse sclerodermic plaques on the abdomen, back, suprapubic area and lower limbs. Skin biopsy showed rectified epidermis and mild hyperorthokeratosis, reticular dermis with perivascular and periadnexal infiltrates of lymphocytes and mononuclear cells, and reticular dermis and sweat gland sclerosis surrounded by a dense collagen tissue, compatible with scleroderma. The patient fulfilled the GM subtype criteria. Methotrexate and prednisone were introduced. At 4 years and 3 months, new scleroderma lesions occurred and azathioprine was associated with previous therapy, with no apparent changes after two months. A case of harlequin ichthyosis associated with a GM was reported. The treatment of these two conditions is a challenge and requires a multidisciplinary team. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

  12. Foundation for Ichthyosis & Related Skin Types

    MedlinePlus

    ... Our Community Learn How About Us Mission Statement/Core Values History Annual Report & Financials Board of Directors ... Ichthyosis New Parent Information About Us Mission Statement & Core Values History Annual Report & Financials Board of Directors ...

  13. Updated strategies for the management, pathogenesis and molecular genetics of different forms of ichthyosis syndromes with prominent hair abnormalities.

    PubMed

    Rasheed, Madiha; Shahzad, Shaheen; Zaeem, Afifa; Afzal, Imran; Gul, Asma; Khalid, Sumbal

    2017-12-01

    Syndromic ichthyosis is rare inherited disorders of cornification with varied disease complications. This disorder appears in seventeen subtypes associated with severe systematic manifestations along with medical, cosmetic and social problems. Syndromic ichthyosis with prominent hair abnormalities covers five major subtypes: Netherton syndrome, trichothiodystrophy, ichthyosis hypotrichosis syndrome, ichthyosis hypotrichosis sclerosing cholangitis and ichthyosis follicularis atrichia photophobia syndrome. These syndromes mostly prevail in high consanguinity states, with distinctive clinical features. The known pathogenic molecules involved in ichthyosis syndromes with prominent hair abnormalities include SPINK5, ERCC2, ERCC3, GTF2H5, MPLKIP, ST14, CLDN1 and MBTPS2. Despite underlying genetic origin, most of the health professionals solely rely on phenotypic expression of these disorders that leads to improper management of patients, hence making these patients living an orphanage life. After dermal features, association of other systems such as nervous system, skeletal system, hair abnormalities or liver problems may sometimes give clues for diagnosis but still leaving place for molecular screening for efficient diagnosis. In this paper, we have presented a review of ichthyosis syndrome with prominent hair abnormalities, with special emphasis on their updated genetic consequences and disease management. Additionally, we aim to update health professionals about the practice of molecular screening in ichthyosis syndromes for appropriate diagnosis and treatment.

  14. Genetics Home Reference: ichthyosis with confetti

    MedlinePlus

    ... from the University of Kansas Medical Center: Ichthyosis Scientific Articles on PubMed (1 link) PubMed OMIM (1 link) ... 1;330(6000):94-7. doi: 10.1126/science.1192280. Epub 2010 Aug 26. Citation on PubMed or Free article on PubMed Central Krunic AL, Palcesky D, Busbey S, ...

  15. Short- and medium-term efficacy of specific hydrotherapy in inherited ichthyosis.

    PubMed

    Bodemer, C; Bourrat, E; Mazereeuw-Hautier, J; Boralevi, F; Barbarot, S; Bessis, D; Blanchet-Bardon, C; Bourdon-Lanoy, E; Stalder, J-F; Ribet, V; Guerrero, D; Sibaud, V

    2011-11-01

    Management of inherited ichthyoses is symptomatic. Despite treatment, skin symptoms have a major impact on patients' quality of life (QoL). To assess the short- and medium-term efficacy of hydrotherapy on QoL and clinical symptoms of patients with inherited ichthyosis. In this 9-month prospective, open-label, multicentre study, 20 children and 24 adults with ichthyosis were enrolled in several French reference and competence centres, 2 months before undergoing a 3-week treatment with specific hydrotherapeutic management at Avène Hydrotherapy Centre. At baseline (2 months before hydrotherapy), beginning (D0) and end of hydrotherapy (D18), and 3 and 6 months later at the reference and competence centres, patients self-assessed QoL using the Dermatology Life Quality Index (DLQI) or its paediatric version (Children's DLQI), and investigators evaluated ichthyosis severity using a specific clinical ichthyosis score. The DLQI scores were significantly improved not only at the end of the hydrotherapy treatment (-56% vs. baseline; mean ± SD 3·59 ± 4·30 at D18 vs. 8·35 ± 5·71 at D0; P < 0·0001), but also at 3 months (-28% vs. baseline; P = 0·01) and 6 months after hydrotherapy (-26% vs. baseline; mean ± SD 5·21 ± 5·11 vs. 6·89 ± 5·38; P = 0·03) (primary criterion). Clinical symptoms were also significantly improved at all post-treatment visits, with a decrease of the mean clinical ichthyosis score by -38% between D0 and D18, by -30% at 3 months and by -31% at 6 months vs. baseline. A 3-week treatment at Avène Hydrotherapy Centre provided significant and persisting improvement of QoL and clinical symptoms in patients with inherited ichthyoses. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

  16. Apremilast Use in a Case of Cicatricial Ectropion Secondary to Severe Lamellar Ichthyosis.

    PubMed

    Abboud, Jean-Paul J; Whittington, Alexander; Ahmed, Masih; Himebaugh, Jesse T; Wiley, Lee A; Haffar, Ahmad; Nguyen, John

    Ichthyosis is a cutaneous disorder characterized by excessive amounts of dry thickened skin surface scales. Ocular manifestations of ichthyosis include cicatricial ectropion, which may cause exposure keratoconjunctivitis and rarely corneal perforation. Topical emollients, anti-inflammatory ointments, and systemic retinoids have been used to control the disease process, while surgical correction with donor graft has been reserved for severe cases involving corneal exposure. The authors report a case of a Caucasian male with lamellar ichthyosis with severe bilateral upper and lower eyelid cicatricial ectropion and corneal ulceration requiring surgical correction. Treatment with apremilast, a novel phosphodiesterase-4 inhibitor, for the treatment of a concomitant plaque psoriasis achieved good control of his skin diseases and minimized the recurrence of eyelid ectropion.

  17. Family burden in inherited ichthyosis: creation of a specific questionnaire.

    PubMed

    Dufresne, Hélène; Hadj-Rabia, Smail; Méni, Cécile; Sibaud, Vincent; Bodemer, Christine; Taïeb, Charles

    2013-02-15

    The concept of individual burden, associated with disease, has been introduced recently to determine the "disability" caused by the pathology in the broadest sense of the word (psychological, social, economic, physical). Inherited ichthyosis belong to a large heterogeneous group of Mendelian Disorders of Cornification. Skin symptoms have a major impact on patients' Quality of Life but little is known about the burden of the disease on the families of patients. To develop and validate a specific burden questionnaire for the families of patients affected by ichthyosis. Two steps were required. First, the creation of the questionnaire which followed a strict methodological process involving a multidisciplinary team and families. Secondarily, the validation of the questionnaire, including the assessment of its reliability, external validity, reproducibility and sensitivity, was carried out on a population of patients affected by autosomal recessive congenital ichthyosis. A population of parents of patients affected by ichthyosis was enrolled to answer the new questionnaire in association with the Short Form Q12 questionnaire (SF-12) and a clinical severity score was filled for each patient. Ninety four families were interviewed to construct the verbatim in order to create the questionnaire and a cognitive debriefing was realized. The concept of burden could be structured around five components: "economic", "daily life", "familial and personal relationship", "work", and "psychological impact". As a result, "Family Burden Ichthyosis" (FBI) reproducible questionnaire of 25 items was created.Forty two questionnaires were analyzable for psychometric validation. Reliability (Cronbach's alpha coefficient = 0.89), reflected the good homogeneity of the questionnaire. The correlation between mental dimensions of the SF-12 and the FBI questionnaire was statistically significant which confirmed the external validity. The mean FBI score was 71.7 ± 18.8 and a significant

  18. Lamellar ichthyosis in a female neonate without a collodion membrane.

    PubMed

    Chao, Kevin; Aleshin, Maria; Goldstein, Zachary; Worswick, Scott; Hogeling, Marcia

    2018-02-15

    The term, autosomal recessive congenital ichthyosis (ARCI), describes a group of rare genetic skin diseases of cornification involving hyperkeratotic scaling at birth. The defective skin barrier function may lead to dehydration, body temperature instability, and high susceptibility to infections. In most cases of ARCI, neonates are born with a collodion membrane covering the body, often presenting with ectropion and eclabium. We report a premature female neonate presenting with hyperkeratotic scaling at birth without a collodion membrane. She was managed with placement in a humidified isolette, prophylactic antibiotics, dilute bleach baths, petrolatum ointment, and artificial eye drops. By the fourth week of life, there was marked improvement in her skin with the large, brown, plate-like scales on the trunk and extremities becoming lighter in color and finer in appearance. The ichthyosis genetic panel showed mutations in the ABCA12 gene resulting in the lamellar ichthyosis phenotype of ARCI. Our literature review revealed at least 28 patients with ARCI who were not born as collodion babies. Although collodion babies are a hallmark of most ARCI cases, clinicians should be aware of neonates with ARCI born without a collodion membrane and expedite appropriate workup and treatment.

  19. Ichthyosis associated with widespread tinea corporis: report of three cases.

    PubMed

    Freitas, Camila Fernanda Novak Pinheiro de; Mulinari-Brenner, Fabiane; Fontana, Hanae Rafaela; Gentili, Arthur Conelian; Hammerschmidt, Mariana

    2013-01-01

    Ichthyoses are a common group of keratinization disorders. A non-inflammatory generalized persistent skin desquamation is observed. It is characterized by increased cell turnover, thickening of the stratum corneum and functional changes of sebaceous and sweat glands. All of these favor fungal proliferation. Dermatophytes may infect skin, hair and nails causing ringworm or tinea. They have the ability to obtain nutrients from keratinized material. One of its most prevalent genera is Trichophyton rubrum. Although tineas and ichthyoses are quite common, the association of the two entities is rarely reported in the literature. Three cases of ichthyosis associated with widespread infection by T. rubrum are presented. Resistance to several antifungal treatments was responsible for worsening of ichthyosis signs and symptoms.

  20. Role of molecular testing in the multidisciplinary diagnostic approach of ichthyosis.

    PubMed

    Diociaiuti, Andrea; El Hachem, May; Pisaneschi, Elisa; Giancristoforo, Simona; Genovese, Silvia; Sirleto, Pietro; Boldrini, Renata; Angioni, Adriano

    2016-01-13

    The term ichthyosis describes a generalized disorder of cornification characterized by scaling and/or hyperkeratosis of different skin regions. Mutations in a broad group of genes related to keratinocyte differentiation and epidermal barrier function have been demonstrated to play a causative role in disease development. Ichthyosis may be classified in syndromic or non-syndromic forms based on the occurrence or absence of extracutaneous signs. In this setting, the diagnosis of ichthyosis is an integrated multistep process requiring a multidisciplinary approach in order to formulate the appropriate diagnostic hypothesis and to address the genetic testing. Due to the complex features of the different ichthyoses and the high number of genes involved we have investigated a group of 64 patients, affected by syndromic and non-syndromic diseases, using Next Generation Sequencing as a new tool for the molecular diagnosis. Using this innovative molecular approach we were able to find pathogenic mutations in 53 out of 64 patients resulting in 82.8 % total detection rate. An interesting result from the analysis of the data is the high rate of novel sequence variations found compared to known mutations and the relevant rate of homozygous mutations. The possibility to analyze a large number of genes associated with various diseases allows to study cases with phenotypes not well-determined, giving the opportunity to make new genotype-phenotype correlation. In some cases there were discrepancies between clinical features and histology or electron microscopy and only molecular analysis allowed to definitively resolve the diagnostic dilemma. The genetic diagnosis of ichthyosis leads to a more accurate and effective genetic counseling, allowing correct evaluation of the risk of recurrence, particularly in families with consanguineous background.

  1. Ichthyosis associated with widespread tinea corporis: report of three cases*

    PubMed Central

    de Freitas, Camila Fernanda Novak Pinheiro; Mulinari-Brenner, Fabiane; Fontana, Hanae Rafaela; Gentili, Arthur Conelian; Hammerschmidt, Mariana

    2013-01-01

    Ichthyoses are a common group of keratinization disorders. A non-inflammatory generalized persistent skin desquamation is observed. It is characterized by increased cell turnover, thickening of the stratum corneum and functional changes of sebaceous and sweat glands. All of these favor fungal proliferation. Dermatophytes may infect skin, hair and nails causing ringworm or tinea. They have the ability to obtain nutrients from keratinized material. One of its most prevalent genera is Trichophyton rubrum. Although tineas and ichthyoses are quite common, the association of the two entities is rarely reported in the literature. Three cases of ichthyosis associated with widespread infection by T. rubrum are presented. Resistance to several antifungal treatments was responsible for worsening of ichthyosis signs and symptoms. PMID:24068140

  2. Expanding the Genotypic Spectrum of Bathing Suit Ichthyosis

    PubMed Central

    Marukian, Nareh V.; Hu, Rong-Hua; Craiglow, Brittany G.; Milstone, Leonard M.; Zhou, Jing; Theos, Amy; Kaymakcalan, Hande; Akkaya, Deniz A.; Uitto, Jouni J.; Vahidnezhad, Hassan; Youssefian, Leila; Bayliss, Susan J.; Paller, Amy S.; Boyden, Lynn M.

    2017-01-01

    Importance Bathing suit ichthyosis (BSI) is a rare congenital disorder of keratinization characterized by restriction of scale to sites of relatively higher temperature such as the trunk, with cooler areas remaining unaffected. Fewer than 40 cases have been reported in the literature. Bathing suit ichthyosis is caused by recessive, temperature-sensitive mutations in the transglutaminase-1 gene (TGM1). Clear genotype-phenotype correlations have been difficult to establish because several of the same TGM1 mutations have been reported in BSI and other forms of congenital ichthyosis. We identify novel and recurrent mutations in 16 participants with BSI. Objective To expand the genotypic spectrum of BSI, identifying novel TGM1 mutations in patients with BSI, and to use BSI genotypes to draw inferences about the temperature sensitivity of TGM1 mutations. Design, Setting, and Participants A total of 16 participants with BSI from 13 kindreds were identified from 6 academic medical centers. A detailed clinical history was obtained from each participant, including phenotypic presentation at birth and disease course. Each participant underwent targeted sequencing of TGM1. Main Outcomes and Measures Phenotypic and genotypic characteristics in these patients from birth onward. Results Of the 16 participants, 7 were male, and 9 were female (mean age, 12.6 years; range, 1-39 years). We found 1 novel TGM1 indel mutation (Ile469_Cys471delinsMetLeu) and 8 TGM1 missense mutations that to our knowledge have not been previously reported in BSI: 5 have been previously described in non–temperature-sensitive forms of congenital ichthyosis (Arg143Cys, Gly218Ser, Gly278Arg, Arg286Gln, and Ser358Arg), and 3 (Tyr374Cys, Phe495Leu, and Ser772Arg) are novel mutations. Three probands were homozygous for Arg264Trp, Arg286Gln, or Arg315Leu, indicating that these mutations are temperature sensitive. Seven of 10 probands with a compound heterozygous TGM1 genotype had a mutation at either arginine

  3. Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis.

    PubMed

    Hotz, Alrun; Oji, Vinzenz; Bourrat, Emmanuelle; Jonca, Nathalie; Mazereeuw-Hautier, Juliette; Betz, Regina C; Blume-Peytavi, Ulrike; Stieler, Karola; Morice-Picard, Fanny; Schönbuchner, Ines; Markus, Susanne; Schlipf, Nina; Fischer, Judith

    2016-05-01

    Twenty-six families with keratinopathic ichthyoses (epidermolytic ichthyosis, superficial epidermolytic ichthyosis or congenital reticular ichthyosiform erythroderma) were studied. Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. In this study mutations were found in KRT1, KRT2 and KRT10, including 8 mutations that are novel pathogenic variants. We report here the first case of a patient with congenital reticular ichthyosiform erythroderma carrying a mutation in KRT10 that does not lead to an arginine-rich reading frame. Novel clinical features found in patients with congenital reticular ichthyosiform erythroderma are described, such as mental retardation, spasticity, facial dysmorphisms, symblepharon and malposition of the 4th toe.

  4. Threshold levels of 25-hydroxyvitamin D and parathyroid hormone for impaired bone health in children with congenital ichthyosis and type IV and V skin.

    PubMed

    Sethuraman, G; Sreenivas, V; Yenamandra, V K; Gupta, N; Sharma, V K; Marwaha, R K; Bhari, N; Irshad, M; Kabra, M; Thulkar, S

    2015-01-01

    Patients with congenital ichthyosis, especially those with darker skin types, are at increased risk of developing vitamin D deficiency and rickets. The relationships between 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH) and bone health have not been studied previously, in ichthyosis. To determine the threshold levels of 25(OH)D and PTH for impaired bone health in children with congenital ichthyosis. In this cross-sectional study, 119 children with ichthyosis and 168 controls were recruited. Serum 25(OH)D, PTH, calcium, phosphate and alkaline phosphatase (ALP) were measured. Radiological screening for rickets was carried out only in children with ichthyosis. Forty-seven children with ichthyosis had either clinical or radiological evidence of rickets. The correlation between serum 25(OH)D and PTH showed that a serum level of 25(OH)D 8 ng mL(-1) was associated with a significant increase in PTH. The correlation between PTH and ALP showed that a serum PTH level of 75 pg mL(-1) was associated with a significant increase in ALP levels. Of the different clinical phenotypes of ichthyosis, both autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis (EI) were found to have significantly increased PTH, ALP and radiological rickets scores compared with common ichthyosis. Serum levels of 25(OH)D ≤ 8 ng mL(-1) and PTH ≥ 75 pg mL(-1) significantly increases the risk for development of rickets [odds ratio (OR) 2·8; 95% confidence interval (CI) 1·05-7·40; P = 0·04] in ichthyosis. Among the different types, patients with ARCI (OR 4·83; 95% CI 1·74-13·45; P < 0·01) and EI (OR 5·71; 95% CI 1·74-18·79; P < 0·01) are at an increased risk of developing rickets. © 2014 British Association of Dermatologists.

  5. A de novo variant in the ASPRV1 gene in a dog with ichthyosis.

    PubMed

    Bauer, Anina; Waluk, Dominik P; Galichet, Arnaud; Timm, Katrin; Jagannathan, Vidhya; Sayar, Beyza S; Wiener, Dominique J; Dietschi, Elisabeth; Müller, Eliane J; Roosje, Petra; Welle, Monika M; Leeb, Tosso

    2017-03-01

    Ichthyoses are a heterogeneous group of inherited cornification disorders characterized by generalized dry skin, scaling and/or hyperkeratosis. Ichthyosis vulgaris is the most common form of ichthyosis in humans and caused by genetic variants in the FLG gene encoding filaggrin. Filaggrin is a key player in the formation of the stratum corneum, the uppermost layer of the epidermis and therefore crucial for barrier function. During terminal differentiation of keratinocytes, the precursor profilaggrin is cleaved by several proteases into filaggrin monomers and eventually processed into free amino acids contributing to the hydration of the cornified layer. We studied a German Shepherd dog with a novel form of ichthyosis. Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding "aspartic peptidase, retroviral-like 1", which is also known as skin aspartic protease (SASPase). The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro). ASPRV1 encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. By immunofluorescence staining we showed that the filaggrin expression pattern was altered in the affected dog. Thus, our findings provide strong evidence that the identified de novo variant is causative for the ichthyosis in the affected dog and that ASPRV1 plays an essential role in skin barrier formation. ASPRV1 is thus a novel candidate gene for unexplained human forms of ichthyoses.

  6. Mutations in ABCA12 Underlie the Severe Congenital Skin Disease Harlequin Ichthyosis

    PubMed Central

    Kelsell, David P.; Norgett, Elizabeth E.; Unsworth, Harriet; Teh, Muy-Teck; Cullup, Thomas; Mein, Charles A.; Dopping-Hepenstal, Patricia J.; Dale, Beverly A.; Tadini, Gianluca; Fleckman, Philip; Stephens, Karen G.; Sybert, Virginia P.; Mallory, Susan B.; North, Bernard V.; Witt, David R.; Sprecher, Eli; E. M. Taylor, Aileen; Ilchyshyn, Andrew; Kennedy, Cameron T.; Goodyear, Helen; Moss, Celia; Paige, David; Harper, John I.; Young, Bryan D.; Leigh, Irene M.; Eady, Robin A. J.; O’Toole, Edel A.

    2005-01-01

    Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide–polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation. PMID:15756637

  7. Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis.

    PubMed

    Bradshaw, K D; Carr, B R

    1986-07-01

    PSD-X-linked ichthyosis are manifestations of a similar disorder of an inborn error of metabolism characterized by a deficiency of steroid sulfatase. The decreased enzyme activity is due to the absence of the expression of enzyme (steroid sulfatase) protein. Affected individuals with this disorder are males (X-linked inheritance) with a frequency of 1/2000 to 1/6000 births. Homozygous females from cosanguineous marriages have been reported with this disorder. The diagnosis is suspected and confirmed by: Low estriol excretion; Negative DHEAS loading test Increased DHEAS in amnionic fluid; Normal DHEAS in cord plasma; Possible delayed or abnormal labor patterns; Decreased sulfatase activity in the placenta, fibroblast, erythrocytes, lymphocytes or leukocytes of affected individuals; Development of ichthyosis in male infants at 2 to 3 months of age.

  8. Keratitis-Ichthyosis-Deafness syndrome: A rare congenital disorder

    PubMed Central

    Shanker, Vinay; Gupta, Mudita; Prashar, Aditi

    2012-01-01

    Keratitis-Icthyosis-Deafness syndrome is a rare congenital disorder characterized by keratitis, ichthyosis, and deafness. We report a 13 year old female child who presented with diffuse alopecia of the scalp and body. There was erythrokeratoderma of face and discrete hyperkeratotic hyperpigmented papulo plaque lesions on the body. Patient also had reticulate hyperkeratosis of palms and soles. There was history of recurrent episodes of folliculitis over the scalp and body. There was no evidence of any malignancy. Eye involvement in the form of bilateral vascularising keratitis was present. There was bilateral mixed hearing loss. PMID:23130264

  9. Connexin 26 (GJB2) mutation in an Argentinean patient with keratitis-ichthyosis-deafness (KID) syndrome: a case report.

    PubMed

    Dalamón, Viviana Karina; Buonfiglio, Paula; Larralde, Margarita; Craig, Patricio; Lotersztein, Vanesa; Choate, Keith; Pallares, Norma; Diamante, Vicente; Elgoyhen, Ana Belén

    2016-05-04

    Keratitis-Ichthyosis-Deafness (KID) syndrome is a rare condition characterized by pre-lingual sensorineural deafness with skin hyperkeratinization. The primary cause of the disease is a loss-of-function mutation in the GJB2 gene. Mutations in Argentinean patients have not been described. We studied a 2 year-old boy with bilateral congenital sensorineural deafness with dry skin over the entire body, hypotrichosis of the scalp, thin and light-blond hair. Analysis of the GJB2 gene nucleotide sequence revealed the substitution of guanine-148 by adenine predicted to result in an Asp50Asn amino acid substitution. This is the first KID report in a patient from Argentina. This de novo mutation proved to be the cause of keratitis-ichthyosis-deafness syndrome (KID-syndrome) in the patient, and has implications in medical genetic practice.

  10. Topographic and biomechanical evaluation of cornea in patients with ichthyosis vulgaris.

    PubMed

    Kara, Necip; Yildirim, Yusuf; Demircan, Ali; Cankaya, Ilker; Kutlubay, Zekayi; Engin, Burhan; Serdaroglu, Server

    2012-10-01

    To compare the topographic and biomechanical properties of corneas in eyes of patients with ichthyosis vulgaris (IV) and eyes of healthy individuals. Thirty healthy individuals (control group) and 30 patients with IV (study group) were enrolled in this prospective study. Topographic measurements, including keratometry values, irregularity, and surface asymmetry index in the right eye of each participant were obtained using Scheimpflug camera with a Placido disc topographer (Sirius). Corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated intraocular pressure (IOPcc) and Goldman-related intraocular pressure (IOPg) were measured using the Reichert Ocular Response Analyzer (ORA). Central corneal thickness (CCT) was also measured with ultrasonic pachymetry and the Sirius corneal topography system. Topographic parameters were not significantly different between both groups (p>0.05). Although mean CH was not significantly different between the groups, the CRF was significantly lower in patients with IV (p=0.249 and p=0.005, respectively). The CCT was significantly lower in patients with IV compared to healthy controls (p<0.001). The IOPg and IOPcc were significantly lower in the patients with ichthyosis than in healthy controls (p=0.001 and p=0.004, respectively). The study demonstrated that while the eyes of patients with IV had corneal topographic findings and corneal hysteresis similar to those of healthy controls, some of corneal biomechanical properties such CRF and CCT and IOP values such as IOPg and IOPcc were significantly lower in patients with IV. These results should be taken into account when planning a corneal refractive surgery and glaucoma screening for patients with IV. Copyright © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

  11. Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis.

    PubMed

    Bochner, Ron; Samuelov, Liat; Sarig, Ofer; Li, Qiaoli; Adase, Christopher A; Isakov, Ofer; Malchin, Natalia; Vodo, Dan; Shayevitch, Ronna; Peled, Alon; Yu, Benjamin D; Fainberg, Gilad; Warshauer, Emily; Adir, Noam; Erez, Noam; Gat, Andrea; Gottlieb, Yehonatan; Rogers, Tova; Pavlovsky, Mor; Goldberg, Ilan; Shomron, Noam; Sandilands, Aileen; Campbell, Linda E; MacCallum, Stephanie; McLean, W H Irwin; Ast, Gil; Gallo, Richard L; Uitto, Jouni; Sprecher, Eli

    2017-02-01

    Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that

  12. Ichthyosis prematurity syndrome with separation of fetal membranes and neonatal asphyxia

    PubMed Central

    Dereksson, Kristjan; Kjartansson, Sveinn; Hjartardóttir, Hulda; Arngrimsson, Reynir

    2012-01-01

    Ichthyosis prematurity syndrome (IPS) is a rare inherited skin disorder. Children are born prematurely with thick skin and have been found to develop neonatal asphyxia due to occlusions in the bronchial tree from debris in the amniotic fluid. At 31 weeks of gestation, separation of amniotic and chorionic membranes was identified as well as polyhydramnion. The child was born 2 weeks later, with thickened skin with a granular appearance and required immediate ventilation and intensive care. At 2 years of age, the patient has developed an atopic skin condition with severe itching, recurrent skin infections, food intolerance and periods of wheezing. Prenatal observation of separation of foetal membranes or dense amniotic fluid may be signs of IPS and severe complication immediately after birth. PMID:22927265

  13. Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype.

    PubMed

    Oji, Vinzenz; Hautier, Juliette Mazereeuw; Ahvazi, Bijan; Hausser, Ingrid; Aufenvenne, Karin; Walker, Tatjana; Seller, Natalia; Steijlen, Peter M; Küster, Wolfgang; Hovnanian, Alain; Hennies, Hans Christian; Traupe, Heiko

    2006-11-01

    Bathing suit ichthyosis (BSI) is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by pronounced scaling on the bathing suit areas but sparing of the extremities and the central face. Here we report on a series of 10 BSI patients. Our genetic, ultrastructural and biochemical investigations show that BSI is caused by transglutaminase-1 (TGase-1) deficiency. Altogether, we identified 13 mutations in TGM1-among them seven novel missense mutations and one novel nonsense mutation. Structural modeling for the Tyr276Asn mutation reveals that the residue is buried in the hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas demonstrated an almost normal TGase activity, in contrast to the affected BSI skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The distribution of TGase-1 substrates in the epidermis of affected skin corresponded to the situation in TGase-1 deficiency. Interestingly, the expression of TGase-3 and cathepsin D was reduced. Digital thermography validated a striking correlation between warmer body areas and presence of scaling in patients suggesting a decisive influence of the skin temperature. In situ TGase testing in skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 to 37 degrees C. We conclude that BSI is caused by TGase-1 deficiency and suggest that it is a temperature-sensitive phenotype.

  14. Porokeratotic eccrine duct and hair follicle nevus (PEHFN) associated with keratitis-ichthyosis-deafness (KID) syndrome.

    PubMed

    Criscione, Vincent; Lachiewicz, Anne; Robinson-Bostom, Leslie; Grenier, Nicole; Dill, Sara Worthing

    2010-01-01

    Porokeratotic eccrine ostial and dermal duct nevus is a rare hamartomatous malformation, histologically characterized by cornoid lamellae overlying dilated eccrine ostia. The nevus most commonly presents in the form of multiple filiform keratotic spines in a linear arrangement, usually on the distal extremities. Porokeratotic eccrine and hair follicle nevus is thought to be a variant of porokeratotic eccrine ostial and dermal duct nevus that additionally involves hair follicle infundibula. We report a case of widespread Porokeratotic eccrine and hair follicle nevus that developed in a 15-year-old woman with keratitis-ichthyosis-deafness syndrome. © 2010 Wiley Periodicals, Inc.

  15. A Novel SLC27A4 Splice Acceptor Site Mutation in Great Danes with Ichthyosis.

    PubMed

    Metzger, Julia; Wöhlke, Anne; Mischke, Reinhard; Hoffmann, Annalena; Hewicker-Trautwein, Marion; Küch, Eva-Maria; Naim, Hassan Y; Distl, Ottmar

    2015-01-01

    Ichthyoses are a group of various different types of hereditary disorders affecting skin cornification. They are characterized by hyperkeratoses of different severity levels and are associated with a dry and scaling skin. Genome-wide association analysis of nine affected and 13 unaffected Great Danes revealed a genome-wide significant peak on chromosome 9 at 57-58 Mb in the region of SLC27A4. Sequence analysis of genomic DNA of SLC27A4 revealed the non-synonymous SNV SLC27A4:g.8684G>A in perfect association with ichthyosis-affection in Great Danes. The mutant transcript of SLC27A4 showed an in-frame loss of 54 base pairs in exon 8 probably induced by a new splice acceptor site motif created by the mutated A- allele of the SNV. Genotyping 413 controls from 35 different breeds of dogs and seven wolves revealed that this mutation could not be found in other populations except in Great Danes. Affected dogs revealed high amounts of mutant transcript but only low levels of the wild type transcript. Targeted analyses of SLC27A4 protein from skin tissues of three affected and two unaffected Great Danes indicated a markedly reduced or not detectable wild type and truncated protein levels in affected dogs but a high expression of wild type SLC27A4 protein in unaffected controls. Our data provide evidence of a new splice acceptor site creating SNV that results in a reduction or loss of intact SLC27A4 protein and probably explains the severe skin phenotype in Great Danes. Genetic testing will allow selective breeding to prevent ichthyosis-affected puppies in the future.

  16. Lamellar ichthyosis maps to chromosome 14q11

    SciTech Connect

    Russell, L.J.; Compton, J.G.; Bale, S.J.

    1994-09-01

    Lamellar ichthyosis (LI) is a serious skin disorder inherited as an autosomal recessive trait and characterized by large, brown plate-like scales covering the body. Skin involvement is apparent at birth, often as a collodion membrane. Scarring alopecia, ectropion, and secondary hypohidrosis are frequent. We used a panel of candidates genes that are expressed in the epidermis to study seven multiplex Caucasian families in the U.S. and six inbred (multiplex and simplex) families in Egypt. We find no recombination (Z=9.11 at {theta}=0) in either set of families with transglutaminse 1 (TGM1), the gene encoding the enzyme responsible for cross-linking proteins tomore » the cell envelope in the upper-most layer of the epidermis. In addition, striking homozygosity is observed in the inbred families for markers neighboring TGM1, defining a 9.3 cM candidate region which is bounded by MYH7 and D14S275. This is the first report of linkage in LI and suggests that further study of the TGM1 gene may identify the underlying pathogenesis of this severe, disfiguring disorder. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families.« less

  17. [Mutation analysis for a pedigree affected with keratitis-ichthyosis-deafness syndrome].

    PubMed

    Li, Lulu; Li, Yuan; Lin, Wei; Zhao, Xiuli

    2017-10-10

    To identify mutation of GJB2 gene and provide genetic counseling for a family affected with keratitis-ichthyosis-deafness (KID) syndrome. Genomic DNA was extracted from peripheral blood samples with a standard phenol-chloroform method. PCR and Sanger sequencing were used to analyze potential mutation in the proband. Suspected mutation was verified with a PCR-high-resolution melting (PCR-HRM) method. T-clone sequencing was applied to determine the parental origin of the mutation. A heterozygous mutation, c.148G>A (p.Asp50Asn), which is located in the exon 1 of the GJB2 gene, was found in the proband. The results was confirmed by HRM analysis. Cloning sequencing suggested that the mutation was derived from the father's germline. The hot-spot mutation c.148G>A (p.Asp50Asn) in the GJB2 gene probably underlies the KID syndrome in this Chinese family. A PCR-HRM method has been established to rapidly detect common mutations associated with this disease.

  18. Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q

    SciTech Connect

    Russell, L.J.; Compton, J.G.; Bale, S.J.

    The authors have mapped the locus for lamellar ichthyosis (LI), an autosomal recessive skin disease characterized by abnormal cornification of the epidermis. Analysis using both inbred and outbred families manifesting severe LI showed complete linkage to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were also found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. Several transcribed genes have been mapped to the chromosome 14 region containing the LI gene. The transglutaminase 1 gene (TGM1), which encodes one of themore » enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus was completely linked to LI (Z = 9.11), suggesting that TGM1 is a good candidate for further investigation of this disorder. The genes for four serine proteases also map to this region but are expressed only in hematopoietic or mast cells, making them less likely candidates.« less

  19. Case Report: Whole exome sequencing helps in accurate molecular diagnosis in siblings with a rare co-occurrence of paternally inherited 22q12 duplication and autosomal recessive non-syndromic ichthyosis.

    PubMed Central

    Gupta, Aayush; Sharma, Yugal; Deo, Kirti; Vellarikkal, Shamsudheen; Jayarajan, Rijith; Dixit, Vishal; Verma, Ankit; Scaria, Vinod; Sivasubbu, Sridhar

    2015-01-01

    Lamellar ichthyosis (LI), considered an autosomal recessive monogenic genodermatosis, has an incidence of approximately 1 in 250,000. Usually associated with mutations in the transglutaminase gene ( TGM1), mutations in six other genes have, less frequently, been shown to be causative. Two siblings, born in a collodion membrane, presented with fish like scales all over the body. Karyotyping revealed duplication of the chromosome arm on 22q12+ in the father and two siblings. Whole exome sequencing revealed a homozygous p.Gly218Ser variation in TGM1; a variation reported earlier in an isolated Finnish population in association with autosomal recessive non-syndromic ichthyosis. This concurrence of a potentially benign 22q12+ duplication and LI, both rare individually, is reported here likely for the first time. PMID:26594337

  20. [Diagnostics of keratitis-ichthyosis-deafness syndrome (KID- syndrome)].

    PubMed

    Markova, T G; Brazhkina, N B; Bliznets, E V; Poliakov, A V; Tavartkiladze, G A

    2012-01-01

    The combination of pre-lingual and sensorinerual deafness with skin hyperkeratinization is a relatively rare pathology. Only 11 families affected by this disorder were described in the literature during the last 30 years (from 1975 to 2002). To date, there are no more than 50 cases of this condition known in the world. Modern molecular methods revealed in all such patients a mutation in the GJB2 gene as the primary cause of the disease. We studied a 4 year-old girl with bilateral congenital grade IV sensorineural deafness. Her unusual appearance drew attention aas early as the primary examination; the patient had the deep-set eyes and dry skin over the entire body, she presented with hypotrichosis of the scalp, thin and light-blond hair. Analysis of the nucleotide sequence of the GJB2 gene revealed the substitution of guanine-148 by adenine that led to D50N amino acid substitution. This dominant mutation proved to be the cause of keratitis-ichthyosis-deafness syndrome (KID-syndrome). A review of the literature concerning molecular diagnostics and clinical features of this syndrome is presented. The results of molecular-genetic investigations provided the data on pathogenesis of different variants of sensorineural deafness and the associated genotype-phenotype relationships that may be used as a basis for the further development of the methods for the prevention and treatment of KID-syndrome.

  1. Prenatal diagnose of a fetus with Harlequin ichthyosis in a Chinese family.

    PubMed

    Jian, Wei; Du, Qi-Ting; Lai, Zhen-Fei; Li, Yu-Fan; Li, Shi-Quan; Xiong, Zhong-Tang; Chen, Dun-Jin; Chen, Min; Chen, Jing-Si

    2018-06-01

    Harlequin ichthyosis (HI) was the most severe form of ichthyoses, which leaded to neonatal death in 50% of cases. It was the result of mutations in ABCA12 gene. With the development of ultrasound skills and genetic analysis, HI could be prenatal diagnosed. Here, we reported a case of HI, which was prenatal diagnosed by ultrasound examination and genetic analysis. The fetus was found that severe ectropion, eclabium, flattened nose, and rudimentary ears by ultrasound at 20 weeks gestation. A molecular genetic analysis was performed and revealed two mutations in the ABCA12 gene. One of two mutations were not reported in the past. The fetus was terminated. HI was associated with the poor prognosis of HI neonates. Prenatal ultrasound and genetic analysis were important for prenatal diagnosis of HI and were helpful to give sufficient prenatal counsels for the family with HI baby. Copyright © 2018. Published by Elsevier B.V.

  2. Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects.

    PubMed

    Rodríguez-Pazos, L; Ginarte, M; Fachal, L; Toribio, J; Carracedo, A; Vega, A

    2011-10-01

      Mutations in six genes have been identified in autosomal recessive congenital ichthyosis (ARCI). To date, few studies have analysed the spectrum of these mutations in specific populations. We have studied the characteristics of patients with ARCI in Galicia (NW Spain). Methods  We recruited patients by contacting all dermatology departments of Galicia and the Spanish patient organization for ichthyosis. TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 were analysed in the patients and their relatives. We identified 23 patients with ARCI and estimated a prevalence of 1 : 122 000. Twenty of the patients were studied. Seventeen of them were clinically categorized as having lamellar ichthyosis (LI) and three as having congenital ichthyosiform erythroderma (CIE). TGM1 and ALOXE3 mutations were identified in 12/16 (75%) probands whereas no ALOX12B, NIPAL4 and CYP4F22 mutations were found. TGM1 mutations were found in 11/13 (85%) of LI probands. ALOXE3 mutations were identified in a single patient with CIE. Remarkably, mutations p.Arg760X, p.Asp408ValfsX21 and c.984+1G>A of TGM1 were present in six, four and two families, accounting for 41%, 23% and 14% of all TGM1 mutant alleles, respectively. The high percentage of patients with the same TGM1 mutations, together with the high number of homozygous probands (64%), indicates the existence of a strong founder effect in our population. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

  3. Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions.

    PubMed

    Pigors, Manuela; Sarig, Ofer; Heinz, Lisa; Plagnol, Vincent; Fischer, Judith; Mohamad, Janan; Malchin, Natalia; Rajpopat, Shefali; Kharfi, Monia; Lestringant, Giles G; Sprecher, Eli; Kelsell, David P; Blaydon, Diana C

    2016-08-04

    SERPINS comprise a large and functionally diverse family of serine protease inhibitors. Here, we report three unrelated families with loss-of-function mutations in SERPINB8 in association with an autosomal-recessive form of exfoliative ichthyosis. Whole-exome sequencing of affected individuals from a consanguineous Tunisian family and a large Israeli family revealed a homozygous frameshift mutation, c.947delA (p.Lys316Serfs(∗)90), and a nonsense mutation, c.850C>T (p.Arg284(∗)), respectively. These two mutations are located in the last exon of SERPINB8 and, hence, would not be expected to lead to nonsense-mediated decay of the mRNA; nonetheless, both mutations are predicted to lead to loss of the reactive site loop of SERPINB8, which is crucial for forming the SERPINB8-protease complex. Using Sanger sequencing, a homozygous missense mutation, c.2T>C (p.Met1?), predicted to result in an N-terminal truncated protein, was identified in an additional family from UAE. Histological analysis of a skin biopsy from an individual homozygous for the variant p.Arg284(∗) showed disadhesion of keratinocytes in the lower epidermal layers plus decreased SERPINB8 levels compared to control. In vitro studies utilizing siRNA-mediated knockdown of SERPINB8 in keratinocytes demonstrated that in the absence of the protein, there is a cell-cell adhesion defect, particularly when cells are subjected to mechanical stress. In addition, immunoblotting and immunostaining revealed an upregulation of desmosomal proteins. In conclusion, we report mutations in SERPINB8 that are associated with exfoliative ichthyosis and provide evidence that SERPINB8 contributes to the mechanical stability of intercellular adhesions in the epidermis. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  4. Severe Phenotype of Keratitis-Ichthyosis-Deafness Syndrome With Presumed Ocular Surface Squamous Neoplasia.

    PubMed

    Serrano-Ahumada, Ana Silvia; Cortes-González, Vianney; González-Huerta, Luz María; Cuevas, Sergio; Aguilar-Lozano, Luis; Villanueva-Mendoza, Cristina

    2018-02-01

    The aim of this study was to describe a case of severe keratitis-ichthyosis-deafness (KID) syndrome with ocular surface squamous neoplasia. The affected patient underwent complete ocular and systemic examinations. The molecular studies included polymerase chain reaction amplification and automated DNA sequencing of the complete gap junction beta-2 (GJB2) gene coding sequence. A 30-year-old man presented with generalized erythro-hyperkeratosis and deafness and complaints of decreased visual acuity, tearing, and photophobia. Ophthalmic examination showed corneal erosion, vascularization, and a gray gelatinous lesion partially covering the right cornea, suggestive of squamous neoplasia. The clinical features were characteristic of KID syndrome. This diagnosis was confirmed with a DNA analysis showing the pathogenic variant p.D50N in the GJB2 gene. Presumed squamous neoplasia was treated with topical interferon α2b. KID syndrome is a very rare disease that has been reported with an incremental incidence of squamous cell carcinoma of the mucous membranes and skin (12%-15%). Here, we presented a case of severe systemic KID syndrome with ocular surface squamous neoplasia.

  5. Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia.

    PubMed

    Aldahmesh, Mohammed A; Mohamed, Jawahir Y; Alkuraya, Hisham S; Verma, Ishwar C; Puri, Ratna D; Alaiya, Ayodele A; Rizzo, William B; Alkuraya, Fowzan S

    2011-12-09

    Very-long-chain fatty acids (VLCFAs) play important roles in membrane structure and cellular signaling, and their contribution to human health is increasingly recognized. Fatty acid elongases catalyze the first and rate-limiting step in VLCFA synthesis. Heterozygous mutations in ELOVL4, the gene encoding one of the elongases, are known to cause macular degeneration in humans and retinal abnormalities in mice. However, biallelic ELOVL4 mutations have not been observed in humans, and murine models with homozygous mutations die within hours of birth as a result of a defective epidermal water barrier. Here, we report on two human individuals with recessive ELOVL4 mutations revealed by a combination of autozygome analysis and exome sequencing. These individuals exhibit clinical features of ichthyosis, seizures, mental retardation, and spasticity-a constellation that resembles Sjögren-Larsson syndrome (SLS) but presents a more severe neurologic phenotype. Our findings identify recessive mutations in ELOVL4 as the cause of a neuro-ichthyotic disease and emphasize the importance of VLCFA synthesis in brain and cutaneous development. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  6. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

    PubMed Central

    Lovric, Svjetlana; Goncalves, Sara; Oskouian, Babak; Srinivas, Honnappa; Choi, Won-Il; Shril, Shirlee; Ashraf, Shazia; Tan, Weizhen; Rao, Jia; Airik, Merlin; Schapiro, David; Braun, Daniela A.; Sadowski, Carolin E.; Schmidt, Johanna Magdalena; Girik, Vladimir; Capitani, Guido; Suh, Jung H.; Lachaussée, Noëlle; Arrondel, Christelle; Patat, Julie; Furlano, Monica; Boyer, Olivia; Schmitt, Alain; Vuiblet, Vincent; Hashmi, Seema; Wilcken, Rainer; Bernier, Francois P.; Innes, A. Micheil; Parboosingh, Jillian S.; Lamont, Ryan E.; Midgley, Julian P.; Wright, Nicola; Majewski, Jacek; Zenker, Martin; Schaefer, Franz; Kuss, Navina; Giese, Thomas; Schwarz, Klaus; Catheline, Vilain; Franke, Ingolf; Sznajer, Yves; Truant, Anne S.; Adams, Brigitte; Désir, Julie; Biemann, Ronald; Pei, York; Lloberas, Nuria; Madrid, Alvaro; Dharnidharka, Vikas R.; Connolly, Anne M.; Willing, Marcia C.; Cooper, Megan A.; Lifton, Richard P.; Simons, Matias; Riezman, Howard; Antignac, Corinne; Saba, Julie D.

    2017-01-01

    Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS. PMID:28165339

  7. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics.

    PubMed

    Akiyama, M

    2010-03-01

    Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic eczema (AE), initially in European populations. Subsequently, FLG mutations were identified in Japanese, Chinese, Taiwanese and Korean populations. It was demonstrated that FLG mutations are closely associated with AE in the Japanese population. Notably, the same FLG mutations identified in the European population were rarely found in Asians. These results exemplify differences in filaggrin population genetics between Europe and Asia. For mutation screening, background information needs to be obtained on prevalent FLG mutations for each geographical population. It is therefore important to establish the global population genetics maps for FLG mutations. Mutations at any site within FLG, even mutations in C-terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C-terminal region is essential for proper processing of profilaggrin into filaggrin. Thus, no genotype-phenotype correlation has been observed in patients with FLG mutations. A restoration of the barrier function seems a feasible and promising strategy for treatment and prevention in individuals with filaggrin deficiency.

  8. Aberrant connexin26 hemichannels underlying keratitis-ichthyosis-deafness syndrome are potently inhibited by mefloquine

    PubMed Central

    Levit, Noah A.; Sellitto, Caterina; Wang, Hong-Zhan; Li, Leping; Srinivas, Miduturu; Brink, Peter R.; White, Thomas W.

    2014-01-01

    Keratitis-ichthyosis-deafness (KID) syndrome is an ectodermal dysplasia caused by dominant mutations of connexin26 (Cx26). Loss of Cx26 function causes non-syndromic sensorineural deafness, without consequence in the epidermis. Functional analyses have revealed that a majority of KID-causing mutations confer a novel expansion of hemichannel activity, mediated by connexin channels in a non-junctional configuration. Inappropriate Cx26 hemichannel opening is hypothesized to compromise keratinocyte integrity and epidermal homeostasis. Pharmacological modulators of Cx26 are needed to assess the pathomechanistic involvement of hemichannels in the development of hyperkeratosis in KID syndrome. We have used electrophysiological assays to evaluate small molecule analogs of quinine for suppressive effects on aberrant hemichannel currents elicited by KID mutations. Here, we show that mefloquine inhibits several mutant hemichannel forms implicated in KID syndrome when expressed in Xenopus laevis oocytes (IC50≈16µM), using an extracellular divalent cation, zinc (Zn++), as a non-specific positive control for comparison (IC50≈3µM). Furthermore, we used freshly isolated transgenic keratinocytes to show that micromolar concentrations of mefloquine attenuated increased macroscopic membrane currents in primary mouse keratinocytes expressing human Cx26-G45E, a mutation causing a lethal form of KID syndrome. PMID:25229253

  9. Treatment of keratitis-ichthyosis- deafness (KID) syndrome in children: a case report and review of the literature.

    PubMed

    Patel, Viraat; Sun, Grace; Dickman, Meghan; Khuu, Phuong; Teng, Joyce M C

    2015-01-01

    Keratitis-ichthyosis-deafness (KID) syndrome is a rare hereditary cornification disorder resulting from mutations in connexin 26, a protein important for intercellular communication. In addition to the characteristic clinical triad of congenital bilateral sensorineural hearing loss, keratitis, and erythrokeratoderma, affected individuals also suffer from chronic bacterial and fungal infections and have an increased risk of benign and malignant cutaneous tumors. Treatments with antibiotics, antifungals, and systemic retinoids have been reported with variable response. Ocular and skeletal toxicity from prolonged exposure to systemic retinoids is a major concern especially in children. We report a case of a 7-year-old boy with KID syndrome complicated by frequent infections who responded well to acitretin 0.5-1.0 mg/kg/day. The patient had significant improvement of the hyperkeratosis on the scalp, trunk, and extremities within 4 weeks after initiating treatment. The patient has been on treatment for over a year without notable ocular, skeletal, or laboratory side effects. A review of the literature focusing on therapeutic options for KID syndrome and concerns about safety and tolerability is presented. © 2014 Wiley Periodicals, Inc.

  10. Autosomal Recessive Congenital Ichthyosis in American Bulldogs Is Associated With NIPAL4 (ICHTHYIN) Deficiency.

    PubMed

    Mauldin, E A; Wang, P; Evans, E; Cantner, C A; Ferracone, J D; Credille, K M; Casal, M L

    2015-07-01

    A minority of patients with nonsyndromic autosomal recessive congenital ichthyosis (ARCI) display mutations in NIPAL4 (ICHTHYIN). This protein plays a role in epidermal lipid metabolism, although the mechanism is unknown. The study describes a moderate form of ARCI in an extended pedigree of American Bulldogs that is linked to the gene encoding ichthyin. The gross phenotype was manifest as a disheveled pelage shortly after birth, generalized scaling, and adherent brown scale with erythema of the abdominal skin. Pedigree analysis indicated an autosomal recessive mode of inheritance. Ultrastructurally, the epidermis showed discontinuous lipid bilayers, unprocessed lipid within corneocytes, and abnormal lamellar bodies. Linkage analysis, performed by choosing simple sequence repeat markers and single-nucleotide polymorphisms near genes known to cause ACRI, revealed an association with NIPAL4. NIPAL4 was identified and sequenced using standard methods. No mutation was identified within the gene, but affected dogs had a SINE element 5' upstream of exon 1 in a highly conserved region. Of 545 DNA samples from American Bulldogs, 32 dogs (17 females, 15 males) were homozygous for the polymerase chain reaction fragment. All affected dogs were homozygous, with parents heterozygous for the insertion. Immunolabeling revealed an absence of ichthyin in the epidermis. This is the first description of ARCI associated with decreased expression of NIPAL4 in nonhuman species. © The Author(s) 2014.

  11. Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss

    PubMed Central

    Sanchez, Helmuth A.; Verselis, Vytas K.

    2014-01-01

    Mutation of the GJB2 gene, which encodes the connexin 26 (Cx26) gap junction (GJ) protein, is the most common cause of hereditary, sensorineural hearing loss. Cx26 is not expressed in hair cells, but is widely expressed throughout the non-sensory epithelial cells of the cochlea. Most GJB2 mutations produce non-syndromic deafness, but a subset produces syndromic deafness in which profound hearing loss is accompanied by a diverse array of infectious and neoplastic cutaneous disorders that can be fatal. Although GJ channels, which are assembled by the docking of two, so-called hemichannels (HCs), have been the main focus of deafness-associated disease models, it is now evident that the HCs themselves can function in the absence of docking and contribute to signaling across the cell membrane as a novel class of ion channel. A notable feature of syndromic deafness mutants is that the HCs exhibit aberrant behaviors providing a plausible basis for disease that is associated with excessive or altered contributions of Cx26 HCs that, in turn, lead to compromised cell integrity. Here we discuss some of the aberrant Cx26 HC properties that have been described for mutants associated with keratitis-ichthyosis-deafness (KID) syndrome, a particularly severe Cx26-associated syndrome, which shed light on genotype-phenotype relationships and causes underlying cochlear dysfunction. PMID:25386120

  12. A Novel N14Y Mutation in Connexin26 in Keratitis-Ichthyosis-Deafness Syndrome

    PubMed Central

    Arita, Ken; Akiyama, Masashi; Aizawa, Tomoyasu; Umetsu, Yoshitaka; Segawa, Ikuo; Goto, Maki; Sawamura, Daisuke; Demura, Makoto; Kawano, Keiichi; Shimizu, Hiroshi

    2006-01-01

    Connexins (Cxs) are transmembranous proteins that connect adjacent cells via channels known as gap junctions. The N-terminal 21 amino acids of Cx26 are located at the cytoplasmic side of the channel pore and are thought to be essential for the regulation of channel selectivity. We have found a novel mutation, N14Y, in the N-terminal domain of Cx26 in a case of keratitis-ichthyosis-deafness syndrome. Reduced gap junctional intercellular communication was observed in the patient’s keratinocytes by the dye transfer assay using scrape-loading methods. The effect of this mutation on molecular structure was investigated using synthetic N-terminal peptides from both wild-type and mutated Cx26. Two-dimensional 1H nuclear magnetic resonance and circular dichroism measurements demonstrated that the secondary structures of these two model peptides are similar to each other. However, several novel nuclear Overhauser effect signals appeared in the N14Y mutant, and the secondary structure of the mutant peptide was more susceptible to induction of 2,2,2-trifluoroethanol than wild type. Thus, it is likely that the N14Y mutation induces a change in local structural flexibility of the N-terminal domain, which is important for exerting the activity of the channel function, resulting in impaired gap junctional intercellular communication. PMID:16877344

  13. Inability of keratinocytes lacking their specific transglutaminase to form cross-linked envelopes: absence of envelopes as a simple diagnostic test for lamellar ichthyosis.

    PubMed

    Jeon, S; Djian, P; Green, H

    1998-01-20

    Epidermal keratinocytes, late in their terminal differentiation, form cross-linked envelopes resistant to ionic detergent and reducing agent. Because the cross-linking process is catalyzed by the keratinocyte transglutaminase, the absence of active transglutaminase should result in failure of the keratinocyte to form a cross-linked envelope. Three keratinocyte strains bearing mutations in the keratinocyte transglutaminase were examined: two contained no detectable transglutaminase mRNA and none contained active enzyme. All three were unable to form cross-linked envelopes, either spontaneously in stratified cultures or upon induction with Ca2+. Although stratum corneum of normal humans and scales from patients with different ichthyotic diseases contain cross-linked envelopes, those from patients with transglutaminase-negative lamellar ichthyosis do not. Therefore, the disease due to the absence of transglutaminase may be readily distinguished from other ichthyotic disease by a simple test for cross-linked envelopes.

  14. Heterozygous p.Asp50Asn mutation in the GJB2 gene in two Cameroonian patients with keratitis-ichthyosis-deafness (KID) syndrome.

    PubMed

    Wonkam, Ambroise; Noubiap, Jean Jacques N; Bosch, Jason; Dandara, Collet; Toure, Geneviève Bengono

    2013-08-07

    Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect that consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. KID appears to be genetically heterogeneous and most cases are caused by GJB2 mutations. Mutations in African patients have been rarely described. We report on two unrelated Cameroonian individuals affected with sporadic KID, presenting with the classic phenotypic triad. The two patients were heterozygous for the most frequent p.Asp50Asn mutation. This first report in patients from sub-Saharan African origin supports the hypothesis that the occurrence of KID due to p.Asp50Asn mutation in GJB2 seems not to be population specific. Our finding has implication in medical genetic practice, specifically in the molecular diagnosis of KID in Africans. These cases also reveal and emphasize the urgent need to develop appropriate policies to care for patients with rare/orphan diseases in Sub-Saharan Africa, as many of these cases become more and more recognizable.

  15. A rare connexin 26 mutation in a patient with a forme fruste of keratitis-ichthyosis-deafness (KID) syndrome.

    PubMed

    Neoh, Ching Yin; Chen, Huijia; Ng, See Ket; Lane, Ellen Birgitte; Common, John Edmund Armourer

    2009-10-01

    Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia characterized by generalized erythrokeratotic plaques, sensorineural hearing loss, and vascularizing keratitis. Cutaneous changes and hearing loss typically present in early childhood, whereas ocular symptoms present later. Mutations in the connexin (Cx) 26 gene, GJB2, are now established to underlie many of the affected cases, with the majority of patients harboring the p.D50N mutation. A rare patient demonstrating features of incomplete KID syndrome associated with an uncommon Cx26 gene mutation is described. The patient presented late in adolescence with partial features of KID syndrome. There was limited cutaneous involvement and the rare association of cystic acne. Both hearing impairment and ophthalmic involvement were mild in severity. Genetic mutation analysis revealed a previously described, rare mutation in GJB2, resulting in a glycine to arginine change at codon 12 (p.G12R). This report describes a patient exhibiting characteristics suggestive of a late-onset, incomplete form of KID syndrome with the GJB2 mutation (p.G12R). The p.G12R mutation has only been described in one other patient with KID syndrome, whose clinical presentation was not characterized.

  16. Inability of keratinocytes lacking their specific transglutaminase to form cross-linked envelopes: Absence of envelopes as a simple diagnostic test for lamellar ichthyosis

    PubMed Central

    Jeon, Saewha; Djian, Philippe; Green, Howard

    1998-01-01

    Epidermal keratinocytes, late in their terminal differentiation, form cross-linked envelopes resistant to ionic detergent and reducing agent. Because the cross-linking process is catalyzed by the keratinocyte transglutaminase, the absence of active transglutaminase should result in failure of the keratinocyte to form a cross-linked envelope. Three keratinocyte strains bearing mutations in the keratinocyte transglutaminase were examined: two contained no detectable transglutaminase mRNA and none contained active enzyme. All three were unable to form cross-linked envelopes, either spontaneously in stratified cultures or upon induction with Ca2+. Although stratum corneum of normal humans and scales from patients with different ichthyotic diseases contain cross-linked envelopes, those from patients with transglutaminase-negative lamellar ichthyosis do not. Therefore, the disease due to the absence of transglutaminase may be readily distinguished from other ichthyotic diseases by a simple test for cross-linked envelopes. PMID:9435253

  17. Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis

    PubMed Central

    Ullah, Rahim; Ansar, Muhammad; Durrani, Zaka Ullah; Lee, Kwanghyuk; Santos-Cortez, Regie Lyn P.; Muhammad, Dost; Ali, Mahboob; Zia, Muhammad; Ayub, Muhammad; Khan, Suliman; Smith, Josh D.; Nickerson, Deborah A.; Shendure, Jay; Bamshad, Michael; Leal, Suzanne M.; Ahmad, Wasim

    2016-01-01

    Background Ichthyoses are clinically characterized by scaling or hyperkeratosis of the skin or both. It can be an isolated condition limited to the skin or appear secondarily with involvement of other cutaneous or systemic abnormalities. Methods The present study investigated clinical and molecular characterization of three consanguineous families (A, B, C) segregating two different forms of autosomal recessive congenital ichthyosis (ARCI). Linkage in three consanguineous families (A, B, C) segregating two different forms of ARCI was searched by typing microsatellite and single nucleotide polymorphism marker analysis. Sequencing of the two genes TGM1 and ALOXE3 was performed by the dideoxy chain termination method. Results Genome-wide linkage analysis established linkage in family A to TGM1 gene on chromosome 14q11 and in families B and C to ALOXE3 gene on chromosome 17p13. Subsequently, sequencing of these genes using samples from affected family members led to the identification of three novel mutations: a missense variant p.Trp455Arg in TGM1 (family A); a nonsense variant p.Arg140* in ALOXE3 (family B); and a complex rearrangement in ALOXE3 (family C). Conclusion The present study further extends the spectrum of mutations in the two genes involved in causing ARCI. Characterizing the clinical spectrum resulting from mutations in the TGM1 and ALOXE3 genes will improve diagnosis and may direct clinical care of the family members. PMID:26578203

  18. Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

    PubMed

    Heinz, Lisa; Kim, Gwang-Jin; Marrakchi, Slaheddine; Christiansen, Julie; Turki, Hamida; Rauschendorf, Marc-Alexander; Lathrop, Mark; Hausser, Ingrid; Zimmer, Andreas D; Fischer, Judith

    2017-06-01

    Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  19. Heterozygous p.Asp50Asn mutation in the GJB2 gene in two Cameroonian patients with keratitis-ichthyosis-deafness (KID) syndrome

    PubMed Central

    2013-01-01

    Background Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect that consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. KID appears to be genetically heterogeneous and most cases are caused by GJB2 mutations. Mutations in African patients have been rarely described. Case presentation We report on two unrelated Cameroonian individuals affected with sporadic KID, presenting with the classic phenotypic triad. The two patients were heterozygous for the most frequent p.Asp50Asn mutation. This first report in patients from sub-Saharan African origin supports the hypothesis that the occurrence of KID due to p.Asp50Asn mutation in GJB2 seems not to be population specific. Conclusions Our finding has implication in medical genetic practice, specifically in the molecular diagnosis of KID in Africans. These cases also reveal and emphasize the urgent need to develop appropriate policies to care for patients with rare/orphan diseases in Sub-Saharan Africa, as many of these cases become more and more recognizable. PMID:23924173

  20. A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E.

    PubMed

    Jonard, Laurence; Feldmann, Delphine; Parsy, Christophe; Freitag, Sylvie; Sinico, Martine; Koval, Céleste; Grati, Mhamed; Couderc, Remy; Denoyelle, Françoise; Bodemer, Christine; Marlin, Sandrine; Hadj-Rabia, Smail

    2008-01-01

    Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect. KID consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. A rare form of the KID syndrome is a fatal course in the first year of life due to severe skin lesion infections and septicaemia. KID appears to be genetically heterogeneous and may be caused by mutations in connexin 26 or connexin 30 genes. GJB2 mutations in the connexin 26 gene are the main cause of the disease. Most of the cases caused by GJB2 mutations are sporadic, but dominant transmission has also been described. To date, the rare lethal form of the disease has been only observed in two Caucasian sporadic patients with the GJB2 mutation, with the p.Gly45Glu (G45E) arising de novo. We have reported an African family with dizygotic twins suffering from a lethal form of KID. The dizygosity of the twins was confirmed by microsatellite markers. The two patients were heterozygous for the G45E mutation of GJB2, whereas the mutation was not detected in the two parents. The unusual transmission of the disease observed in this family could be explained by the occurrence of a somatic or more probably a germinal mosaic in one of the parents.

  1. A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.

    PubMed

    Zazo Seco, Celia; Castells-Nobau, Anna; Joo, Seol-Hee; Schraders, Margit; Foo, Jia Nee; van der Voet, Monique; Velan, S Sendhil; Nijhof, Bonnie; Oostrik, Jaap; de Vrieze, Erik; Katana, Radoslaw; Mansoor, Atika; Huynen, Martijn; Szklarczyk, Radek; Oti, Martin; Tranebjærg, Lisbeth; van Wijk, Erwin; Scheffer-de Gooyert, Jolanda M; Siddique, Saadat; Baets, Jonathan; de Jonghe, Peter; Kazmi, Syed Ali Raza; Sadananthan, Suresh Anand; van de Warrenburg, Bart P; Khor, Chiea Chuen; Göpfert, Martin C; Qamar, Raheel; Schenck, Annette; Kremer, Hannie; Siddiqi, Saima

    2017-02-01

    A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*), in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2. © 2017. Published by The Company of Biologists Ltd.

  2. A Mouse Model of Harlequin Ichthyosis Delineates a Key Role for Abca12 in Lipid Homeostasis

    PubMed Central

    Smyth, Ian; Mukhamedova, Nigora; Meikle, Peter J.; Ellis, Sarah; Slattery, Keith; Collinge, Janelle E.; de Graaf, Carolyn A.; Bahlo, Melanie; Sviridov, Dmitri

    2008-01-01

    Harlequin Ichthyosis (HI) is a severe and often lethal hyperkeratotic skin disease caused by mutations in the ABCA12 transport protein. In keratinocytes, ABCA12 is thought to regulate the transfer of lipids into small intracellular trafficking vesicles known as lamellar bodies. However, the nature and scope of this regulation remains unclear. As part of an original recessive mouse ENU mutagenesis screen, we have identified and characterised an animal model of HI and showed that it displays many of the hallmarks of the disease including hyperkeratosis, loss of barrier function, and defects in lipid homeostasis. We have used this model to follow disease progression in utero and present evidence that loss of Abca12 function leads to premature differentiation of basal keratinocytes. A comprehensive analysis of lipid levels in mutant epidermis demonstrated profound defects in lipid homeostasis, illustrating for the first time the extent to which Abca12 plays a pivotal role in maintaining lipid balance in the skin. To further investigate the scope of Abca12's activity, we have utilised cells from the mutant mouse to ascribe direct transport functions to the protein and, in doing so, we demonstrate activities independent of its role in lamellar body function. These cells have severely impaired lipid efflux leading to intracellular accumulation of neutral lipids. Furthermore, we identify Abca12 as a mediator of Abca1-regulated cellular cholesterol efflux, a finding that may have significant implications for other diseases of lipid metabolism and homeostasis, including atherosclerosis. PMID:18802465

  3. A practical approach to ichthyoses with systemic manifestations.

    PubMed

    Saral, S; Vural, A; Wollenberg, A; Ruzicka, T

    2017-06-01

    Inherited ichthyoses are rare disorders in terms of patient numbers, but abundant in terms of clinical-genetic subtypes. These disorders are often associated with severe systemic manifestations, in addition to significant medical, cosmetic and social problems. There are 17 subtypes of syndromic ichthyosis identified so far and most patients with these syndromes are living in countries with high consanguinity rates. Frequently, clinicians cannot make a definitive diagnosis and patients are not managed properly owing to the rarity and complexity of these disorders. These difficulties make this group of ichthyosis and the patients living with them 'orphan'. After skin and skin appendages, nervous system is the most frequently involved system in ichthyosis syndromes. Thus, association of ichthyosis with neurological symptoms provides an important clue for diagnosis. In this article, we aim to increase clinicians' comprehension of ichthyosis syndromes by providing a symptomatology-based approach based on this observation. Additionally, we provide a review of ichthyosis syndromes, with special emphasis on neurological symptoms, hoping to attract interest to this complicated field. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

    PubMed Central

    Mhaske, Pallavi V.; Levit, Noah A.; Li, Leping; Wang, Hong-Zhan; Lee, Jack R.; Shuja, Zunaira; Brink, Peter R.

    2013-01-01

    Mutations in the human gene encoding connexin 26 (Cx26 or GJB2) cause either nonsyndromic deafness or syndromic deafness associated with skin diseases. That distinct clinical disorders can be caused by different mutations within the same gene suggests that different channel activities influence the ear and skin. Here we use three different expression systems to examine the functional characteristics of two Cx26 mutations causing either mild (Cx26-D50A) or lethal (Cx26-A88V) keratitis-ichthyosis-deafness (KID) syndrome. In either cRNA-injected Xenopus oocytes, transfected HeLa cells, or transfected primary human keratinocytes, we show that both Cx26-D50A and Cx26-A88V form active hemichannels that significantly increase membrane current flow compared with wild-type Cx26. This increased membrane current accelerated cell death in low extracellular calcium solutions and was not due to increased mutant protein expression. Elevated mutant hemichannel currents could be blocked by increased extracellular calcium concentration. These results show that these two mutations exhibit a shared gain of functional activity and support the hypothesis that increased hemichannel activity is a common feature of human Cx26 mutations responsible for KID syndrome. PMID:23447037

  5. Keratitis-Ichthyosis-Deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43

    PubMed Central

    García, Isaac E.; Maripillán, Jaime; Jara, Oscar; Ceriani, Ricardo; Palacios-Muñoz, Angelina; Ramachandran, Jayalakshimi; Olivero, Pablo; Pérez-Acle, Tomás; González, Carlos; Sáez, Juan C.; Contreras, Jorge E.; Martínez, Agustín D.

    2015-01-01

    Mutations in Cx26 gene are found in most cases of human genetic deafness. Some mutations produce syndromic deafness associated with skin disorders, like Keratitis Ichthyosis Deafness syndrome (KID). Because in the human skin Cx26 is co-expressed with other connexins, like Cx43 and Cx30, and since KID syndrome is inherited as autosomal dominant condition, it is possible that KID mutations change the way Cx26 interacts with other co-expressed connexins. Indeed, some Cx26 syndromic mutations showed gap junction dominant negative effect when co-expressed with wild type connexins, including Cx26 and Cx43. The nature of these interactions and the consequences on hemichannels and gap junction channels functions remain unknown. In this study we demonstrate that syndromic mutations at the N-terminus segment of Cx26, change connexin oligomerization compatibility, allowing aberrant interactions with Cx43. Strikingly, heteromeric oligomer formed by Cx43/Cx26 (syndromic mutants) show exacerbated hemichannel activity, but nonfunctional gap junction channels; this also occurs for those Cx26 KID mutants that do not show functional homomeric hemichannels. Heterologous expression of these hyperactive heteromeric hemichannels increases cell membrane permeability, favoring ATP release and Ca2+ overload. The functional paradox produced by oligomerization of Cx43 and Cx26 KID mutants could underlie the severe syndromic phenotype in human skin. PMID:25625422

  6. Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26

    SciTech Connect

    Gudmundsson, Sanna; Wilbe, Maria; Ekvall, Sara

    Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G >more » A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. Finally to our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.« less

  7. Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26

    DOE PAGES

    Gudmundsson, Sanna; Wilbe, Maria; Ekvall, Sara; ...

    2017-02-01

    Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G >more » A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. Finally to our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.« less

  8. Hyperlipidemia secondary to acitretin therapy for lamellar ichthyosis associated with a NIPAL4 mutation improves on a plant-based diet and relapses on a standard Western diet.

    PubMed

    Lin, Jonathan C; Massera, Daniele; Ghalib, Mohammad; Marion, Robert; Graf, Lauren; Cohen, Steven R; Ostfeld, Robert J

    2018-04-01

    Oral retinoids are commonly prescribed for many dermatological conditions and may induce hyperlipidemia. We document the case of a 35-year-old man taking acitretin for congenital lamellar ichthyosis associated with a homozygous deleterious mutation in NIPAL4 who developed retinoid-induced hyperlipidemia that responded dramatically to a whole-food plant-based (WFPB) diet. On presentation, his diet consisted of chicken, fish, low fat meats and dairy, grains, and some fruits and vegetables. He then adopted a WFPB diet without making changes to his medications. His serum lipid levels dropped and his exercise capacity improved. Five months later, after discontinuing the plant-based diet and returning to his baseline diet, his hyperlipidemia returned and persisted despite adjustments to his medications. After a year and a half, the patient again adopted a plant-based diet and his lipid levels fell sharply again. A WFPB diet helped improve and control serum lipid levels in a patient with retinoid-induced hyperlipidemia. Future interventions should focus on ways to help patients successfully adopt and maintain a WFPB diet, as increased adherence to a healthy lifestyle is associated with greater health benefits. Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

  9. Ichthyosis

    MedlinePlus

    ... this research; and the dissemination of information on research progress in these diseases. Contact Us NIAMS Archive Viewers and Players Social Media Moderation Policy FOIA Privacy Statement Accessibility Disclaimer Digital Strategy ...

  10. Lamellar ichthyosis

    MedlinePlus

    ... with LI may have these symptoms: Very large scales that cover most of the body Decreased ability ... skin moist to minimize the thickness of the scales. Measures include: Moisturizers applied to the skin Medicines ...

  11. Ichthyosis vulgaris

    MedlinePlus

    ... eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies . 4th ed. Philadelphia, PA: Elsevier Saunders; 2014:chap 107. ... keratinization. In: Patterson JW, ed. Weedon's Skin Pathology . 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2016:chap ...

  12. A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome.

    PubMed

    Koppelhus, U; Tranebjaerg, L; Esberg, G; Ramsing, M; Lodahl, M; Rendtorff, N D; Olesen, H V; Sommerlund, M

    2011-03-01

    Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome. © The Author(s). CED © 2010 British Association of Dermatologists.

  13. Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B).

    PubMed

    Igawa, Satomi; Kishibe, Mari; Honma, Masaru; Murakami, Masamoto; Mizuno, Yuki; Suga, Yasushi; Seishima, Mariko; Ohguchi, Yuka; Akiyama, Masashi; Hirose, Kenji; Ishida-Yamamoto, Akemi; Iizuka, Hajime

    2013-10-01

    Atopic dermatitis (AD), Netherton syndrome (NS) and peeling skin syndrome type B (PSS) may show some clinical phenotypic overlap. Corneodesmosomes are crucial for maintaining stratum corneum integrity and the components' localization can be visualized by immunostaining tape-stripped corneocytes. In normal skin, they are detected at the cell periphery. To determine whether AD, NS, PSS and ichthyosis vulgaris (IV) have differences in the corneodesmosomal components' distribution and corneocytes surface areas. Corneocytes were tape-stripped from a control group (n=12) and a disease group (37 AD cases, 3 IV cases, 4 NS cases, and 3 PSS cases), and analyzed with immunofluorescent microscopy. The distribution patterns of corneodesmosomal components: desmoglein 1, corneodesmosin, and desmocollin 1 were classified into four types: peripheral, sparse diffuse, dense diffuse and partial diffuse. Corneocyte surface areas were also measured. The corneodesmosome staining patterns were abnormal in the disease group. Other than in the 3 PSS cases, all three components showed similar patterns in each category. In lesional AD skin, the dense diffuse pattern was prominent. A high rate of the partial diffuse pattern, loss of linear cell-cell contacts, and irregular stripping manners were unique to NS. Only in PSS was corneodesmosin staining virtually absent. The corneocyte surface areas correlated significantly with the rate of combined sparse and dense diffuse patterns of desmoglein 1. This method may be used to assess abnormally differentiated corneocytes in AD and other diseases tested. In PSS samples, tape stripping analysis may serve as a non-invasive diagnostic test. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  14. Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

    PubMed Central

    Ohno, Yusuke; Nakamichi, Shota; Ohkuni, Aya; Kamiyama, Nozomi; Naoe, Ayano; Tsujimura, Hisashi; Yokose, Urara; Sugiura, Kazumitsu; Ishikawa, Junko; Akiyama, Masashi; Kihara, Akio

    2015-01-01

    A skin permeability barrier is essential for terrestrial animals, and its impairment causes several cutaneous disorders such as ichthyosis and atopic dermatitis. Although acylceramide is an important lipid for the skin permeability barrier, details of its production have yet to be determined, leaving the molecular mechanism of skin permeability barrier formation unclear. Here we identified the cytochrome P450 gene CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22) as the long-sought fatty acid ω-hydroxylase gene required for acylceramide production. CYP4F22 has been identified as one of the autosomal recessive congenital ichthyosis-causative genes. Ichthyosis-mutant proteins exhibited reduced enzyme activity, indicating correlation between activity and pathology. Furthermore, lipid analysis of a patient with ichthyosis showed a drastic decrease in acylceramide production. We determined that CYP4F22 was a type I membrane protein that locates in the endoplasmic reticulum (ER), suggesting that the ω-hydroxylation occurs on the cytoplasmic side of the ER. The preferred substrate of the CYP4F22 was fatty acids with a carbon chain length of 28 or more (≥C28). In conclusion, our findings demonstrate that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase responsible for acylceramide production and provide important insights into the molecular mechanisms of skin permeability barrier formation. Furthermore, based on the results obtained here, we proposed a detailed reaction series for acylceramide production. PMID:26056268

  15. Deletion patterns of the STS gene and flanking sequences in Israeli X-linked ichthyosis patients and carriers: analysis by polymerase chain reaction and fluorescence in situ hybridization techniques.

    PubMed

    Aviram-Goldring, A; Goldman, B; Netanelov-Shapira, I; Chen-Shtoyerman, R; Zvulunov, A; Tal, O; Ilan, T; Peleg, L

    2000-03-01

    Deletion of the entire steroid sulfatase (STS) gene is the most common molecular defect in X-linked ichthyosis (XLI) patients. Usually, additional flanking sequences are also missing. The aim of this study was to estimate the extent of deletions in an ethnically heterogeneous population of Israeli XLI patients. Multiplex polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) techniques were applied in the analysis of blood samples of 24 patients and amniotic cells of seven affected fetuses from 22 unrelated families. In 19 families, a large deletion of the 2-3 megabase was found. It included the whole STS gene and spanned adjacent areas up- and downstream between the loci DXS 1139 and DXS 1132. Two unrelated families of Iraqi ancestry had a partial deletion of the gene and its centromeric adjacent sequence. In another family, the telomeric end of the extragenic segment was only partially missing. Application of FISH on metaphase blood cells and interphase amniotic cells confirmed the diagnosis of XLI in all patients, except the three with partial intragenic deletion. In those cases, the remaining fraction of the gene was sufficient to provide a false negative result. Diagnosis of carriers and prenatal diagnosis in uncultured cells was applicable only by FISH. Our study revealed a remarkable heterogeneity in the deletion pattern among Israeli patients with XLI. This heterogeneity could not be attributed to specific ethnic groups because of the small size of the study group. More studies involving patients of various ancestries should be carried out. In addition, this study demonstrated the usefulness of the FISH technique in the prenatal diagnosis of fetuses with suspected XLI.

  16. Defect of Hepatocyte Growth Factor Activator Inhibitor Type 1/Serine Protease Inhibitor, Kunitz Type 1 (Hai-1/Spint1) Leads to Ichthyosis-Like Condition and Abnormal Hair Development in Mice

    PubMed Central

    Nagaike, Koki; Kawaguchi, Makiko; Takeda, Naoki; Fukushima, Tsuyoshi; Sawaguchi, Akira; Kohama, Kazuyo; Setoyama, Mitsuru; Kataoka, Hiroaki

    2008-01-01

    Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/serine protease inhibitor, Kunitz type 1 (SPINT1) is a membrane-bound, serine proteinase inhibitor initially identified as an inhibitor of hepatocyte growth factor activator. It also inhibits matriptase and prostasin, both of which are membrane-bound serine proteinases that have critical roles in epidermal differentiation and function. In this study, skin and hair phenotypes of mice lacking the Hai-1/Spint1 gene were characterized. Previously, we reported that the homozygous deletion of Hai-1/Spint1 in mice resulted in embryonic lethality attributable to impaired placental development. To test the role of Hai-1/Spint1 in mice, the placental function of Hai-1/Spint1-mutant mice was rescued. Injection of Hai-1/Spint1+/+ blastocysts with Hai-1/Spint1−/− embryonic stem cells successfully generated high-chimeric Hai-1/Spint1−/− embryos (B6Hai-1−/−High) with normal placentas. These embryos were delivered without apparent developmental abnormalities, confirming that embryonic lethality of Hai-1/Spint1−/− mice was caused by placental dysfunction. However, newborn B6Hai-1−/−High mice showed growth retardation and died by 16 days. These mice developed scaly skin because of hyperkeratinization, reminiscent of ichthyosis, and abnormal hair shafts that showed loss of regular cuticular septation. The interfollicular epidermis showed acanthosis with enhanced Akt phosphorylation. Immunoblot analysis revealed altered proteolytic processing of profilaggrin in Hai-1/Spint1-deleted skin with impaired generation of filaggrin monomers. These findings indicate that Hai-1/Spint1 has critical roles in the regulated keratinization of the epidermis and hair development. PMID:18832587

  17. Genetics Home Reference: Sjögren-Larsson syndrome

    MedlinePlus

    ... view the expand/collapse boxes. Description Sjögren-Larsson syndrome is a condition characterized by dry, scaly skin (ichthyosis); neurological problems; and eye problems. These symptoms are apparent by early childhood ...

  18. Genetics Home Reference: nonbullous congenital ichthyosiform erythroderma

    MedlinePlus

    ... Fürstenberger G, Hennies HC. Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal ... A, Krieg P, Sprecher E, Hennies HC. Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: ...

  19. Genetics Home Reference: harlequin ichthyosis

    MedlinePlus

    ... Hepenstal PJ, Dale BA, Tadini G, Fleckman P, Stephens KG, Sybert VP, Mallory SB, North BV, Witt ... Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of ...

  20. Cellular Basis of Secondary Infections and Impaired Desquamation in Certain Inherited Ichthyoses

    PubMed Central

    Chan, Aegean; Godoy-Gijon, Elena; Nuno-Gonzalez, Almudena; Crumrine, Debra; Hupe, Melanie; Choi, Eung-Ho; Gruber, Robert; Williams, Mary L.; Choate, Keith; Fleckman, Philip H.; Elias, Peter M.

    2015-01-01

    IMPORTANCE Secondary infections and impaired desquamation complicate certain inherited ichthyoses, but their cellular basis remains unknown. In healthy human epidermis, the antimicrobial peptides cathelicidin (LL-37) and human β-defensin 2 (HBD2), as well as the desquamatory protease kallikrein-related peptidase 7 (KLK7), are delivered to the stratum corneum (SC) interstices by lamellar body (LB) exocytosis. OBJECTIVE To assess whether abnormalities in the LB secretory system could account for increased risk of infections and impaired desquamation in inherited ichthyoses with known abnormalities in LB assembly (Harlequin ichthyosis [HI]), secretion (epidermolytic ichthyosis [EI]), or postsecretory proteolysis (Netherton syndrome [NS]). DESIGN, SETTING, AND PARTICIPANTS Samples from library material were taken from patients with HI, EI, NS, and other ichthyoses, but with a normal LB secretory system, and in healthy controls and were evaluated by electron microscopy and immunohistochemical analysis from July 1, 2010, through March 31, 2013. MAIN OUTCOME AND MEASURES Changes in LB secretion and in the fate of LB-derived enzymes and antimicrobial peptides in ichthyotic patients vs healthy controls. RESULTS In healthy controls and patients with X-linked ichthyosis, neutral lipid storage disease with ichthyosis, and Gaucher disease, LB secretion is normal, and delivery of LB-derived proteins and LL-37 immunostaining persists high into the SC. In contrast, proteins loaded into nascent LBs and their delivery to the SC interstices decrease markedly in patients with HI, paralleled by reduced immunostaining for LL-37, HBD2, and KLK7 in the SC. In patients with EI, the cytoskeletal abnormality impairs the exocytosis of LB contents and thus results in decreased LL-37, HBD2, and KLK7 secretion, causing substantial entombment of these proteins within the corneocyte cytosol. Finally, in patients with NS, although abundant enzyme proteins loaded in parallel with accelerated LB

  1. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children

    PubMed Central

    Brown, SJ; Relton, CL; Liao, H; Zhao, Y; Sandilands, A; McLean, WHI; Cordell, HJ; Reynolds, NJ

    2009-01-01

    Background Null mutations within the filaggrin gene (FLG) cause ichthyosis vulgaris and are associated with atopic eczema. However, the dermatological features of filaggrin haploinsufficiency have not been clearly defined. Objectives This study investigated the genotype–phenotype association between detailed skin phenotype and FLG genotype data in a population-based cohort of children. Methods Children (n= 792) aged 7–9 years were examined by a dermatologist. Features of ichthyosis vulgaris, atopic eczema and xerosis were recorded and eczema severity graded using the Three Item Severity score. Each child was genotyped for the six most prevalent FLG null mutations (R501X, 2282del4, R2447X, S3247X, 3702delG, 3673delC). Fisher’s exact test was used to compare genotype frequencies in phenotype groups; logistic regression analysis was used to estimate odds ratios and penetrance of the FLG null genotype and a permutation test performed to investigate eczema severity in different genotype groups. Results Ten children in this cohort had ichthyosis vulgaris, of whom five had mild–moderate eczema. The penetrance of FLG null mutations with respect to flexural eczema was 55·6% in individuals with two mutations, 16·3% in individuals with one mutation and 14·2% in wild-type individuals. Summating skin features known to be associated with FLG null mutations (ichthyosis, keratosis pilaris, palmar hyperlinearity and flexural eczema) showed a penetrance of 100% in children with two FLG mutations, 87·8% in children with one FLG mutation and 46·5% in wild-type individuals (P< 0·0001, Fisher exact test). FLG null mutations were associated with more severe eczema (P= 0·0042) but the mean difference was only 1–2 points in severity score. Three distinct patterns of palmar hyperlinearity were observed and these are reported for the first time. Conclusions Filaggrin haploinsufficiency appears to be highly penetrant when all relevant skin features are included in the

  2. Expanding the phenotype of alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome): description of an additional case and review of the literature.

    PubMed

    Schell-Apacik, Chayim; Hardt, Michael; Ertl-Wagner, Birgit; Klopocki, Eva; Möhrenschlager, Matthias; Heinrich, Uwe; von Voss, Hubertus

    2008-09-01

    Alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome; OMIM 203550) is a very rare genetic disorder with distinct features. To our knowledge, there have been four cases documented to date. In addition, another three patients, previously described as having IFAP syndrome (OMIM %308205), may also have ACD syndrome. We report on one patient with short stature, total alopecia, ichthyosis, photophobia, seizures, ectrodactyly, vertebral anomalies, scoliosis, multiple contractures, mental retardation, and striking facial and other features (e.g. microdolichocephaly, missing eyebrows and eyelashes, long nose, large ears) consistent with ACD syndrome. Results of laboratory testing in the literature case reports were normal, although in none of them, array-CGH (microarray-based comparative genomic hybridization) analysis was performed. In conclusion, the combination of specific features, including total alopecia, ichthyosis, mental retardation, and skeletal anomalies are suggestive of ACD syndrome. We propose that children with this syndrome undergo a certain social pediatric protocol including EEG diagnostics, ophthalmological investigation, psychological testing, management of dermatologic and orthopedic problems, and genetic counseling.

  3. A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity

    PubMed Central

    2014-01-01

    Background A rare neuro-ichthyotic disorder characterized by ichthyosis, spastic quadriplegia and intellectual disability and caused by recessive mutations in ELOVL4, encoding elongase-4 protein has recently been described. The objective of the study was to search for sequence variants in the gene ELOVL4 in three affected individuals of a consanguineous Pakistani family exhibiting features of neuro-ichthyotic disorder. Methods Linkage in the family was searched by genotyping microsatellite markers linked to the gene ELOVL4, mapped at chromosome 6p14.1. Exons and splice junction sites of the gene ELOVL4 were polymerase chain reaction amplified and sequenced in an automated DNA sequencer. Results DNA sequence analysis revealed a novel homozygous nonsense mutation (c.78C > G; p.Tyr26*). Conclusions Our report further confirms the recently described ELOVL4-related neuro-ichthyosis and shows that the neurological phenotype can be absent in some individuals. PMID:24571530

  4. Cutaneous manifestations of non-Hodgkin's lymphoma.

    PubMed

    Kumar, S S; Kuruvilla, M; Pai, G S; Dinesh, M

    2003-01-01

    Thirty-two confirmed cases of non -Hodgkin's lymphoma (NHL) were examined for cutaneous manifestations for a period of 2 years from November 1998 in KMC Hospital Attavar, Mangalore. Cutaneous manifestations in the study group were compared to a control group of 32 patients. Specific infiltrates were present in all (5/5) CTCL patients and one out of twenty-seven patients with low grade NHL. Morphologically they presented as papules, plaques, nodules and erythroderma. Infective conditions seen in the study group were superficial fungal (7/32) and viral infections (2/ 32). Non-infective conditions were acquired ichthyosis (10/32), generalised pruritus (5/32), insect bite reaction (1/32) and drug eruption (1/32). When compared to control patients only acquired ichthyosis and generalised pruritus were found to be statistically significant. The study group also showed changes due to chemotherapy like diffuse alopecia (24/29), bluish pigmentation of proximal part of nail (4/29), localised pigmentation of palms and soles (1 /29), diffuse pigmentation at injection site (1 /29), pigmentation at scar site (1 /29) and stomatitis (4/29).

  5. A patient case highlighting the myriad of cutaneous adverse effects of prolonged use of hydroxyurea.

    PubMed

    Neill, Brett; Ryser, Ted; Neill, John; Aires, Daniel; Rajpara, Anand

    2017-11-15

    Hydroxyurea is an antimetabolite primarily used to treat myeloproliferative disorders, and chronic treatment is associated with many cutaneous adverse effects ranging in severity from ichthyosis to aggressive nonmelanoma skin cancer. We report a 67-year-oldman with a history of polycythemia vera who was referred for management of progressively worsening dorsal hand lesions. The patient presented withhyperpigmentation, ichthyosis, plantar keratoderma, dermatomyositis-like eruptions, two squamous cell carcinomas, and actinic keratoses. The adversereactions observed were acknowledged to be related to chronic hydroxyurea use. The patient underwent Mohs excision of the squamous cell carcinomas and thehydroxyurea was promptly discontinued; subsequent cutaneous improvement of the dermatomyositislike lesions ensued. Another clinically suspicious aggressive squamous cell carcinoma was suspected and the patient was referred to the plastic surgery department for complete excision because of the size of the lesion. The patient remains on periodic dermatology follow up. We report a case that exemplifies the cutaneous adverse effects of chronic hydroxyurea therapy. Although many cases improve after drug discontinuation, strict photoprotection and ongoing surveillance are indicated given the recently proposed premalignant potential of dermatomyositis-like eruptions and the aggressive nature of hydroxyurea-induced nonmelanoma skin cancer.

  6. Genetics Home Reference: keratitis-ichthyosis-deafness syndrome

    MedlinePlus

    ... outermost layer of skin (the epidermis ). The GJB2 gene mutations that cause KID syndrome change single protein building ... in KID syndrome. It is unclear how GJB2 gene mutations affect the eye. Because at least one of ...

  7. Tay's syndrome: MRI.

    PubMed

    Porto, L; Weis, R; Schulz, C; Reichel, P; Lanfermann, H; Zanella, F E

    2000-11-01

    Tay's syndrome is a trichothiodystrophy associated with congenital ichthyosis. We report the findings on MRI and spectroscopy in a young girl with sparse, short, ruffled hair, dry skin and delayed milestones. T2-weighted images showed prominent diffuse confluent increase in signal symmetrically in all the supratentorial white matter. These findings are similar to those in a previously described case, and consistent with dysmyelination. Spectroscopy showed increased myoinositol and decreased choline.

  8. Hyperkeratosis of the nipple and areola.

    PubMed

    Kuhlman, D S; Hodge, S J; Owen, L G

    1985-10-01

    Hyperkeratosis of the nipple and areola is a rare condition. We report two cases of hyperkeratosis of the nipple and areola occurring in men with no underlying endocrinopathy or synthetic estrogenic drug therapy. Both patients demonstrated prompt resolution of the hyperkeratosis of the nipples with a keratolytic gel. Because our cases were not associated with ichthyosis or epidermal nevus, they best fit into the category of nevoid hyperkeratosis of the nipples.

  9. Sjögren-Larsson syndrome in dizygous twin sisters.

    PubMed

    David, T J

    1980-01-01

    Two dizygous twin sisters with the Sjögren-Larsson syndrome are described. There was parental consanguinity, and the condition is inherited as an autosomal recessive. The main features are mental retardation, spastic diplegia and ichthyosis. Sensory defects of gums and abnormal facial movements were found in the twins, these being recognised features of the syndrome. It is suggested that the condition may be due to an abnormality of the neural crest.

  10. Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene

    SciTech Connect

    Parenti, G.; Rizzolo, M.G.; Ghezzi, M.

    We report on the clinical and molecular characterization of 3 sibs with X-linked ichthyosis and variable expression of Kallmann syndrome. One of the affected brothers had mild hyposmia and showed normal pubertal progression. However, we demonstrated the same partial deletion of the X-linked Kallmann gene, sparing the first exon in the mildly affected patient as well as in one of his severely affected brothers. 13 refs., 1 fig., 1 tab.

  11. Measuring the impact of dermatological conditions on family and caregivers: a review of dermatology-specific instruments.

    PubMed

    Sampogna, F; Finlay, A Y; Salek, S S; Chernyshov, P; Dalgard, F J; Evers, A W M; Linder, D; Manolache, L; Marron, S E; Poot, F; Spillekom-van Koulil, S; Svensson, Å; Szepietowski, J C; Tomas-Aragones, L; Abeni, D

    2017-09-01

    The patient is the centre of a web of relationships, and the impact of his/her disease on family members and caregivers must be taken into account. The aim of this study was to identify the specific instruments that measure the impact of a dermatological disease on the quality of life (QoL) of family members, by performing a systematic search of the literature. Fifteen papers were identified, describing the creation and validation of nine instruments. Four of them concerned atopic dermatitis (Dermatitis Family Index, DFI; Parents' Index QoL Atopic Dermatitis, PiQoL-AD; QoL in primary caregivers of children with atopic dermatitis, QPCAD; Childhood Atopic Dermatitis Impact Scale, CADIS), two measured the impact of psoriasis in family members (Psoriasis Family Index, PFI; FamilyPso), one the impact of epidermolysis bullosa (Epidermolysis Bullosa Burden of Disease, EB-BoD), one of ichthyosis (Family Burden Ichthyosis, FBI), and one was generic for dermatological conditions (Family Dermatology Life Quality Index, FDLQI). The European Academy of Dermatology and Venereology quality of life taskforce recommends that the impact of a skin disease on family and caregivers should be measured as part of any thorough evaluation of the burden of a disease. Guidelines are given to choose the most appropriate instruments. © 2017 European Academy of Dermatology and Venereology.

  12. Acral peeling skin syndrome associated with a novel CSTA gene mutation.

    PubMed

    Muttardi, K; Nitoiu, D; Kelsell, D P; O'Toole, E A; Batta, K

    2016-06-01

    Acral peeling skin syndrome (APSS) is a rare autosomal recessive condition, characterized by asymptomatic peeling of the skin of the hands and feet, often linked to mutations in the gene TGM5. However, more recently recessive loss of function mutations in CSTA, encoding cystatin A, have been linked with APSS and exfoliative ichthyosis. We describe the clinical features in two sisters with APSS, associated with a novel large homozygous deletion encompassing exon 1 of CSTA. © 2015 British Association of Dermatologists.

  13. Severe steatohepatitis in a patient with a rare neutral lipid storage disorder due to ABHD5 mutation.

    PubMed

    Ronchetti, Anna; Prati, Daniele; Pezzotta, Maria Grazia; Tavian, Daniela; Colombo, Roberto; Callea, Francesco; Colli, Agostino

    2008-09-01

    Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dyslipidemia and impaired glucose tolerance, but inherited disorders can sometimes be involved. We report the case of a 40-year-old woman with steatohepatitis and severe portal hypertension, associated with ichthyosis, cataract and hypoacusia. The clinical, pathological and genetic findings were consistent with a diagnosis of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive inherited neutral lipid storage disorder, and genetic analysis showed that a novel ABHD5 mutation is responsible.

  14. Novel duplication mutation in the patatin domain of adipose triglyceride lipase (PNPLA2) in neutral lipid storage disease with severe myopathy.

    PubMed

    Akiyama, Masashi; Sakai, Kaori; Ogawa, Masaya; McMillan, James R; Sawamura, Daisuke; Shimizu, Hiroshi

    2007-12-01

    Recently, mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) were reported to underlie a neutral lipid storage disease (NLSD) subgroup characterized by mild myopathy and the absence of ichthyosis. In the present study a novel homozygous PNPLA2 mutation c.475_478dupCTCC (p.Gln160ProfsX19) in the patatin domain, the ATGL active site, was detected in a woman with NLSD and severe myopathy. The present results suggest that a premature truncation mutation in the patatin domain causes NLSD with severe myopathy.

  15. Schools of pharmacology: retinoid update.

    PubMed

    Scheinfeld, Noah

    2006-10-01

    The most widely used retinoids include topical tretinoin (Retin-A), adapalene (Differin), topical tazarotene (Tazorac), isotretinoin (Accutane), and acitretin (Soriatane). This article will review new uses and developments in tazarotene (its failure to secure FDA approval in oral form for psoriasis), adapalene (its new 0.3% gel form and use in rosacea), alitretinoin (its use in photoaging), bexarotene (its use for psoriasis and chronic hand dermatitis), isotretinoin (the IPledge program, its use for neuroblastoma and branded formulation pharmacological superiority to generics), and retinoic acid metabolism-blocking agents (RAMBAs) (liarazole use for ichthyosis and psoriasis).

  16. Follicular Dowling Degos disease: a rare variant of an evolving dermatosis.

    PubMed

    Singh, Saurabh; Khandpur, Sujay; Verma, Parul; Singh, Manoj

    2013-01-01

    Dowling Degos disease is a rare, reticulate pigmentary disorder with variable phenotypic expression that manifests as hyperpigmented macules and reticulate pigmentary anomaly of the flexures. Many variants of this condition and its overlap with other reticulate pigmentary disorders have been reported in the literature. We present here two cases of DDD with follicular localization, both clinically and histologically. It was associated with ichthyosis vulgaris in one case. Follicular DDD is an uncommon variant of this evolving dermatosis. Our report supports the possible role for disordered follicular keratinisation in its pathogenesis.

  17. Hepatic hypervitaminosis A: a familial observation.

    PubMed

    Sarles, J; Scheiner, C; Sarran, M; Giraud, F

    1990-01-01

    Four siblings with hepatic fibrosis are described. The liver damage in these patients was secondary to chronic ingestion of massive doses of vitamin A for congenital ichthyosis. Although the extrahepatic manifestations were helpful in the diagnosis of hypervitaminosis A, the distinctive features of hepatic histopathology were confirmatory. The plasma concentrations of vitamin A and retinol-binding protein were misleading. The recovery from the liver damage in these patients was slow despite a complete withdrawal of the vitamin A intake. These cases show the importance of hepatic vitamin A assessment in the diagnosis of hepatic fibrosis.

  18. Mouse neutrophils lacking lamin B receptor expression exhibit aberrant development and lack critical functional responses

    PubMed Central

    Gaines, Peter; Tien, Chiung W.; Olins, Ada L.; Olins, Donald E.; Shultz, Leonard D.; Carney, Lisa; Berliner, Nancy

    2008-01-01

    Objective The capacity of neutrophils to eradicate bacterial infections is dependent on normal development and the activation of functional responses, which include chemotaxis and the generation of oxygen radicals during the respiratory burst. A unique feature of the neutrophil is its highly lobulated nucleus, which is thought to facilitate chemotaxis but may also play a role in other critical neutrophil functions. Nuclear lobulation is dependent on the expression of the inner nuclear envelope protein, the lamin B receptor (LBR), mutations of which cause hypolobulated neutrophil nuclei in human Pelger-Huët anomaly (PHA) and the "ichthyosis" (ic) phenotype in mice. In this study we have investigated roles for LBR in mediating neutrophil development and the activation of multiple neutrophil functions, including chemotaxis and the respiratory burst. Materials and Methods A progenitor EML cell line was generated from an ic/ic mouse, and derived cells that lacked LBR expression were induced to mature neutrophils and then examined for abnormal morphology and functional responses. Results Neutrophils derived from EML-ic/ic cells exhibited nuclear hypolobulation identical to that observed in ichthyosis mice. The ic/ic neutrophils also displayed abnormal chemotaxis, supporting the notion that nuclear segmentation augments neutrophil extravasation. Furthermore, promyelocytic forms of ic/ic cells displayed decreased proliferative responses and produced a deficient respiratory burst upon terminal maturation. Conclusions Our studies of promyelocytes that lack LBR expression have identified roles for LBR in regulating not only the morphologic maturation of the neutrophil nucleus but also proliferative and functional responses that are critical to innate immunity. PMID:18550262

  19. Acral peeling skin syndrome resulting from a homozygous nonsense mutation in the CSTA gene encoding cystatin A.

    PubMed

    Krunic, Aleksandar L; Stone, Kristina L; Simpson, Michael A; McGrath, John A

    2013-01-01

    Acral peeling skin syndrome (APSS) is a clinically and genetically heterogeneous disorder. We used whole-exome sequencing to identify the molecular basis of APSS in a consanguineous Jordanian-American pedigree. We identified a homozygous nonsense mutation (p.Lys22X) in the CSTA gene, encoding cystatin A, that was confirmed using Sanger sequencing. Cystatin A is a protease inhibitor found in the cornified cell envelope, and loss-of-function mutations have previously been reported in two cases of exfoliative ichthyosis. Our study expands the molecular pathology of APSS and demonstrates the value of next-generation sequencing in the genetic characterization of inherited skin diseases. © 2013 Wiley Periodicals, Inc.

  20. Insights into rare diseases from social media surveys.

    PubMed

    Davies, William

    2016-11-09

    The internet, and social media platforms, are increasingly being used by substantial sectors of the worldwide population. By engaging effectively with online and social media, scientists and clinicians can obtain unprecedented access to relatively large cohorts of individuals with rare diseases, as well as their relatives, carers and professionals involved in their healthcare. Online surveys of these stakeholder groups may provide important new insights into rare conditions and their management relatively quickly and easily, with the possibility of rapid translation into healthcare interventions and policy. Here, I describe our recent positive experience with the online survey approach to a rare disease (X-linked ichthyosis), and review its advantages and limitations.

  1. The role of filaggrin in the skin barrier and disease development.

    PubMed

    Armengot-Carbo, M; Hernández-Martín, Á; Torrelo, A

    2015-03-01

    Filaggrin is a structural protein that is fundamental in the development and maintenance of the skin barrier. The function of filaggrin and its involvement in various cutaneous and extracutaneous disorders has been the subject of considerable research in recent years. Mutations in FLG, the gene that encodes filaggrin, have been shown to cause ichthyosis vulgaris, increase the risk of atopic dermatitis and other atopic diseases, and exacerbate certain conditions. The present article reviews the current knowledge on the role of filaggrin in the skin barrier, FLG mutations, and the consequences of filaggrin deficiency. Copyright © 2013 Elsevier España, S.L.U. and AEDV. All rights reserved.

  2. A man with nevoid hyperkeratosis of the areola.

    PubMed

    English, J C; Coots, N V

    1996-05-01

    Nevoid hyperkeratosis of the nipple and areola is a unique clinical entity and a diagnosis of exclusion. The patient presenting with nipple/areolar hyperkeratosis must be examined carefully for other underlying cutaneous diseases such as epidermal nevi, ichthyosis, acanthosis nigricans, Darier's disease, cutaneous T-cell lymphoma, and other chronic skin dermatitides that may be responsible for the changes. If no other clinical findings are evident, the diagnosis can be made. Although the disorder is more common in women of childbearing age, men may show nevoid changes after estrogen therapy or idiopathically. The use of topical 12 percent lactic acid lotion (Lac-Hydrin) resolves the skin changes over a six-month period.

  3. Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features.

    PubMed

    Zhou, Yaoyao; Zhang, Junfeng

    2014-09-20

    Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare but fatal autosomal recessive multisystem disorder caused by mutations in the VPS33B or VIPAR gene. The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Additional features include ichthyosis, central nervous system malformation, platelet anomalies, and severe failure to thrive. Diagnosis of ARC syndrome relies on clinical features, organ biopsy, and mutational analysis. However, no specific treatment currently exists for this syndrome. This is an overview of the latest knowledge regarding the genetic features and clinical manifestations of ARC syndrome. Greater awareness and understanding of this syndrome should allow more timely intervention with potential for improving long-term outcome.

  4. Ichthyosis linearis circumflexa with bamboo hair: challenges in the diagnosis and management.

    PubMed

    Dev, Tanvi; Raman Kumar, Marwaha; Sethuraman, Gomathy

    2017-05-28

    A 15-year-old boy had persistent and refractory erythroderma since early childhood. His parents noticed polycyclic skin lesions and hair fragility around the age of 5 years. He was treated by a local untrained practitioner for more than 3 years without any significant improvement, and he developed weight gain, thinning of skin, muscle weakness and growth retardation. He was evaluated in 2015 and found to have iatrogenic Cushing's disease with severe skeletal complications and pituitary-adrenal-gonadal suppression, which persisted despite gradual withdrawal of steroids. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  5. Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy

    SciTech Connect

    Najmabadi, H.; Huang, V.; Bhasin, D.

    1996-04-01

    Genes on the long arm of Y (Yq), particularly within interval 6, are believed to play a critical role in human spermatogenesis. Cytogenetically detectable deletions of this region are associated with azoospermia in men, but are relatively uncommon. The objective of this study was to validate a sequence-tagged site (STS)-mapping strategy for the detection of Yq microdeletions and to use this method to determine the proportion of men with idiopathic azoospermia or severe oligozoospermia who carry microdeletions in Yq. STS mapping of a sufficiently large sample of infertile men should also help further localize the putative gene(s) involved in themore » pathogenesis of male infertility. Genomic DNA was extracted from peripheral leukocytes of 16 normal fertile men, 7 normal fertile women, 60 infertile men, and 15 patients with the X-linked disorder, ichthyosis. PCR primers were synthesized for 26 STSs that span Yq interval 6. None of the 16 normal men of known fertility had microdeletions. Seven normal fertile women failed to amplify any of the 26 STSs, providing evidence of their Y specificity. No microdeletions were detected in any of the 15 patients with ichthyosis. Of the 60 infertile men typed with 26 STSs, 11 (18%; 10 azoospermic and 1 oligozoospermic) failed to amplify 1 or more STS. Interestingly, 4 of the 11 patients had microdeletions in a region that is outside the Yq region from which the DAZ (deleted in azoospermia gene region) gene was cloned. In an additional 3 patients, microdeletions were present both inside and outside the DAZ region. The physical locations of these microdeletions provide further support for the concept that a gene(s) on Yq deletion interval 6 plays an important role in spermatogenesis. The presence of deletions that do not overlap with the DAZ region suggests that genes other than the DAZ gene may also be implicated in the pathogenesis of some subsets of male infertility. 48 refs., 2 figs., 2 tabs.« less

  6. Mindfulness-Based Cognitive Hypnotherapy and Skin Disorders.

    PubMed

    Shenefelt, Philip D

    2018-07-01

    Mindfulness-based cognitive hypnotherapy integrates mindfulness, cognitive-behavioral therapy, and hypnotherapy to improve physical, emotional, mental, and/or spiritual aspects of skin disorders. Meditation, including mindfulness meditation, and hypnosis both utilize trance phenomena to help produce focalization and specific improvements in skin disorders through psycho-neuro-endocrine-immunologic mechanisms. Hypnosis, cognitive hypnotherapy, focused meditation, and mindfulness meditation are discussed with respect to improving various skin disorders including acne, acne excoriée, alopecia areata, atopic dermatitis, congenital ichthyosiform erythroderma, dyshidrotic dermatitis, erythema nodosum, erythromelalgia, furuncles, glossodynia, herpes simplex, hyperhidrosis, ichthyosis vulgaris, lichen planus, neurodermatitis, nummular dermatitis, postherpetic neuralgia, prurigo nodularis, pruritus, psoriasis, rosacea, trichotillomania, urticaria, verruca vulgaris, and vitiligo. Their integration into mindfulness-based cognitive hypnotherapy is then discussed and illustrated with improvement in a patient with systemic lupus erythematosus.

  7. Atopic eczema and the filaggrin story.

    PubMed

    Brown, Sara J; Irvine, Alan D

    2008-06-01

    The discovery that null mutations in the filaggrin gene (FLG) are associated with atopic eczema represents the single most significant breakthrough in understanding the genetic basis of this complex disorder. The association has been replicated in multiple independent studies during the past 2 years with the use of various methodologies, from populations in Europe, the United States, and Japan. Filaggrin plays a key role in epidermal barrier function, and its association with atopic eczema emphasizes the importance of barrier dysfunction in eczema pathogenesis. This review aims to summarize the current state of knowledge regarding the role of FLG mutations in ichthyosis vulgaris, atopic eczema, and other skin disorders, with an emphasis on potential clinical applications. Further research is needed to clarify the precise role of filaggrin in skin and systemic atopic disease, to pave the way for novel therapeutic interventions.

  8. [The role of psychological factors and psychiatric disorders in skin diseases].

    PubMed

    Kieć-Swierczyńska, Marta; Dudek, Bohdan; Krecisz, Beata; Swierczyńska-Machura, Dominika; Dudek, Wojciech; Garnczarek, Adrianna; Turczyn, Katarzyna

    2006-01-01

    In this paper, the relation between psychological factors and psychiatric disorders in patients with skin diseases is discussed. On the one hand psychological factors (stress, negative emotions) can influence the generation and aggravation of skin disorders (urticaria, atopic dermatitis, vitiligo), on the other hand psychological disorders can result in some skin diseases (psoriasis, atopic dermatitis). In the majority of cases the quality of life is poorly estimated by patients with skin problems. Psychodermatology is divided into three categories according to the relationship between skin diseases and mental disorders: 1) psychophysiologic disorders caused by skin diseases triggering different emotional states (stress), but not directly combined with mental disorders (psoriasis, eczema); 2) primary psychiatric disorders responsible for self-induced skin disorders (trichotillomania); and 3) secondary psychiatric disorders caused by disfiguring skin (ichthyosis, acne conglobata, vitiligo), which can lead to states of fear, depression or suicidal thoughts.

  9. Altered epidermal lipid processing and calcium distribution in the KID syndrome mouse model Cx26S17F.

    PubMed

    Bosen, Felicitas; Celli, Anna; Crumrine, Debra; vom Dorp, Katharina; Ebel, Philipp; Jastrow, Holger; Dörmann, Peter; Winterhager, Elke; Mauro, Theodora; Willecke, Klaus

    2015-07-08

    The keratitis-ichthyosis-deafness (KID) syndrome is caused by mutations in the gap junctional channel protein connexin 26 (Cx26), among them the mutation Cx26S17F. Heterozygous Cx26S17F mice resemble the human KID syndrome, i.e. exhibiting epidermal hyperplasia and hearing impairments. Newborn Cx26S17F mice show a defective epidermal water barrier as well as altered epidermal lipid secretion and location. Linoleoyl ω-esterified ceramides are strongly decreased on the skin surface of Cx26S17F mice. Moreover, the epidermal calcium gradient is altered in the mutant mice. These alterations may be caused by an abnormal Cx26S17F channel function that leads to a defective epidermal water barrier, which in turn may trigger the hyperproliferation seen in the KID syndrome. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  10. One remarkable molecule: Filaggrin

    PubMed Central

    Brown, Sara J.; McLean, W. H. Irwin

    2011-01-01

    The discovery, in 2006, that loss-of-function mutations in the filaggrin gene (FLG) are the cause of ichthyosis vulgaris – the most common disorder of keratinization – and also a strong genetic risk factor for atopic eczema, marked a significant breakthrough in the understanding of eczema pathogenesis. Subsequent investigations of the role of FLG null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis and peanut allergy. However, many questions remain to be answered in relation to the precise mechanisms by which deficiency of an intracellular protein expressed primarily in the differentiating epidermis may contribute to the development of cutaneous and systemic pathology. This review aims to highlight the key milestones in filaggrin research over the past 25 years, to discuss the mechanistic, clinical and therapeutic implications and to consider possible future directions for ongoing investigation. PMID:22158554

  11. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it all in your mind?

    PubMed

    Shenefelt, Philip D

    2003-01-01

    Biofeedback can improve cutaneous problems that have an autonomic nervous system component. Examples include biofeedback of galvanic skin resistance (GSR) for hyperhidrosis and biofeedback of skin temperature for Raynaud's disease. Hypnosis may enhance the effects obtained by biofeedback. Cognitive-behavioral methods may resolve dysfunctional thought patterns (cognitive) or actions (behavioral) that damage the skin or interfere with dermatologic therapy. Responsive diseases include acne excoriée, atopic dermatitis, factitious cheilitis, hyperhidrosis, lichen simplex chronicus, needle phobia, neurodermatitis, onychotillomania, prurigo nodularis, trichotillomania, and urticaria. Hypnosis can facilitate aversive therapy and enhance desensitization and other cognitive-behavioral methods. Hypnosis may improve or resolve numerous dermatoses. Examples include acne excoriée, alopecia areata, atopic dermatitis, congenital ichthyosiform erythroderma, dyshidrotic dermatitis, erythromelalgia, furuncles, glossodynia, herpes simplex, hyperhidrosis, ichthyosis vulgaris, lichen planus, neurodermatitis, nummular dermatitis, postherpetic neuralgia, pruritus, psoriasis, rosacea, trichotillomania, urticaria, verruca vulgaris, and vitiligo. Hypnosis can also reduce the anxiety and pain associated with dermatologic procedures.

  12. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.

    PubMed

    Oji, Vinzenz; Eckl, Katja-Martina; Aufenvenne, Karin; Nätebus, Marc; Tarinski, Tatjana; Ackermann, Katharina; Seller, Natalia; Metze, Dieter; Nürnberg, Gudrun; Fölster-Holst, Regina; Schäfer-Korting, Monika; Hausser, Ingrid; Traupe, Heiko; Hennies, Hans Christian

    2010-08-13

    Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.

  13. Loss of Corneodesmosin Leads to Severe Skin Barrier Defect, Pruritus, and Atopy: Unraveling the Peeling Skin Disease

    PubMed Central

    Oji, Vinzenz; Eckl, Katja-Martina; Aufenvenne, Karin; Nätebus, Marc; Tarinski, Tatjana; Ackermann, Katharina; Seller, Natalia; Metze, Dieter; Nürnberg, Gudrun; Fölster-Holst, Regina; Schäfer-Korting, Monika; Hausser, Ingrid; Traupe, Heiko; Hennies, Hans Christian

    2010-01-01

    Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past. PMID:20691404

  14. Indication of prenatal diagnosis in pregnancies complicated by undetectable second-trimester maternal serum estriol levels.

    PubMed

    Minsart, Anne-Frédérique; Van Onderbergen, Anne; Jacques, Francotte; Kurt, Crener; Gillerot, Yves

    2008-07-01

    Undetectable maternal serum unconjugated estriol levels in the second-trimester screening test have been associated with congenital pathology and an adverse pregnancy outcome. We reviewed outcomes of pregnancies with undetectable levels of estriol (<0.25 ng/ml) in the triple-marker screening test and assessed the clinical value of this finding. We studied estriol values in 6,018 pregnant patients who underwent a triple-marker screening test during a seven-year period. 26 women had estriol levels at or below the sensitivity of the assay. The most common explanations were dating errors, prematurity, growth restriction and X-linked ichthyosis. We also observed one fetal death at 16 weeks, one severe threatened fetal abortion, one case of multiple congenital anomalies and one case of isolated adrenocorticotropin hormone deficiency. There were 6 women remaining with unexplained undetectable estriol. Undetectable maternal estriol values may indicate a severe fetal pathology and should lead to further investigations.

  15. Effect of a new moisturizing lotion on immediate and cumulative skin hydration: Two randomized, intra-individual, vehicle- and comparator-controlled studies.

    PubMed

    Nogueira, Alessandra; Sidou, Farzaneh; Brocard, Sylvie

    2011-08-01

    Moisturizers increase skin hydration and can serve as adjunctive care in dermatologic conditions such as xerosis, psoriasis vulgaris, atopic dermatitis and ichthyosis, in which dry skin is implicated. A non-irritating hydrating lotion (CDA lotion) was recently developed. We assessed the effect of CDA lotion on skin hydration in two randomized, evaluator-blind and intra-individual comparison studies. After a single application, CDA lotion induced significantly greater hydration than the non-treated control for at least 24 hours (p < 0.001). After 4 days of twice-daily application, compared with the non-treated control, CDA lotion induced significantly greater skin hydration up to 3 days after treatment cessation (p < 0.05) and significant improvement in the clinical skin dryness score up to 7 days after treatment cessation (p < 0.05). The immediate and cumulative hydration effects of CDA lotion were also compared to those of several currently available moisturizing products. In summary, application of CDA lotion increases skin hydration and alleviates the condition of skin dryness.

  16. Deoxysphingolipid precursors indicate abnormal sphingolipid metabolism in individuals with primary and secondary disturbances of serine availability.

    PubMed

    Ferreira, C R; Goorden, S M I; Soldatos, A; Byers, H M; Ghauharali-van der Vlugt, J M M; Beers-Stet, F S; Groden, C; van Karnebeek, C D; Gahl, W A; Vaz, F M; Jiang, X; Vernon, H J

    2018-05-07

    Patients with primary serine biosynthetic defects manifest with intellectual disability, microcephaly, ichthyosis, seizures and peripheral neuropathy. The underlying pathogenesis of peripheral neuropathy in these patients has not been elucidated, but could be related to a decrease in the availability of certain classical sphingolipids, or to an increase in atypical sphingolipids. Here, we show that patients with primary serine deficiency have a statistically significant elevation in specific atypical sphingolipids, namely deoxydihydroceramides of 18-22 carbons in acyl length. We also show that patients with aberrant plasma serine and alanine levels secondary to mitochondrial disorders also display peripheral neuropathy along with similar elevations of atypical sphingolipids. We hypothesize that the etiology of peripheral neuropathy in patients with primary mitochondrial disorders is related to this elevation of deoxysphingolipids, in turn caused by increased availability of alanine and decreased availability of serine. These findings could have important therapeutic implications for the management of these patients. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Revertant mosaicism in heritable skin diseases: mechanisms of natural gene therapy.

    PubMed

    Pasmooij, Anna M G; Jonkman, Marcel F; Uitto, Jouni

    2012-09-01

    Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the revertant mutations occur? 4) How do you recognize revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The revertant skin could potentially be used to treat the patient's own affected skin.

  18. The Regulation of Steroid Action by Sulfation and Desulfation

    PubMed Central

    Mueller, Jonathan W.; Gilligan, Lorna C.; Idkowiak, Jan; Arlt, Wiebke

    2015-01-01

    Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined. PMID:26213785

  19. PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

    PubMed Central

    Grond, Susanne; Eichmann, Thomas O.; Dubrac, Sandrine; Kolb, Dagmar; Schmuth, Matthias; Fischer, Judith; Crumrine, Debra; Elias, Peter M.; Haemmerle, Guenter; Zechner, Rudolf; Lass, Achim; Radner, Franz P.W.

    2017-01-01

    Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency. PMID:27751867

  20. Phenotype in a patient with p.D50N mutation in GJB2 gene resemble both KID and Clouston syndromes.

    PubMed

    Markova, T G; Brazhkina, N B; Bliznech, E A; Bakhshinyan, V V; Polyakov, A V; Tavartkiladze, G A

    2016-02-01

    Keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210) is a rare ectodermal dysplasia syndrome characterized by vascularizing keratitis, congenital profound sensorineural hearing loss, and progressive erythrokeratoderma. We have found a 148G-A transition in the GJB2 gene, resulting in an asp50-to-asn (D50N) substitution in a girl with congenital deafness. This finding allowed us to diagnose а KID syndrome. But clinical features were uncommon because of a mild skin manifestation, lack of keratitis and unusual appearance resembling Clouston syndrome. Molecular genetic tests showed that it was de novo mutation because parents have normal genotype. Several autosomal dominant mutations in the GJB2 gene (сonnexin 26) now established to underlie many of the affected cases, with the majority of patients harboring the p.D50N mutation. Skin disease-associated mutation of connexin proteins can cause functional disturbances in gap junction intercellular conductance. It is likely that multiple disease mechanisms are involved across the wide spectrum of hereditary diseases relating to connexin proteins. The clinical data may provide additional insights into the dysregulation mechanisms of mutations result in the disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. Filaggrin gene polymorphism associated with Epstein-Barr virus-associated tumors in China.

    PubMed

    Yang, Yang; Liu, Wen; Zhao, Zhenzhen; Zhang, Yan; Xiao, Hua; Luo, Bing

    2017-08-01

    Mutations of filaggrin gene (FLG) have been identified as the cause of ichthyosis vulgaris, while recently FLG mutations were found to be associated with gastric cancer. This study aimed to investigate the association of filaggrin polymorphism with Epstein-Barr virus-associated tumors in China. A total of 200 patients with three types of tumors and 117 normal control samples were genotyped at three common FLG mutation loci (rs3126085, K4671X, R501X) by using Sequenom MassARRAY technique. The χ 2 test was used to evaluate the relationship between the mutation and the three kinds of tumors. A two-sided P value of <0.05 was considered statistically significant. The results showed that two single-nucleotide polymorphism (SNP) loci (rs3126085, K4671X) were significantly associated with nasopharyngeal carcinoma in genetic model. In addition, the two SNPs K4671X and rs3126085 were related to Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC), respectively. Furthermore, allele distributions in EBVaGC and EBVnGC were verified to be different in both SNP loci.

  2. Keratin 1 maintains skin integrity and participates in an inflammatory network in skin through interleukin-18.

    PubMed

    Roth, Wera; Kumar, Vinod; Beer, Hans-Dietmar; Richter, Miriam; Wohlenberg, Claudia; Reuter, Ursula; Thiering, Sören; Staratschek-Jox, Andrea; Hofmann, Andrea; Kreusch, Fatima; Schultze, Joachim L; Vogl, Thomas; Roth, Johannes; Reichelt, Julia; Hausser, Ingrid; Magin, Thomas M

    2012-11-15

    Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) are major constituents of the intermediate filament cytoskeleton in suprabasal epidermis. KRT1 mutations cause epidermolytic ichthyosis in humans, characterized by loss of barrier integrity and recurrent erythema. In search of the largely unknown pathomechanisms and the role of keratins in barrier formation and inflammation control, we show here that Krt1 is crucial for maintenance of skin integrity and participates in an inflammatory network in murine keratinocytes. Absence of Krt1 caused a prenatal increase in interleukin-18 (IL-18) and the S100A8 and S100A9 proteins, accompanied by a barrier defect and perinatal lethality. Depletion of IL-18 partially rescued Krt1(-/-) mice. IL-18 release was keratinocyte-autonomous, KRT1 and caspase-1 dependent, supporting an upstream role of KRT1 in the pathology. Finally, transcriptome profiling revealed a Krt1-mediated gene expression signature similar to atopic eczema and psoriasis, but different from Krt5 deficiency and epidermolysis bullosa simplex. Our data suggest a functional link between KRT1 and human inflammatory skin diseases.

  3. Resveratrol induces human keratinocyte damage via the activation of class III histone deacetylase, Sirt1.

    PubMed

    Lee, Ju-Hee; Kim, Jin-Shang; Park, Sang-Youel; Lee, You-Jin

    2016-01-01

    Human skin diseases are various and induce chronic inflammatory disorders, including psoriasis, atopic dermatitis and certain forms of ichthyosis. Psoriasis is a chronic inflammatory skin disease characterized by circumscribed, red, thickened plaques. Regulation of the balance between growth, differentiation and death is critical to keratinocytes; when altered, epidermal keratinocytes undergo hyperproliferation, abnormal differentiation and inflammatory infiltration. In the present study, we focused on the effects of resveratrol, found in red wine and peanuts, on the cell death of keratinocytes. We additionally studied the mechanism of resveratrol on Sirt1, a class III histone deacetylase, and Akt phosphorylation. Resveratrol caused apoptosis and increased Sirt1 expression in human HaCaT keratinocytes, following a decrease in the p62 protein level. Inhibition of Sirt1 by Sirt1 inhibitor restored cell viability and protein levels. Furthermore, we showed that resveratrol-induced Sirt1 blocked Akt phosphorylation. The present results indicated that resveratrol inhibited the Akt pathways by inducing Sirt1, thus leading to cell death. These data suggest that resveratrol-mediated activation of Sirt1 histone deacetylase may be a potential therapeutic target for skin diseases including psoriasis.

  4. Nucleotide excision repair and human syndromes.

    PubMed

    de Boer, J; Hoeijmakers, J H

    2000-03-01

    DNA damage is implicated in cancer and aging, and several DNA repair mechanisms exist that safeguard the genome from these deleterious consequences. Nucleotide excision repair (NER) removes a wide diversity of lesions, the main of which include UV-induced lesions, bulky chemical adducts and some forms of oxidative damage. The NER process involves the action of at least 30 proteins in a 'cut-and-paste'-like mechanism. The consequences of a defect in one of the NER proteins are apparent from three rare recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and the photosensitive form of the brittle hair disorder trichothiodystrophy (TTD). Sun-sensitive skin is associated with skin cancer predisposition in the case of XP, but remarkably not in CS and TTD. Moreover, the spectrum of clinical symptoms differs considerably between the three syndromes. CS and TTD patients exhibit a spectrum of neurodevelopmental abnormalities and, in addition, TTD is associated with ichthyosis and brittle hair. These typical CS and TTD abnormalities are difficult to comprehend as a consequence of defective NER. This review briefly describes the biochemistry of the NER process, summarizes the clinical features of the NER disorders and speculates on the molecular basis underlying these pleitropic syndromes.

  5. Sebaceous Gland, Hair Shaft, and Epidermal Barrier Abnormalities in Keratosis Pilaris with and without Filaggrin Deficiency

    PubMed Central

    Gruber, Robert; Sugarman, Jeffrey L.; Crumrine, Debra; Hupe, Melanie; Mauro, Theodora M.; Mauldin, Elizabeth A.; Thyssen, Jacob P.; Brandner, Johanna M.; Hennies, Hans-Christian; Schmuth, Matthias; Elias, Peter M.

    2016-01-01

    Although keratosis pilaris (KP) is common, its etiopathogenesis remains unknown. KP is associated clinically with ichthyosis vulgaris and atopic dermatitis and molecular genetically with filaggrin-null mutations. In 20 KP patients and 20 matched controls, we assessed the filaggrin and claudin 1 genotypes, the phenotypes by dermatoscopy, and the morphology by light and transmission electron microscopy. Thirty-five percent of KP patients displayed filaggrin mutations, demonstrating that filaggrin mutations only partially account for the KP phenotype. Major histologic and dermatoscopic findings of KP were hyperkeratosis, hypergranulosis, mild T helper cell type 1-dominant lymphocytic inflammation, plugging of follicular orifices, striking absence of sebaceous glands, and hair shaft abnormalities in KP lesions but not in unaffected skin sites. Changes in barrier function and abnormal paracellular permeability were found in both interfollicular and follicular stratum corneum of lesional KP, which correlated ultrastructurally with impaired extracellular lamellar bilayer maturation and organization. All these features were independent of filaggrin genotype. Moreover, ultrastructure of corneodesmosomes and tight junctions appeared normal, immunohistochemistry for claudin 1 showed no reduction in protein amounts, and molecular analysis of claudin 1 was unremarkable. Our findings suggest that absence of sebaceous glands is an early step in KP pathogenesis, resulting in downstream hair shaft and epithelial barrier abnormalities. PMID:25660180

  6. Keratosis Pilaris Revisited: Is It More Than Just a Follicular Keratosis?

    PubMed Central

    Thomas, Mary; Khopkar, Uday Sharadchandra

    2012-01-01

    Background: Keratosis pilaris (KP) is characterized by keratinous plugs in the follicular orifices and varying degrees of perifollicular erythema. The most accepted theory of its pathogenesis proposes defective keratinization of the follicular epithelium resulting in a keratotic infundibular plug. We decided to test this hypothesis by doing dermoscopy of patients diagnosed clinically as keratosis pilaris. Materials and Methods: Patients with a clinical diagnosis of KP seen between September 2011 and December 2011 were included in the study. A clinical history was obtained and examination and dermoscopic evaluation were performed on the lesions of KP. Results: The age of the patients ranged from 6-38 years. Sixteen patients had history of atopy. Nine had concomitant ichthyosis vulgaris. All the 25 patients were found to have coiled hair shafts within the affected follicular infundibula. The hair shafts were extracted with the help of a sterile needle and were found to retain their coiled nature. Perifollicular erythema was seen in 11 patients; perifollicular scaling in 9. Conclusion: Based on our observations and previously documented histological data of KP, we infer that KP may not be a disorder of keratinization, but caused by the circular hair shaft which ruptures the follicular epithelium leading to inflammation and abnormal follicular keratinization. PMID:23766609

  7. al mena: a comprehensive resource of human genetic variants integrating genomes and exomes from Arab, Middle Eastern and North African populations.

    PubMed

    Koshy, Remya; Ranawat, Anop; Scaria, Vinod

    2017-10-01

    Middle East and North Africa (MENA) encompass very unique populations, with a rich history and encompasses characteristic ethnic, linguistic and genetic diversity. The genetic diversity of MENA region has been largely unknown. The recent availability of whole-exome and whole-genome sequences from the region has made it possible to collect population-specific allele frequencies. The integration of data sets from this region would provide insights into the landscape of genetic variants in this region. We integrated genetic variants from multiple data sets systematically, available from this region to create a compendium of over 26 million genetic variations. The variants were systematically annotated and their allele frequencies in the data sets were computed and available as a web interface which enables quick query. As a proof of principle for application of the compendium for genetic epidemiology, we analyzed the allele frequencies for variants in transglutaminase 1 (TGM1) gene, associated with autosomal recessive lamellar ichthyosis. Our analysis revealed that the carrier frequency of selected variants differed widely with significant interethnic differences. To the best of our knowledge, al mena is the first and most comprehensive repertoire of genetic variations from the Arab, Middle Eastern and North African region. We hope al mena would accelerate Precision Medicine in the region.

  8. Fatty Aldehyde and Fatty Alcohol Metabolism: Review and Importance for Epidermal Structure and Function

    PubMed Central

    Rizzo, William B.

    2014-01-01

    Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. PMID:24036493

  9. Generalized peeling skin syndrome: Case report and review of the literature.

    PubMed

    Kharfi, Monia; Khaled, Aida; Ammar, Donia; Ezzine, Nadia; El Fekih, Nadia; Fazaa, Becima; Jaafoura, Hiabib; Kamoun, Mohamed Ridha

    2010-03-15

    Peeling skin syndrome (PSS) is a rare form of ichthyosis with a probable autosomal recessive inheritance that exhibits superficial, painless, continual, or seasonal cutaneous exfoliation. The syndrome generally appears at birth or in infancy. We report a case of generalized PSS and provide a literature review. A 34-year-old woman reported a lifelong history of generalized and painless peeling of the skin that worsened in summer. Her parents were third degree cousins. Her twin sister and her two cousins presented with the same condition. Physical examination showed widespread superficial sheets of variable size that could be easily removed without bleeding or pain. No underlying erythema was noted. Otherwise, the patient was in good health. Histological findings showed an epidermal cleavage within the stratum corneum. The generalized form of PSS is classified into 3 types, A, B, and C, according to the classification system of Traupe and Mevorah. We have tried to classify the cases of generalized PSS already reported in the literature into one of these three types. Thirteen reported cases probably presented PSS-type A. Sixteen patients are best described as PSS-type B. Two patients exhibit PSS-type C. Fifteen reported patients had an acral form of peeling skin syndrome. The classification of the eleven remaining patients was difficult to determine. Our patient presented clinical and histological features of generalized PSS-type A.

  10. Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise

    PubMed Central

    Chamcheu, Jean Christopher; Wood, Gary S.; Siddiqui, Imtiaz A.; Syed, Deeba N.; Adhami, Vaqar M.; Teng, Joyce M.; Mukhtar, Hasan

    2012-01-01

    Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy. PMID:22716242

  11. Genetic homogeneity in Sjoegren-Larsson syndrome: Linkage to chromosome 17p in families of different non-Swedish ethnic origins

    SciTech Connect

    Rogers, G.R.; Lee, M.; Compton, J.G.

    1995-11-01

    Sjoegren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder that is characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. Three United States families, three Egyptian families, and one Israeli Arab family were investigated for linkage of the SLS gene to a region of chromosome 17. Pairwise and multipoint linkage analysis with nine markers mapped the SLS gene to the same region of the genome as that reported in Swedish SLS pedigrees. Examination of recombinants by haplotype analysis showed that the gene lies in the region containing the markers D17S953, D17S805, D17S689, and D17S842. D17S805 is pericentromeric onmore » 17p. Patients in two consanguineous Egyptian families were homozygous at the nine marker loci tested, and another patient from a third family was homozygous for eight of the nine, suggesting that within each of these families the region of chromosome 17 carrying the SLS gene is identical by descent. Linkage of the SLS gene to chromosome 17p in families of Arabic, mixed European, Native American, and Swedish descent provides evidence for a single SLS locus and should prove useful for diagnosis and carrier detection in worldwide cases. 25 refs., 4 figs., 1 tab.« less

  12. Hair and Scalp Disorders in a Tuscan Pediatric Dermatological Outpatient Clinic: A Clinical and Epidemiological Evaluation.

    PubMed

    Conti, Rossana; Colucci, Roberta; Arunachalam, Meena; Berti, Samantha; Fabroni, Caterina; De Martino, Maurizio; Dragoni, Federica; Lazzeri, Linda; Pisaneschi, Lisa; Moretti, Silvia

    2016-01-01

    The aim of this study was to evaluate the clinical and epidemiological profile of hair and scalp disorders in children referred to the Pediatric Dermatology Outpatient Clinic. We performed a retrospective study of children with hair loss problems or scalp diseases who turned to the Pediatric Dermatology Service, Anna Meyer Pediatric Hospital, Florence, Italy, from January 1, 2009, to December 31, 2009. Demographics, personal and familial medical history, laboratory tests, clinical examination, final diagnosis and therapeutic interventions were obtained from the manual chart review. Of the 2,640 children who had access to the Pediatric Dermatology Service, 190 (7.19%) had a hair or scalp disorder. Among the 190 children, 60 (31.57%) presented with nonscarring alopecia, 56 (29.47%) had benign neoplasias, hamartomas or vascular malformations of the scalp, 51 (26.84%) had scalp inflammatory diseases, 14 (7.36%) had scarring alopecia, 5 (2.63%) had infections and 2 (1.05%) had infestation of the scalp. A case of constitutional hypertrichosis (0.52%) and also a case (0.52%) of lamellar ichthyosis were diagnosed. Our results underline that hair and scalp diseases represent an important percentage of admittances to a dermatological pediatric outpatient clinic. The variety and complexity of the diseases observed in this study included diseases commonly found also in adulthood. © 2015 S. Karger AG, Basel.

  13. Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise.

    PubMed

    Chamcheu, Jean Christopher; Wood, Gary S; Siddiqui, Imtiaz A; Syed, Deeba N; Adhami, Vaqar M; Teng, Joyce M; Mukhtar, Hasan

    2012-07-01

    Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy. © 2012 John Wiley & Sons A/S.

  14. Localization of the Netherton Syndrome Gene to Chromosome 5q32, by Linkage Analysis and Homozygosity Mapping

    PubMed Central

    Chavanas, Stéphane; Garner, Chad; Bodemer, Christine; Ali, Mohsin; Teillac, Dominique Hamel-; Wilkinson, John; Bonafé, Jean-Louis; Paradisi, Mauro; Kelsell, David P.; Ansai, Shin-ichi; Mitsuhashi, Yoshihiko; Larrègue, Marc; Leigh, Irene M.; Harper, John I.; Taïeb, Alain; Prost, Yves de; Cardon, Lon R.; Hovnanian, Alain

    2000-01-01

    Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Iα, the α subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor β2, and the diastrophic dysplasia sulfate–transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity. PMID:10712206

  15. Increased retinoic acid levels through ablation of Cyp26b1 determine the processes of embryonic skin barrier formation and peridermal development

    PubMed Central

    Okano, Junko; Lichti, Ulrike; Mamiya, Satoru; Aronova, Maria; Zhang, Guofeng; Yuspa, Stuart H.; Hamada, Hiroshi; Sakai, Yasuo; Morasso, Maria I.

    2012-01-01

    The process by which the periderm transitions to stratified epidermis with the establishment of the skin barrier is unknown. Understanding the cellular and molecular processes involved is crucial for the treatment of human pathologies, where abnormal skin development and barrier dysfunction are associated with hypothermia and perinatal dehydration. For the first time, we demonstrate that retinoic acid (RA) levels are important for periderm desquamation, embryonic skin differentiation and barrier formation. Although excess exogenous RA has been known to have teratogenic effects, little is known about the consequences of elevated endogenous retinoids in skin during embryogenesis. Absence of cytochrome P450, family 26, subfamily b, polypeptide 1 (Cyp26b1), a retinoic-acid-degrading enzyme, results in aberrant epidermal differentiation and filaggrin expression, defective cornified envelopes and skin barrier formation, in conjunction with peridermal retention. We show that these alterations are RA dependent because administration of exogenous RA in vivo and to organotypic skin cultures phenocopy Cyp26b1−/− skin abnormalities. Furthermore, utilizing the Flaky tail (Ft/Ft) mice, a mouse model for human ichthyosis, characterized by mutations in the filaggrin gene, we establish that proper differentiation and barrier formation is a prerequisite for periderm sloughing. These results are important in understanding pathologies associated with abnormal embryonic skin development and barrier dysfunction. PMID:22366455

  16. Phenotypic variability in gap junction syndromic skin disorders: experience from KID and Clouston syndromes' clinical diagnostics.

    PubMed

    Kutkowska-Kaźmierczak, Anna; Niepokój, Katarzyna; Wertheim-Tysarowska, Katarzyna; Giza, Aleksandra; Mordasewicz-Goliszewska, Maria; Bal, Jerzy; Obersztyn, Ewa

    2015-08-01

    Connexins belong to the family of gap junction proteins which enable direct cell-to-cell communication by forming channels in adjacent cells. Mutations in connexin genes cause a variety of human diseases and, in a few cases, result in skin disorders. There are significant differences in the clinical picture of two rare autosomal dominant syndromes: keratitis-ichthyosis-deafness (KID) syndrome and hidrotic ectodermal dysplasia (Clouston syndrome), which are caused by GJB2 and GJB6 mutations, respectively. This is despite the fact that, in both cases, malfunctioning of the same family proteins and some overlapping clinical features (nail dystrophy, hair loss, and palmoplantar keratoderma) is observed. KID syndrome is characterized by progressive vascularizing keratitis, ichthyosiform erythrokeratoderma, and neurosensory hearing loss, whereas Clouston syndrome is characterized by nail dystrophy, hypotrichosis, and palmoplantar keratoderma. The present paper presents a Polish patient with sporadic KID syndrome caused by the mutation of p.Asp50Asn in GJB2. The patient encountered difficulties in obtaining a correct diagnosis. The other case presented is that of a family with Clouston syndrome (caused by p.Gly11Arg mutation in GJB6), who are the first reported patients of Polish origin suffering from this disorder. Phenotype diversity among patients with the same genotypes reported to date is also summarized. The conclusion is that proper diagnosis of these syndromes is still challenging and should always be followed by molecular verification.

  17. Severe X-linked chondrodysplasia punctata in nine new female fetuses.

    PubMed

    Lefebvre, Mathilde; Dufernez, Fabienne; Bruel, Ange-Line; Gonzales, Marie; Aral, Bernard; Saint-Onge, Judith; Gigot, Nadège; Desir, Julie; Daelemans, Caroline; Jossic, Frédérique; Schmitt, Sébastien; Mangione, Raphaele; Pelluard, Fanny; Vincent-Delorme, Catherine; Labaune, Jean-Marc; Bigi, Nicole; D'Olne, Dominique; Delezoide, Anne-Lise; Toutain, Annick; Blesson, Sophie; Cormier-Daire, Valérie; Thevenon, Julien; El Chehadeh, Salima; Masurel-Paulet, Alice; Joyé, Nicole; Vibert-Guigue, Claude; Rigonnot, Luc; Rousseau, Thierry; Vabres, Pierre; Hervé, Philippe; Lamazière, Antonin; Rivière, Jean-Baptiste; Faivre, Laurence; Laurent, Nicole; Thauvin-Robinet, Christel

    2015-07-01

    Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations. © 2015 John Wiley & Sons, Ltd.

  18. Epidermal hyperproliferation in mice lacking fatty acid transport protein 4 (FATP4) involves ectopic EGF receptor and STAT3 signaling

    PubMed Central

    Lin, Meei-Hua; Chang, Kuo-Wei; Lin, Shu-Chun; Miner, Jeffrey H.

    2010-01-01

    Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective epidermal barrier; they die neonatally due to dehydration and restricted movements. Both the skin phenotype and the lethality are rescued by transgene-driven expression of FATP4 solely in suprabasal keratinocytes. Here we show that Fatp4 mutants exhibit epidermal hyperplasia resulting from an increased number of proliferating suprabasal cells. In addition, barrier formation initiates precociously but never progresses to completion. To investigate possible mechanisms whereby Fatp4 influences skin development, we identified misregulated genes in Fatp4 mutants. Remarkably, three members of the epidermal growth factor (EGF) family (Ereg, Areg, and Epgn) showed increased expression that was associated with elevated epidermal activation of the EGF receptor (EGFR) and STAT3, a downstream effector of EGFR signaling. Both Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, and curcumin, an inhibitor of both STAT3 and EGFR, attenuated STAT3 activation/nuclear translocation, reduced skin thickening, and partially suppressed the barrier abnormalities. These data identify FATP4 activity as negatively influencing EGFR activation and the resulting STAT3 signaling during normal skin development. These findings have important implications for understanding the pathogenesis of ichthyosis prematurity syndrome, a disease recently shown to be caused by FATP4 mutations. PMID:20513444

  19. Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation

    PubMed Central

    Kralund, Henrik H.; Ousager, Lilian; Jaspers, Nicolaas G.; Raams, Anja; Pedersen, Erling B.; Gade, Else; Bygum, Anette

    2013-01-01

    Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD) and Cockayne Syndrome (CS) are rare, recessive disorders caused by mutational defects in the Nucleotide Excision Repair (NER) pathway and/or disruption of basic cellular DNA transcription. To date, a multitude of mutations in the XPD/ERCC2 gene have been described, many of which give rise to NER- and DNA transcription related diseases, which share certain diagnostic features and few overlap patients have been described. Despite increasing understanding of the roles of XPD/ERCC2 in mammalian cells, there is still weak predictability of somatic outcome from many of these mutations. We demonstrate a patient, believed to represent an overlap between XP and TTD/CS. In addition to other organ dysfunctions, the young man presented with Photosensitivity, Ichthyosis, Brittle hair, Impaired physical and mental development, Decreased fertility and Short stature (PIBIDS) suggestive of TTD, but lacking the almost patognomonic “tiger tail” banding of the hair under polarized light. Additionally, he developed basal cell carcinoma aged 28, as well as adult onset kidney failure, features normally not associated with TTD but rather XP/CS. His freckled appearance also suggested XP, but fibroblast cultures only demonstrated x2 UV-sensitivity with expected NER and TFIIH-activity decrease. Genetic sequencing of the XPD/ERCC2 gene established the patient as heterozygote compound with a novel, N-terminal Y18H mutation and a known C-terminal (TTD) mutation, A725P. The possible interplay between gene products and the patient phenotype is discussed. PMID:25002996

  20. [Clinical analysis of cutaneous manifestations and related factors in patients with ulcerative colitis].

    PubMed

    Tian, Y; Li, J X; Wang, H H; Li, R Y; Liu, X G

    2016-07-01

    To investigate the cutaneous manifestations in patients with ulcerative colitis (UC) and related factors. Patients admitted to Department of Gastroenterology Peking University First Hospital from January 1994 to December 2014 and diagnosed as UC were retrospectively enrolled in this study. Skin disorders were confirmed by the dermatologists. Clinical data were collected and compared between patients with and without cutaneous manifestations. Among the total 373 UC patients, there were 34 cases (9.1%) with cutaneous manifestations, including 11 pyoderma gangrenosum, 8 erythema nodosum, 6 eczema, 3 psoriasis, 2 pemphigus, 1 granulomatous cheilitis, 1 ichthyosis, 1 acne rosacea, and 1 impetigo. The skin manifestations may occur after the diagnosis, simultaneously or even before the diagnosis of UC, which were 24, 7 and 3 patients respectively. The mean age in patients with skin lesions was (47.2±12.1) years, male to female ratio 0.79∶1. More patients with skin manifestations had severe activity of UC compared with non-skin group [50.0%(17/34) vs 25.1%(85/339), P=0.01]. In addition, the proportion of extensive colitis in skin lesion group was significantly higher than that in non-skin group [76.5%(26/34) vs 54.6%(185/339), P=0.04]. The cutaneous manifestations associated with UC are polymorphic, erythema nodosums and pyoderma gangrenosums are the most common skin lesions seen in UC patients. Skin lesions occur concurrently, pre or post the diagnosis of UC. Skin lesions in UC patients suggest more severe disease activity. Clinicians need to pay more attention to this group.

  1. The Effect of Multiple Sulfatase Deficiency (MSD) on Dental Development: Can We Use the Teeth as an Early Diagnostic Tool?

    PubMed

    Zilberman, Uri; Bibi, Haim

    2016-01-01

    Multiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of metabolism due to reduced catalytic activity of the different sulfatase. Affected individuals show neurologic deterioration with mental retardation, skeletal anomalies, organomegaly, and skin changes as in X-linked ichthyosis. The only organ that was not examined in MSD patients is the dentition. To evaluate the effect of the metabolic error on dental development in a patient with the intermediate severe late-infantile form of MSD (S155P). Histological and chemical study were performed on three deciduous and five permanent teeth from MSD patient and pair-matched normal patients. Tooth germ size and enamel thickness were reduced in both deciduous and permanent MSD teeth, and the scalloping feature of the DEJ was missing in MSD teeth causing enamel to break off from the dentin. The mineral components in the enamel and dentin were different. The metabolic error insults the teeth in the stage of organogenesis in both the deciduous and permanent dentition. The end result is teeth with very sharp cusp tips, thin hypomineralized enamel, and exposed dentin due to the break off of enamel. These findings are different from all other types of MPS syndromes.Clinically the phenotype of intermediate severe late-infantile form of MSD appeared during the third year of life. In children of parents that are carriers, we can diagnose the disease as early as birth using X-ray radiograph of the anterior upper region or as early as 6-8 months when the first deciduous tooth erupt and consider very early treatment to ameliorate the symptoms.

  2. Impaired quality of life in patients with systemic sclerosis compared to the general population and chronic dermatoses.

    PubMed

    Bretterklieber, Agnes; Painsi, Clemens; Avian, Alexander; Wutte, Nora; Aberer, Elisabeth

    2014-09-02

    Systemic sclerosis (SSc) is a rare and potentially life threatening autoimmune disorder. The burden of disease compared to other dermatoses is unknown. The purpose of this study was to assess both the quality of life in patients with SSc and the variables that are associated with poor quality of life. Forty-one patients with systemic sclerosis (29 limited, 2 diffuse, 10 undifferentiated forms) were assessed with respect to their health status and compared to published data for the normal population, SSc patients from other studies, and patients with chronic skin diseases. For the most part, our SSc patients had better outcomes in all 8 dimensions of the SF-36 than SSc patients from other studies, and poorer scores than the healthy population and those with occupational contact dermatitis, ichthyosis, non-melanoma skin cancer, contact dermatitis, atopic eczema, chronic nail disease, vitiligo, health care workers with work-related disease, and those with other chronic skin diseases, but significantly better scores for mental health than those with nail disease, vitiligo, and health-care workers. Patients with atopic dermatitis, psoriasis and pemphigus had significantly poorer mean scores in social function and mental health than SSc patients. Patients with pemphigus were also significantly impaired in their physical and emotional roles. Patients with systemic lupus erythematosus (SLE) had the significantly poorest mean scores for QoL in all 8 domains except bodily pain and emotional role. Besides SLE, SSc is one of the most severe chronic dermatologic diseases in terms of reduced QoL. Since SSc cannot be cured, treatment strategies should include therapeutic interventions such as psychotherapy, social support, physiotherapy, and spiritual care. Their beneficial effects could be studied in future.

  3. Multiple functions of the SNARE protein Snap29 in autophagy, endocytic, and exocytic trafficking during epithelial formation in Drosophila.

    PubMed

    Morelli, Elena; Ginefra, Pierpaolo; Mastrodonato, Valeria; Beznoussenko, Galina V; Rusten, Tor Erik; Bilder, David; Stenmark, Harald; Mironov, Alexandre A; Vaccari, Thomas

    2014-01-01

    How autophagic degradation is linked to endosomal trafficking routes is little known. Here we screened a collection of uncharacterized Drosophila mutants affecting membrane transport to identify new genes that also have a role in autophagy. We isolated a loss of function mutant in Snap29 (Synaptosomal-associated protein 29 kDa), the gene encoding the Drosophila homolog of the human protein SNAP29 and have characterized its function in vivo. Snap29 contains 2 soluble NSF attachment protein receptor (SNARE) domains and a asparagine-proline-phenylalanine (NPF motif) at its N terminus and rescue experiments indicate that both SNARE domains are required for function, whereas the NPF motif is in part dispensable. We find that Snap29 interacts with SNARE proteins, localizes to multiple trafficking organelles, and is required for protein trafficking and for proper Golgi apparatus morphology. Developing tissue lacking Snap29 displays distinctive epithelial architecture defects and accumulates large amounts of autophagosomes, highlighting a major role of Snap29 in autophagy and secretion. Mutants for autophagy genes do not display epithelial architecture or secretion defects, suggesting that the these alterations of the Snap29 mutant are unlikely to be caused by the impairment of autophagy. In contrast, we find evidence of elevated levels of hop-Stat92E (hopscotch-signal transducer and activator of transcription protein at 92E) ligand, receptor, and associated signaling, which might underlie the epithelial defects. In summary, our findings support a role of Snap29 at key steps of membrane trafficking, and predict that signaling defects may contribute to the pathogenesis of cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma (CEDNIK), a human congenital syndrome due to loss of Snap29.

  4. Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis.

    PubMed

    Subramanian, Gayathri; Chaudhury, Pulkit; Malu, Krishnakumar; Fowler, Samantha; Manmode, Rahul; Gotur, Deepali; Zwerger, Monika; Ryan, David; Roberti, Rita; Gaines, Peter

    2012-01-01

    Lamin B receptor (LBR) is a bifunctional nuclear membrane protein with N-terminal lamin B and chromatin-binding domains plus a C-terminal sterol Δ(14) reductase domain. LBR expression increases during neutrophil differentiation, and deficient expression disrupts neutrophil nuclear lobulation characteristic of Pelger-Huët anomaly. Thus, LBR plays a critical role in regulating myeloid differentiation, but how the two functional domains of LBR support this role is currently unclear. We previously identified abnormal proliferation and deficient functional maturation of promyelocytes (erythroid, myeloid, and lymphoid [EML]-derived promyelocytes) derived from EML-ic/ic cells, a myeloid model of ichthyosis (ic) bone marrow that lacks Lbr expression. In this study, we provide new evidence that cholesterol biosynthesis is important to myeloid cell growth and is supported by the sterol reductase domain of Lbr. Cholesterol biosynthesis inhibitors caused growth inhibition of EML cells that increased in EML-derived promyelocytes, whereas cells lacking Lbr exhibited complete growth arrest at both stages. Lipid production increased during wild-type neutrophil maturation, but ic/ic cells exhibited deficient levels of lipid and cholesterol production. Ectopic expression of a full-length Lbr in EML-ic/ic cells rescued both nuclear lobulation and growth arrest in cholesterol starvation conditions. Lipid production also was rescued, and a deficient respiratory burst was corrected. Expression of just the C-terminal sterol reductase domain of Lbr in ic/ic cells also improved each of these phenotypes. Our data support the conclusion that the sterol Δ(14) reductase domain of LBR plays a critical role in cholesterol biosynthesis and that this process is essential to both myeloid cell growth and functional maturation.

  5. Further Insights in Trichothiodistrophy: A Clinical, Microscopic, and Ultrastructural Study of 20 Cases and Literature Review

    PubMed Central

    Ferrando, Juan; Mir-Bonafé, José M.; Cepeda-Valdés, Rodrigo; Domínguez, Anna; Ocampo-Candiani, Jorge; García-Veigas, Javier; Gómez-Flores, Minerva; Salas-Alanis, Julio C.

    2012-01-01

    Background: Trichothiodistrophy (TTD) is a rare autosomal recessive condition that is characterized by a specific congenital hair shaft dysplasia caused by deficiency of sulfur associated with a wide spectrum of multisystem abnormalities. In this article, we study clinical, microscopic, and ultrastructural findings of 20 patients with TTD with the aim to add further insights regarding to this rare condition. Additionally, analyses of our results are compared with those extracted from the literature in order to enhance its comprehensibility. Materials and Methods: Twenty cases of TTD were included: 7 from Mexico and 14 from Spain. Clinical, microscopic, scanning electron microscopy (SEM) studies and X-ray microanalysis (XrMa) were carried out in all of them. Genetic studies were performed in all seven Mexican cases. Patients with xeroderma pigmentosum and xeroderma pigmentosum/TTD-complex were excluded. Results: Cuticular changes and longitudinal crests of the hair shaft were demonstrated. These crests were irregular, disorganized, following the hair longest axis. Hair shaft sulfur deficiency was disposed discontinuously and intermittently rather than uniformly. This severe decrease of sulfur contents was located close to the trichoschisis areas. Only five patients did not show related disturbances. Micro-dolichocephaly was observed in five cases and represented the most frequent facial dysmorphism found. It is also remarkable that all patients with urologic malformations also combined diverse neurologic disorders. Moreover, three Mexican sisters demonstrated the coexistence of scarce pubic vellus hair, developmental delay, onychodystrophy, and maxillar/mandibullar hypoplasia. Conclusions: TTD phenotype has greatly varied from very subtle forms to severe alterations such as neurologic abnormalities, blindness, lamellar ichthyosis and gonadal malformations. Herein, a multisystem study should be performed mandatorily in patients diagnosed with TTD. PMID:23180925

  6. Clinical comparison of human and canine atopic dermatitis using human diagnostic criteria (Japanese Dermatological Association, 2009): proposal of provisional diagnostic criteria for canine atopic dermatitis.

    PubMed

    Terada, Yuri; Nagata, Masahiko; Murayama, Nobuo; Nanko, Hiroko; Furue, Masutaka

    2011-08-01

    Atopic dermatitis (AD) is a common skin disease encountered in both humans and dogs. Canine AD can be used in the analysis of naturally occurring AD; however, details of clinical comparison have been lacking. The purpose of this study is to compare those clinical features using the human diagnostic criteria (Japanese Dermatological Association, 2009). Fifty-one dogs with canine AD were evaluated by the human criteria. Prior to this study, canine AD was basically diagnosed by the fulfillment of two authentic canine AD criteria and a positive reaction against Dermatophagoides farinae in serum immunoglobulin E levels and/or in intradermal tests. Among the human AD criteria items, behavior corresponding to pruritus was observed in all 51 dogs. Skin lesions corresponding to eczematous dermatitis were seen in 50 dogs, and symmetrical distribution of skin lesions was noted in all 51 dogs. A chronic or chronically relapsing course was observed in 50 dogs. Based on these results, the concordance rate for the criteria was 96% (49/51). Differential diagnoses of AD were also investigated in the same manner. The concordance rate for the criteria was 0% (0/69) in scabies, 2% (1/50) in pyoderma, 0% (0/50) in demodicosis, 0% (0/9) in cutaneous lymphoma, 0% (0/2) in ichthyosis, 25% (2/7) in flea allergy, 48% (24/50) in seborrheic dermatitis and 75% (3/4) in food allergy. Canine AD is thus indicated as a valuable counterpart to human AD in clinical aspects. In addition, the human AD criteria could be applicable, with some modification, as provisional diagnostic criteria for canine AD. © 2011 Japanese Dermatological Association.

  7. Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients.

    PubMed

    Pennisi, Elena Maria; Arca, Marcello; Bertini, Enrico; Bruno, Claudio; Cassandrini, Denise; D'amico, Adele; Garibaldi, Matteo; Gragnani, Francesca; Maggi, Lorenzo; Massa, Roberto; Missaglia, Sara; Morandi, Lucia; Musumeci, Olimpia; Pegoraro, Elena; Rastelli, Emanuele; Santorelli, Filippo Maria; Tasca, Elisabetta; Tavian, Daniela; Toscano, Antonio; Angelini, Corrado

    2017-05-12

    A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases. During the clinical follow-up (range: 2-44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias. The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.

  8. Lamin B receptor (LBR) regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: Implications for cholesterol biosynthesis in regulating myelopoiesis

    PubMed Central

    Subramanian, Gayathri; Chaudhury, Pulkit; Malu, Krishnakumar; Fowler, Samantha; Manmode, Rahul; Gotur, Deepali; Zwerger, Monika; Ryan, David; Roberti, Rita; Gaines, Peter

    2011-01-01

    Lamin B receptor (LBR) is a bifunctional nuclear membrane protein with N-terminal lamin B and chromatin binding domains plus a C-terminal sterol Δ14 reductase domain. LBR expression increases during neutrophil differentiation and deficient expression disrupts neutrophil nuclear lobulation characteristic of Pelger-Huët anomaly. Thus LBR plays a critical role in regulating myeloid differentiation, but how the two functional domains of LBR support this role is currently unclear. We previously identified abnormal proliferation and deficient functional maturation of promyelocytes (EPRO cells) derived from EML-ic/ic cells, a myeloid model of ichthyosis (ic) bone marrow that lacks Lbr expression. Here we provide new evidence that cholesterol biosynthesis is important to myeloid cell growth and is supported by the sterol reductase domain of Lbr. Cholesterol biosynthesis inhibitors caused growth inhibition of EML cells that increased in EPRO cells, whereas cells lacking Lbr exhibited complete growth arrest at both stages. Lipid production increased during wild-type neutrophil maturation, but ic/ic cells exhibited deficient levels of lipid and cholesterol production. Ectopic expression of a full length Lbr in EML-ic/ic cells rescued both nuclear lobulation and growth arrest in cholesterol starvation conditions. Lipid production also was rescued, and a deficient respiratory burst was corrected. Expression of just the C-terminal sterol reductase domain of Lbr in ic/ic cells also improved each of these phenotypes. Our data support the conclusion that the sterol Δ14 reductase domain of LBR plays a critical role in cholesterol biosynthesis, and that this process is essential to both myeloid cell growth and functional maturation. PMID:22140257

  9. Homozygous deletion of six genes including corneodesmosin on chromosome 6p21.3 is associated with generalized peeling skin disease.

    PubMed

    Teye, Kwesi; Hamada, Takahiro; Krol, Rafal P; Numata, Sanae; Ishii, Norito; Matsuda, Mitsuhiro; Ohata, Chika; Furumura, Minao; Hashimoto, Takashi

    2014-07-01

    Peeling skin syndrome (PSS) is a rare autosomal recessive form of ichthyosis showing skin exfoliation. PSS is divided into acral and generalized PSS, and the latter is further classified into non-inflammatory type (PSS type A) and inflammatory type (PSS type B). PSS type B is now called peeling skin disease (PSD). Different loss-of-function mutations in the corneodesmosin (CDSN) gene have been reported to cause PSD. The aim of this study was to determine genetic basis of disease in a 14-year-old Japanese patient with PSD. Immunohistochemical study showed lack of corneodesmosin (CDSN) in the skin, and standard PCR for genomic DNA failed to amplify CDSN product, suggesting CDSN defect. Multiplex ligation-dependent probe amplification and genomic quantitative real-time PCR analyses detected large homozygous deletion of 59,184bp extending from 40.6kb upstream to 13.2kb downstream of CDSN, which included 6 genes (TCF19, CCHCR1, PSORS1C2, PSORS1C1, CDSN and C6orf15). The continuous gene lost did not result in additional clinical features. Inverted repeats with 85% similarity flanking the deletion breakpoint were considered to mediate the deletion by non-homologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication. Parents were clinically unaffected and were heterozygote carriers of the same deletion, which was absent in 284 ethnically matched control alleles. We also developed simple PCR method, which is useful for detection of this deletion. Although 5 other genes were also deleted, homozygous deletion of CDSN was considered to be responsible for this PSD. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  10. Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q

    SciTech Connect

    Fink, J.K.; Wu, C.T.B.; Jones, S.M.

    1994-09-01

    Familial spastic paraplegia (FSP) (MIM No.18260) constitutes a clinically and genetically diverse group of disorders that share the primary feature of progressive, severe, lower extremity spasticity. FSP is classified according to the mode of inheritance and whether progressive spasticity occurs in isolation ({open_quotes}uncomplicated FSP{close_quotes}) or with other neurologic abnormalities ({open_quotes}complicated FSP{close_quotes}), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, or deafness. Recently, autosomal dominant, uncomplicated FSP was shown to be genetically heterogeneous and tightly linked to a group of microsatellite markers on chromosome 14q in one large kindred. We examined 126 members of a non-consanguineous North Americanmore » kindred of Irish descent. FSP was diagnosed in 31 living subjects who developed insidiously progressive gait disturbance between ages 12 and 35 years. Using genetic linkage analysis to microsatellite DNA polymorphisms, we showed that the FSP locus on chromosome 14q was exluded from linkage with the disorder in our family. Subsequently, we searched for genetic linkage between the disorder and microsatellite DNA polymorphisms spanning approximately 50% of the genome. We observed significantly positive, two-point maximum lod scores (Z) for markers on chromosome 15q: D15S128 (Z=9.70, {theta}=0.05), D15S165 (Z=3.30, {theta}=0.10), and UT511 (Z=3.86, {theta}=0.10). Our data clearly establishes that one locus for autosomal dominant, uncomplicated FSP is mapped to the pericentric region of chromosome 15q. Identifying genes responsible for chromosome 15q-linked and chromosome 14q-linked FSP will greatly advance our understanding of this condition and hopefully other inherited and degenerative brain and spinal cord disorders that are also characterized by axonal degeneration.« less

  11. A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy.

    PubMed Central

    Weeda, G; Eveno, E; Donker, I; Vermeulen, W; Chevallier-Lagente, O; Taïeb, A; Stary, A; Hoeijmakers, J H; Mezzina, M; Sarasin, A

    1997-01-01

    Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly

  12. Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy.

    PubMed Central

    Mariani, E; Facchini, A; Honorati, M C; Lalli, E; Berardesca, E; Ghetti, P; Marinoni, S; Nuzzo, F; Astaldi Ricotti, G C; Stefanini, M

    1992-01-01

    Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by photosensitivity, a high incidence of cancer in sun-exposed portions of the skin and a reduced capacity to repair the u.v.-induced DNA damage. One of the XP mutations (XP-D) has also been identified in patients affected by trichothiodystrophy (TTD), a rare autosomal recessive disease characterized by brittle hair, mental and physical retardation, peculiar face and ichthyosis. However, in these patients there is no evidence of increased skin tumour incidence. Since an impairment of cell-mediated immunity has been proposed as a co-factor in the cancer proneness of XP patients, we investigated the involvement of immune defect(s) in five XP patients, five TTD patients, their parents, and 24 TTD relatives. We evaluated the phenotype of circulating lymphocytes, natural killer (NK) cell lytic activity, target cell binding of NK cells at single cell level and the effect of interferons (IFN) alpha and beta on NK cell activity. The relative proportion of CD3+ and CD4+ circulating lymphocytes was reduced in XP but not in TTD patients. NK cell lytic activity was decreased in XP patients and their mothers, but their fathers showed normal lytic activity. NK activity varied among TTD families: four out of five patients and their relatives presented low NK cell activity, and one family was normal. In TTD family members, NK activity increased after incubation with IFN-alpha or IFN-beta, but never reached normal values. In contrast, in XP patients and their mothers, the defect was almost completely corrected after in vitro incubation with IFN-alpha or IFN-beta. Our study indicates impaired NK lytic activity in the majority of TTD and XP patients and that this defect is present also in members of their families. In addition, XP patients present a low number of circulating T cells. These multiple abnormalities, together with DNA repair defects, could be related to the increased cancer risk in XP patients

  13. Altered cellular localization and hemichannel activities of KID syndrome associated connexin26 I30N and D50Y mutations.

    PubMed

    Aypek, Hande; Bay, Veysel; Meşe, Gülistan

    2016-02-02

    Gap junctions facilitate exchange of small molecules between adjacent cells, serving a crucial function for the maintenance of cellular homeostasis. Mutations in connexins, the basic unit of gap junctions, are associated with several human hereditary disorders. For example, mutations in connexin26 (Cx26) cause both non-syndromic deafness and syndromic deafness associated with skin abnormalities such as keratitis-ichthyosis-deafness (KID) syndrome. These mutations can alter the formation and function of gap junction channels through different mechanisms, and in turn interfere with various cellular processes leading to distinct disorders. The KID associated Cx26 mutations were mostly shown to result in elevated hemichannel activities. However, the effects of these aberrant hemichannels on cellular processes are recently being deciphered. Here, we assessed the effect of two Cx26 mutations associated with KID syndrome, Cx26I30N and D50Y, on protein biosynthesis and channel function in N2A and HeLa cells. Immunostaining experiments showed that Cx26I30N and D50Y failed to form gap junction plaques at cell-cell contact sites. Further, these mutations resulted in the retention of Cx26 protein in the Golgi apparatus. Examination of hemichannel function by fluorescent dye uptake assays revealed that cells with Cx26I30N and D50Y mutations had increased dye uptake compared to Cx26WT (wild-type) containing cells, indicating abnormal hemichannel activities. Cells with mutant proteins had elevated intracellular calcium levels compared to Cx26WT transfected cells, which were abolished by a hemichannel blocker, carbenoxolone (CBX), as measured by Fluo-3 AM loading and flow cytometry. Here, we demonstrated that Cx26I30N and D50Y mutations resulted in the formation of aberrant hemichannels that might result in elevated intracellular calcium levels, a process which may contribute to the hyperproliferative epidermal phenotypes of KID syndrome.

  14. Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features.

    PubMed

    Kutkowska-Kaźmierczak, Anna; Rydzanicz, Małgorzata; Chlebowski, Aleksander; Kłosowska-Kosicka, Kamila; Mika, Adriana; Gruchota, Jakub; Jurkiewicz, Elżbieta; Kowalewski, Cezary; Pollak, Agnieszka; Stradomska, Teresa Joanna; Kmieć, Tomasz; Jakubowski, Rafał; Gasperowicz, Piotr; Walczak, Anna; Śladowski, Dariusz; Jankowska-Steifer, Ewa; Korniszewski, Lech; Kosińska, Joanna; Obersztyn, Ewa; Nowak, Wieslaw; Śledziński, Tomasz; Dziembowski, Andrzej; Płoski, Rafał

    2018-06-01

    Ichthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function. To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease. Whole exome sequencing was performed in both patients. The functional effect of prioritised variant in ELOVL1 (very-long-chain fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas chromatography-mass spectrometry in stably transfected HEK2932 cells and in cultured patient's fibroblasts. Probands shared novel heterozygous ELOVL1 p.Ser165Phe mutation (de novo in one family, while in the other family, father could not be tested). In transfected cells p.Ser165Phe: (1) reduced levels of FAs C24:0-C28:0 and C26:1 with the most pronounced effect for C26:0 (P=7.8×10 -6  vs HEK293 cells with wild type (wt) construct, no difference vs naïve HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3×10 -7 , P=1.2×10 -5 , for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2×10 -7 , P=1.9×10 -4 , respectively, comparison vs naïve HEK293). In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0 (P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls. There was a strong correlation (r=0.92, P=0.008) between the FAs profile of patient's fibroblasts and that of p.Ser165Phe transfected HEK293 cells. Serum levels of C20:0-C26:0 FAs were normal, but the C24:0/C22:0 ratio was decreased. The ELOVL1 p.Ser165Phe mutation is a likely cause of IKSHD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. [Spontaneous models of human diseases in dogs: ichthyoses as an example].

    PubMed

    André, Catherine; Grall, Anaïs; Guaguere, Éric; Thomas, Anne; Galibert, Francis

    2013-06-01

    Ichthyoses encompass a heterogeneous group of genodermatoses characterized by abnormal desquamation over the entire body due to defects of the terminal differentiation of keratinocytes and desquamation, which occur in the upper layer of the epidermis. Even though in humans more than 40 genes have already been identified, the genetic causes of several forms remain unknown and are difficult to identify in Humans. Strikingly, several purebred dogs are also affected by specific forms of ichthyoses. In the Golden retriever dog breed, an autosomal recessive form of ichthyosis, resembling human autosomal recessive congenital ichthyoses, has recently been diagnosed with a high incidence. We first characterized the disease occurring in the golden retriever breed and collected cases and controls. A genome-wide association study on 40 unrelated Golden retriever dogs, using the canine 49.000 SNPs (single nucleotide polymorphisms) array (Affymetrix v2), followed by statistical analyses and candidate gene sequencing, allowed to identify the causal mutation in the lipase coding PNPLA1 gene (patatin-like phospholipase domain-containing protein). Screening for alterations in the human ortholog gene in 10 autosomal recessive congenital ichthyoses families, for which no genetic cause has been identified thus far, allowed to identify two recessive mutations in the PNPLA1 protein in two families. This collaborative work between "human" and "canine" geneticists, practicians, histopathologists, biochemists and electron microscopy experts not only allowed to identify, in humans, an eighth gene for autosomal recessive congenital ichthyoses, but also allowed to highlight the function of this as-yet-unknown skin specific lipase in the lipid metabolism of the skin barrier. For veterinary medicine and breeding practices, a genetic test has been developed. These findings illustrate the importance of the discovery of relevant human orthologous canine genetic diseases, whose causes can be tracked

  16. Distribution of ELOVL4 in the Developing and Adult Mouse Brain

    PubMed Central

    Sherry, David M.; Hopiavuori, Blake R.; Stiles, Megan A.; Rahman, Negar S.; Ozan, Kathryn G.; Deak, Ferenc; Agbaga, Martin-Paul; Anderson, Robert E.

    2017-01-01

    ELOngation of Very Long chain fatty acids (ELOVL)-4 is essential for the synthesis of very long chain-fatty acids (fatty acids with chain lengths ≥ 28 carbons). The functions of ELOVL4 and its very long-chain fatty acid products are poorly understood at present. However, mutations in ELOVL4 cause neurodevelopmental or neurodegenerative diseases that vary according to the mutation and inheritance pattern. Heterozygous inheritance of different ELOVL4 mutations causes Stargardt-like Macular Dystrophy or Spinocerebellar Ataxia type 34. Homozygous inheritance of ELOVL4 mutations causes more severe disease characterized by seizures, intellectual disability, ichthyosis, and premature death. To better understand ELOVL4 and very long chain fatty acid function in the brain, we examined ELOVL4 expression in the mouse brain between embryonic day 18 and postnatal day 60 by immunolabeling using ELOVL4 and other marker antibodies. ELOVL4 was widely expressed in a region- and cell type-specific manner, and was restricted to cell bodies, consistent with its known localization to endoplasmic reticulum. ELOVL4 labeling was most prominent in gray matter, although labeling also was present in some cells located in white matter. ELOVL4 was widely expressed in the developing brain by embryonic day 18 and was especially pronounced in regions underlying the lateral ventricles and other neurogenic regions. The basal ganglia in particular showed intense ELOVL4 labeling at this stage. In the postnatal brain, cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, midbrain, pons, and medulla all showed prominent ELOVL4 labeling, although ELOVL4 distribution was not uniform across all cells or subnuclei within these regions. In contrast, the basal ganglia showed little ELOVL4 labeling in the postnatal brain. Double labeling studies showed that ELOVL4 was primarily expressed by neurons, although presumptive oligodendrocytes located in white matter tracts also showed labeling. Little

  17. Corneal dystrophies

    PubMed Central

    Klintworth, Gordon K

    2009-01-01

    , lipidoses, mucolipidoses), and several skin diseases (X-linked ichthyosis, keratosis follicularis spinolosa decalvans). The management of the corneal dystrophies varies with the specific disease. Some are treated medically or with methods that excise or ablate the abnormal corneal tissue, such as deep lamellar endothelial keratoplasty (DLEK) and phototherapeutic keratectomy (PTK). Other less debilitating or asymptomatic dystrophies do not warrant treatment. The prognosis varies from minimal effect on the vision to corneal blindness, with marked phenotypic variability. PMID:19236704

  18. Design and Characterization of a Human Monoclonal Antibody that Modulates Mutant Connexin 26 Hemichannels Implicated in Deafness and Skin Disorders

    PubMed Central

    Xu, Liang; Carrer, Andrea; Zonta, Francesco; Qu, Zhihu; Ma, Peixiang; Li, Sheng; Ceriani, Federico; Buratto, Damiano; Crispino, Giulia; Zorzi, Veronica; Ziraldo, Gaia; Bruno, Francesca; Nardin, Chiara; Peres, Chiara; Mazzarda, Flavia; Salvatore, Anna M.; Raspa, Marcello; Scavizzi, Ferdinando; Chu, Youjun; Xie, Sichun; Yang, Xuemei; Liao, Jun; Liu, Xiao; Wang, Wei; Wang, Shanshan; Yang, Guang; Lerner, Richard A.; Mammano, Fabio

    2017-01-01

    Background: Mutations leading to changes in properties, regulation, or expression of connexin-made channels have been implicated in 28 distinct human hereditary diseases. Eight of these result from variants of connexin 26 (Cx26), a protein critically involved in cell-cell signaling in the inner ear and skin. Lack of non-toxic drugs with defined mechanisms of action poses a serious obstacle to therapeutic interventions for diseases caused by mutant connexins. In particular, molecules that specifically modulate connexin hemichannel function without affecting gap junction channels are considered of primary importance for the study of connexin hemichannel role in physiological as well as pathological conditions. Monoclonal antibodies developed in the last three decades have become the most important class of therapeutic biologicals. Recombinant methods permit rapid selection and improvement of monoclonal antibodies from libraries with large diversity. Methods: By screening a combinatorial library of human single-chain fragment variable (scFv) antibodies expressed in phage, we identified a candidate that binds an extracellular epitope of Cx26. We characterized antibody action using a variety of biochemical and biophysical assays in HeLa cells, organotypic cultures of mouse cochlea and human keratinocyte-derived cells. Results: We determined that the antibody is a remarkably efficient, non-toxic, and completely reversible inhibitor of hemichannels formed by connexin 26 and does not affect direct cell-cell communication via gap junction channels. Importantly, we also demonstrate that the antibody efficiently inhibits hyperative mutant Cx26 hemichannels implicated in autosomal dominant non-syndromic hearing impairment accompanied by keratitis and hystrix-like ichthyosis-deafness (KID/HID) syndrome. We solved the crystal structure of the antibody, identified residues that are critical for binding and used molecular dynamics to uncover its mechanism of action. Conclusions

  19. Encapsulation and controlled release of retinol from silicone particles for topical delivery.

    PubMed

    Shields, C Wyatt; White, John P; Osta, Erica G; Patel, Jerishma; Rajkumar, Shashank; Kirby, Nickolas; Therrien, Jean-Philippe; Zauscher, Stefan

    2018-05-28

    Retinol, a derivative of vitamin A, is a ubiquitous compound used to treat acne, reduce wrinkles and protect against conditions like psoriasis and ichthyosis. While retinol is used as the primary active ingredient (AI) in many skin care formulations, its efficacy is often limited by an extreme sensitivity to degrade and toxicity at high concentrations. While microencapsulation is an appealing method to help overcome these issues, few microencapsulation strategies have made a major translational impact due to challenges with complexity, cost, limited protection of the AI and poor control of the release of the AI. We have developed a class of silicone particles that addresses these challenges for the encapsulation, protection and controlled release of retinol and other hydrophobic compounds. The particles are prepared by the sol-gel polymerization of silane monomers, which enables their rapid and facile synthesis at scale while maintaining a narrow size distribution (i.e., CV < 20%). We show that our particles can: (i) encapsulate retinol with high efficiency (>85%), (ii) protect retinol from degradation (yielding a half-life 9× greater than unencapsulated retinol) and (iii) slowly release retinol over several hours (at rates from 0.14 to 0.67 μg cm -2  s -1/2 ). To demonstrate that the controlled release of retinol from the particles can reduce irritation, we performed a double blind study on human subjects and found that formulations containing our particles were 12-23% less irritating than identical formulations containing Microsponge® particles (an industry standard by Amcol, Inc.). To show that the silicone particles can elicit a favorable biological response, similar to the Microsponge® particles, we applied both formulations to reconstructed human epidermal tissues and found an upregulation of keratin 19 (K19) and a downregulation of K10, indicating that the reduced irritation observed in the human study was not caused by reduced activity. We

  20. Diseases associated with hidranitis suppurativa: part 2 of a series on hidradenitis.

    PubMed

    Scheinfeld, Noah

    2013-06-15

    Hidradenitis suppurativa (HS), a pathologic follicular disease, impacts patients' lives profoundly and usually occurs in isolation. The diseases with the strongest association are obesity, depression, and pain. HS is associated with many diseases including acne conglobata (AC), dissecting cellulitis, pilonidal cysts, and obesity. Pyoderma fistulans sinifica (fox den disease) appears to be the same entity as Hurley Stage 2 of 3 HS. The rate of acne vulgaris in HS patients mirrors unaffected controls. The most common, albeit still uncommon, association is with seronegative, haplotype unlinked arthritis (most importantly B27), in particular spondolyarthritis. Crohn disease and HS occur together at a rate that varies from 0.6% to 38% in retrospective cases series. Ulcerative colitis occurred with HS in 14% of patients in one series. The next most common association is with pyoderma gangrenosum, but this association is likely under-reported. Synovitis-Acne-Pustulosis Hyperostosis-Osteitis (SAPHO) syndrome, which is rare, has more than 10 reports linking it to HS. Nine case reports have linked Dowling-Degos disease (DDD) to HS and two reports related HS to Fox-Fordyce disease (FF), but because both occur in the axilla this might be a mere coincidence. HS is rarely associated with ophthalmic pathology. Specifically, more than 5 reports link it to Keratitis-Ichthyosis-Deafness syndrome (KID); greater than10 cases link it to interstitial keratitis and 2 cases are linked to Behçet's disease. The presence of proteinuria and acute nephritis link HS to the kidney, especially since and reports have documented resolution of HS after renal transplant. Florid steatocystoma multiplex, Sjogren Syndrome, and HS have been linked and their reports likely underestimate their coincidence because all these entities involve occlusion (albeit by different mechanisms). Three reports link HS and amyloid, but both share some common genetic underpinnings and thus the coincidence of these

  1. Topical tacrolimus for atopic dermatitis.

    PubMed

    Cury Martins, Jade; Martins, Ciro; Aoki, Valeria; Gois, Aecio F T; Ishii, Henrique A; da Silva, Edina M K

    2015-07-01

    .98, 1 study, n = 139, low-quality evidence), but the effects were equivocal when evaluating BSA. In the comparison of tacrolimus 0.03% with moderate-to-potent corticosteroids, no difference was found in most of the outcomes measured (including physician's and participant's assessment and also for the secondary outcomes), but in two studies, a marginal benefit favouring the corticosteroid group was found for the EASI and BSA scores.Burning was more frequent in those using calcineurin inhibitors than those using corticosteroid tacrolimus 0.03% (RR 2.48, 95% CI 1.96 to 3.14, 5 studies, 1883 participants, high-quality evidence), but no difference was found for skin infections. Symptoms observed were mild and transient. The comparison between the two calcineurin inhibitors (pimecrolimus and tacrolimus) showed the same overall incidence of adverse events, but with a small difference in the frequency of local effects.Serious adverse events were rare; occurred in both the tacrolimus and corticosteroid groups; and in most cases, were considered to be unrelated to the treatment. No cases of lymphoma were noted in the included studies nor in the non-comparative studies. Cases were only noted in spontaneous reports, cohorts, and case-control studies. Systemic absorption was rarely detectable, only in low levels, and this decreased with time. Exception is made for diseases with severe barrier defects, such as Netherton's syndrome, lamellar ichthyosis, and a few others, with case reports of a higher absorption. We evaluated clinical trials; case reports; and in vivo, in vitro, and animal studies; and didn't find any evidence that topical tacrolimus could cause skin atrophy. Tacrolimus 0.1% was better than low-potency corticosteroids, pimecrolimus 1%, and tacrolimus 0.03%. Results were equivocal when comparing both dose formulations to moderate-to-potent corticosteroids. Tacrolimus 0.03% was superior to mild corticosteroids and pimecrolimus. Both tacrolimus formulations seemed to be