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Sample records for family syndrome kindreds

  1. Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families.

    PubMed

    Marshall, J D; Ludman, M D; Shea, S E; Salisbury, S R; Willi, S M; LaRoche, R G; Nishina, P M

    1997-12-12

    We describe a large Acadian kindred including 8 Alstrom Syndrome (AS) patients, with an age range of 4 to 26 at the time of clinical assessment. The affected subjects come from 5 nuclear families within this kindred. The phenotype includes early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Non-insulin dependent diabetes mellitus and growth retardation appear to be age-related manifestations that occur post-adolescence. Younger affected children are not overtly hyperglycemic and are normal or above average height for age. Although the AS patients in kindred 1 presumably carry the same mutation, many manifestations of the disease are variable. For example, of the 8 children in the Acadian kindred, 4 have scoliosis, 2 have had infantile cardiomyopathy, 2 are hypothyroid, 1 has had hepatic dysfunction and is hypertensive, and 4 have developed asthma. Seven subjects described in this kindred exhibit developmental delay. One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested. The clinical data from this large Acadian kindred, together with information obtained from 4 additional AS patients in 3 unrelated kindreds, confirm and extend clinical observations previously described. In addition, the Acadian kindred with multiple affected individuals, probably arising from a common founder, should allow for identification of the chromosomal localization of a gene causing AS.

  2. Genetic heterogeneity among kindreds with Alport syndrome.

    PubMed Central

    Hasstedt, S J; Atkin, C L; San Juan, A C

    1986-01-01

    Twenty-three kindreds were ascertained through patients at renal clinics at University of Utah Associated Hospitals. Urinalysis indicated glomerulonephritis in 231 of 997 examined kindred members; medical records documented kidney disease consistent with glomerulonephritis in 88 unexamined kindred members. Renal biopsies of 35 persons in a subset of 14 kindreds showed ultrastructural changes and absence of immune phenomena consistent with the diagnosis of Alport syndrome. End-stage renal disease (ESRD) had occurred in 72 (49%) of 148 known affected males and in 13 (8%) of 171 known affected females. No father-son affected pairs occurred in any of the kindreds; 84% of daughters of affected fathers were affected, and 49% of sons and 48% of daughters of affected mothers were affected. One of three phenotypes (juvenile Alport syndrome with deafness, adult Alport syndrome with deafness, or adult Alport syndrome without deafness or other defects) occurred in each of the 23 kindreds. We applied likelihood analysis to test for genetic heterogeneity underlying the phenotypic heterogeneity. In the first application (the admixture test), we tested for the occurrence of two forms of the disease without specifying which kindred had which form; we found insufficient evidence of admixture. In the second application (the predivided-sample test), we tested for genetic heterogeneity expressed as phenotypic heterogeneity. Kindreds were successively divided into two subgroups, with admission to the first subgroup dependent upon: (1) having greater than or equal to 2 males with ESRD, (2) occurrence of deafness in most nephrologically affected male family members, and (3) intrakindred mean age of ESRD in males later than age 31. Weak evidence of heterogeneity was found for category (1); stronger evidence of heterogeneity was found for category (3). Penetrance of microscopic hematuria in female heterozygotes was estimated as 82% overall, 85% for adult Alport syndrome, and 28% for

  3. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.

    PubMed Central

    Stratakis, C A; Carney, J A; Lin, J P; Papanicolaou, D A; Karl, M; Kastner, D L; Pras, E; Chrousos, G P

    1996-01-01

    Carney complex is an autosomal dominant syndrome characterized by multiple neoplasias, including myxomas at various sites and endocrine tumors, and lentiginosis. The genetic defect(s) responsible for the complex remain(s) unknown. We studied 101 subjects, including 51 affected members, from 11 North American kindreds with Carney complex. Blood samples were collected from patients and their family members. Hospital records, photographs, and tissue specimens of deceased individuals were reviewed. DNA was extracted from blood samples, patient-derived cell lines, and/or paraffin-embedded tissues. Linkage analysis was performed with highly polymorphic microsatellite markers, distributed over areas of the human genome harboring the most likely candidate genes. The most prevalent clinical manifestation in patients with Carney complex was spotty skin pigmentation, similar to that observed in Peutz-Jeghers and other lentiginosis syndromes. Skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 62, 30, 31 and 8 percent of the patients, respectively. Linkage was obtained for three markers on the short arm of chromosome 2 (2p16), with a maximum two-point lod score of 5.97 at theta = 0.03 for the marker CA-2 (odds in favor of linkage 10(6):1. The flanking markers CA7 and D2S378 defined a region of approximately 6.4 cM that is likely to contain the gene(s) associated with Carney complex. Candidate genes in the proximity, including the propiomelanocortin and the DNA-mismatch repair hMSH2 genes, were excluded. We conclude that the genetic defect(s) responsible for Carney complex map(s) to the short arm of chromosome 2 (2p16). This region has exhibited cytogenetic aberrations in atrial myxomas associated with the complex, and has been characterized by microsatellite instability in human neoplasias. PMID:8609225

  4. Byler-like familial cholestasis in an extended kindred.

    PubMed

    Bourke, B; Goggin, N; Walsh, D; Kennedy, S; Setchell, K D; Drumm, B

    1996-09-01

    Progressive familial intrahepatic cholestasis (PFIC) occurs in many communities and races. A form of PFIC in five children from two consanguineous marriages in an Irish kindred is described. In addition, a review of clinical information from the records of three deceased members of the kindred strongly implies that they also suffered from PFIC. The children had a history of neonatal diarrhoea, sepsis, and intermittent jaundice that ultimately became permanent. They suffered intractable pruritus and growth retardation. Despite evidence of severe cholestasis, serum gamma-glutamyl transferase and cholesterol were normal in these children. Sweat sodium concentration were raised in three children. Liver histology showed severe intrahepatic cholestasis and hepatocellular injury. Urinary bile acid analysis revealed a non-specific pattern consistent with chronic cholestasis. These children suffer from a form of PFIC remarkably similar to that occurring in members of the Byler kindred.

  5. Families of Orphans: Relation and Disrelation in Octavia Butler's "Kindred."

    ERIC Educational Resources Information Center

    Rushdy, Ashraf H. A.

    1993-01-01

    Discusses the acute representations of familial and historical relations as depicted in Octavia Butler's novel, "Kindred." Suggests that the novel is best understood as a novel of memory, functioning as a means of reconstructing a sense of place and home. (HB)

  6. Clinical analysis of a large kindred with the pallister ulnar-mammary syndrome

    SciTech Connect

    Bamshad, M.; Root, S.; Carey, J.C.

    1996-11-11

    The ulnar-mammary syndrome (UMS) is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies. We present the clinical descriptions of 33 members of a six generation kindred with UMS. The number of affected individuals in this family is more than the sum of all previously reported cases of UMS. The clinical expression of UMS is highly variable. While most patients have limb deficiencies, the range of abnormalities extends from hypoplasia of the terminal phalanx of the 5th digit to complete absence of the ulna and 3rd, 4th, and 5th digits. Moreover, affected individuals may have posterior digital duplications with or without contralateral limb deficiencies. Apocrine gland abnormalities range from diminished axillary perspiration with normal breast development and lactation, to complete absence of the breasts and no axillary perspiration. Dental abnormalities include misplaced or absent teeth. Affected males consistently undergo delayed puberty, and both sexes have diminished to absent axillary hair. Imperforate hymen were seen in some affected women. A gene for UMS was mapped to chromosome area 12q23-q24.1. A mutation in the gene causing UMS can interfere with limb patterning in the proximal/distal, anterior/posterior, and dorsal/ventral axes. This mutation disturbs development of the posterior elements of forearm, wrist, and hand while growth and development of the anterior elements remain normal. 24 refs., 4 figs., 1 tab.

  7. Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review.

    PubMed

    da-Silva, E O

    1991-07-01

    Two large kindreds with Waardenburg I syndrome are described. The total number of affected individuals is 73. The major manifestations are telecanthus (the only constant anomaly in all cases), prominent nasal root, round or square tip of nose, hypoplastic alae, smooth philtrum, bushy eyebrows with synophrys, sensorineural deafness, heterochromia or hypoisochromia iridis, hypopigmented ocular fundus, white forelock, premature greying, and hypopigmented skin lesions. These and other aspects of the syndrome, associated findings, frequency, genetic heterogeneity, pathogenesis, animal models, and gene linkage and mapping are reviewed briefly.

  8. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region

    SciTech Connect

    Kamino, K.; Anderson, L.; O'dahl, S.; Nemens, E.; Bird, T.D.; Schellenberg, G.D.; Wijsman, E.M.; Kukall, W.; Larson, E. ); Heston, L.L.

    1992-11-01

    A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu[yields]Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu[yields]Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambigously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond [theta] = .10 for the Volga German kindreds, [theta] = .20 for early-onset non-Volga Germans, and [theta] = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. 49 refs., 6 figs., 4 tabs.

  9. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region

    PubMed Central

    Kamino, Kouzin; Orr, Harry T.; Payami, Haydeh; Wijsman, Ellen M.; Alonso, Ma. Elisa; Pulst, Stefan M.; Anderson, Leojean; O'dahl, Sheldon; Nemens, Ellen; White, June A.; Sadovnick, Adele D.; Ball, Melvyn J.; Kaye, Jeffery; Warren, Andrew; McInnis, Melvin; Antonarakis, Stylianos E.; Korenberg, Julie R.; Sharma, Vikram; Kukull, Walter; Larson, Eric; Heston, Leonard L.; Martin, George M.; Bird, Thomas D.; Schellenberg, Gerard D.

    1992-01-01

    A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu→Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis–Dutch type Glu→Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambiguously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond θ = .10 for the Volga German kindreds, θ = .20 for early-onset non-Volga Germans, and θ = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. ImagesFigure 4p1009-a PMID:1415269

  10. Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.

    PubMed

    Carbone, Michele; Flores, Erin G; Emi, Mitsuru; Johnson, Todd A; Tsunoda, Tatsuhiko; Behner, Dusty; Hoffman, Harriet; Hesdorffer, Mary; Nasu, Masaki; Napolitano, Andrea; Powers, Amy; Minaai, Michael; Baumann, Francine; Bryant-Greenwood, Peter; Lauk, Olivia; Kirschner, Michaela B; Weder, Walter; Opitz, Isabelle; Pass, Harvey I; Gaudino, Giovanni; Pastorino, Sandra; Yang, Haining

    2015-12-01

    We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

  11. A new autosomal recessive congenital contractural syndrome in an Israeli Bedouin kindred.

    PubMed

    Landau, Daniella; Mishori-Dery, Anat; Hershkovitz, Reli; Narkis, Ginat; Elbedour, Khalil; Carmi, Rivka

    2003-02-15

    We describe 23 cases with a syndrome of congenital contractures belonging to a large, inbred Israeli-Bedouin kindred. The phenotype described is similar to the Finnish type lethal congenital contracture syndrome yet differs in the following ways: by some additional craniofacial/ocular findings, by the lack of hydrops, multiple pterygia, and fractures, and by the normal duration of pregnancy. The major unique and previously undescribed clinical feature in our patients is a markedly distended urinary bladder as well as other urinary abnormalities. The vast majority of the cases died shortly after birth. Sonographic prenatal diagnosis was possible as early as 15 weeks gestation by demonstrating fetal akinesia, limb contractures, hydramnios, and distended urinary bladder. Linkage to 5q and 9q34 loci has been excluded.

  12. Familial idiopathic gonadotropin deficiency not linked to gene for gonadotropin-releasing hormone (GnRH) in Brazilian kindred

    SciTech Connect

    Faraco, J.; Francke, U.; Toledo, S.

    1994-09-01

    Familial idiopathic gonadotropin deficiency (FIGD) is an autosomal recessive disorder which results in failure to develop secondary sexual characteristics. The origin is a hypothalamic defect resulting in insufficient secretion of gonadotropin-releasing hormone GnRH (also called LHRH, luteinizing hormone releasing hormone) and follicle-stimuating hormone (FSH). FIGD has been determined to be a separate entity from Kallmann syndrome which presents with hypogonadism as well as anosmia. The FIGD phenotype appears to be analogous to the phenotype of the hpg (hypogonadal) mouse. Because the hpg phenotype is the result of a structurally abnormal GnRH gene, we have studied the GnRH gene in individuals from a previously reported Brazilian FIGD family. An informative dimorphic marker in the signal peptide sequence of the GnRH gene allowed assessment of linkage between the disease gene and the GnRH locus in this pedigree. We have concluded that the GnRH locus is not linked to the disease-causing mutation in these hypogonadal individuals. Recent evidence suggests that neuropeptide Y (NPY) may play a role in the initiation of puberty. We hypothesize that mutations in NPY may result in failure to secrete GnRH. We have characterized three diallelic frequent-cutter restriction fragment length polymorphisms within the human NPY locus, and are currently using these markers to determine if the NPY gene is linked to, and possibly the site of the disease mutation in this kindred.

  13. The clinical utility of genetic testing in breast cancer kindreds: a prospective study in families without a demonstrable BRCA mutation.

    PubMed

    Møller, Pål; Stormorken, Astrid; Holmen, Marit Muri; Hagen, Anne Irene; Vabø, Anita; Mæhle, Lovise

    2014-04-01

    We report prospectively observed risk for breast cancer in breast cancer kindreds without a demonstrable BRCA1/2 mutation. According to family history, the optimal available member(s) of each breast cancer kindred attending our clinic was tested for BRCA mutations. Women in families without a demonstrable BRCA mutation were subjected to annual mammography. BRCA mutations were demonstrated in 496/2,118 (23 %) breast cancer kindreds. In families without a demonstrable BRCA mutation, a total of 3,161 healthy women aged 25-59 years were prospectively followed for 24,808 observation years. Sixty-four cancers were observed, compared to 34.0 expected (p < 0.01), arriving at a 7.9 % cumulative risk at age 60 compared to 4.0 % in the population [relative risk (RR) = 2.0]. Women with one mother or sister affected ≤50 years and with no other close relatives with breast cancer did not have increased risk (0 cancers observed and 0.6 expected at age 40, 11 cancers observed and 7.9 expected at age 60, p > 0.05). Excluding these, cumulative risk at 60 years was 8.8 % (RR = 2.2). The highest cumulative risk at 60 years was 11.4 %, found in families with two cases ≤55 years (RR = 2.8). In breast cancer kindreds without a demonstrable BRCA mutation, the risk for breast cancer in female first degree relatives was about twice the risk in the general population. Women with one early affected relative only did not have increased risk for early onset breast cancer, while those with more than one young affected relative had close to three times population risk.

  14. Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome.

    PubMed Central

    Viljoen, D; Ramesar, R

    1992-01-01

    A previously unreported family in which seven members in two generations have Beckwith-Wiedemann syndrome (BWS) is documented. Paternal imprinting of the gene responsible for BWS is involved as the mechanism responsible for the aberrant inheritance pattern in this kindred. A review of published reports showed 27 previously published pedigrees with two or more affected subjects with BWS. Paternal imprinting would explain the non-mendelian inheritance of BWS in all but four kindreds. The latter families are examined in more detail and in only one example is the evidence against imprinting totally unexplained. Images PMID:1583639

  15. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance

    PubMed Central

    Bellido, Fernando; Pineda, Marta; Aiza, Gemma; Valdés-Mas, Rafael; Navarro, Matilde; Puente, Diana A.; Pons, Tirso; González, Sara; Iglesias, Silvia; Darder, Esther; Piñol, Virginia; Soto, José Luís; Valencia, Alfonso; Blanco, Ignacio; Urioste, Miguel; Brunet, Joan; Lázaro, Conxi; Capellá, Gabriel; Puente, Xose S.; Valle, Laura

    2016-01-01

    Purpose: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers. Genet Med 18 4, 325–332. Methods: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing. Genet Med 18 4, 325–332. Results: Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors. Genet Med 18 4, 325–332. Conclusion: Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations. Genet Med 18 4, 325–332. PMID:26133394

  16. X-linked inheritance of Alport syndrome: family P revisited.

    PubMed Central

    Hasstedt, S J; Atkin, C L

    1983-01-01

    Likelihood analysis using two autosomal/X-linked mixed models confirmed that Alport syndrome is an X-linked dominant disease in a large Utah kindred, family P. The penetrance was estimated as .85 in females and 1.0 in males. Previously reported abnormal segregation ratios were reexamined. No excess of affected offspring of affected parents was found. Nor was the penetrance in daughters of asymptomatic carrier mothers found to be lower than in the daughters of symptomatic mothers, although the sample size was small. However, there was an unexplained deficiency of sons of affected fathers. There was no deficiency of sons of affected mothers, nor was there a deficiency of males in the kindred. PMID:6650503

  17. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds.

    PubMed

    Tichomirowa, Maria A; Lee, Misu; Barlier, Anne; Daly, Adrian F; Marinoni, Ilaria; Jaffrain-Rea, Marie-Lise; Naves, Luciana A; Rodien, Patrice; Rohmer, Vincent; Faucz, Fabio Rueda; Caron, Philippe; Estour, Bruno; Lecomte, Pierre; Borson-Chazot, Françoise; Penfornis, Alfred; Yaneva, Maria; Guitelman, Mirtha; Castermans, Emily; Verhaege, Catherine; Wémeau, Jean-Louis; Tabarin, Antoine; Fajardo Montañana, Carmen; Delemer, Brigitte; Kerlan, Veronique; Sadoul, Jean-Louis; Cortet Rudelli, Christine; Archambeaud, Françoise; Zacharieva, Sabine; Theodoropoulou, Marily; Brue, Thierry; Enjalbert, Alain; Bours, Vincent; Pellegata, Natalia S; Beckers, Albert

    2012-06-01

    Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

  18. A{sup -2} {yields} G transition at the 3{prime} acceptor splice site of IVS17 characterizes the COL2A1 gene mutation in the original Stickler syndrome kindred

    SciTech Connect

    Williams, C.J.; Ganguly, A.; Considine, E.

    1996-06-14

    Hereditary progressive arthro-ophthalmopathy, or {open_quotes}Stickler syndrome,{close_quotes} is an autosomal dominant osteochondrodysplasia characterized by a variety of ocular and skeletal anomalies which frequently lead to retinal detachment and precocious osteoarthritis. A variety of mutations in the COL2A1 gene have been identified in {open_quotes}Stickler{close_quotes} families; in most cases studied thus far, the consequence of mutation is the premature generation of a stop codon. We report here the characterization of a COL2A1 gene mutation in the original kindred described by Stickler et al. Conformational sensitive gel electrophoresis (CSGE) was used to screen for mutations in the entire COL2A1 gene in an affected member from the kindred. A prominent heteroduplex species was noted in the polymerase chain reaction (PCR) product from a region of the gene including exons 17 to 20. Direct sequencing of PCR-amplified genomic DNA resulted in the identification of a base substitution at the A{sup -2} position of the 3{prime} splice acceptor site of IVS17. Sequencing of DNA from affected and unaffected family members confirmed that the mutation segregated with the disease phenotype. Reverse transcriptase-PCR analysis of poly A+ RNA demonstrated that the mutant allele utilized a cryptic splice site in exon 18 of the gene, eliminating 16 bp at the start of exon 18. This frameshift eventually results in a premature termination codon. These findings are the first report of a splice site mutation in classical Stickler syndrome and they provide a satisfying historical context in which to view COL2A1 mutations in this dysplasia. 25 refs., 3 figs., 1 tab.

  19. Genetic mapping of the gene for Usher syndrome: Linkage analysis in a large Samaritan kindred

    SciTech Connect

    Bonne-Tamir, B.; Korostishevsky, M.; Kalinsky, H.; Seroussi, E.; Beker, R.; Weiss, S. ); Godel, V. )

    1994-03-01

    Usher syndrome is a group of autosomal recessive disorders associated with congenital sensorineural deafness and progressive visual loss due to retinitis pigmentosa. Sixteen members of the small inbred Samaritan isolate with autosomal recessive deafness from 59 individuals including parents and affected and nonaffected sibs were typed for markers on chromosomes 1q and 11q for which linkage has recently been established for Usher syndrome types II and I. Statistically significant linkage was observed with four markers on 11q (D11S533, D11S527, OMP, and INT2) with a maximum six-point location score of 11.61 at the D11S533 locus. Analysis of haplotypes supports the notion that the mutation arose only once in an ancestral chromosome carrying a specific haplotype. The availability of markers closely linked to the disease locus allows indirect genotype analysis and identifies all carriers of the gene within the community. Furthermore, the detection of complete linkage disequilibrium between the D11S533 marker and the Usher gene suggests that these loci are either identical or adjacent and narrows the critical region to which physical mapping efforts are currently directed. 35 refs., 2 figs., 6 tabs.

  20. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?

    PubMed

    Aldea, Anna; Campistol, Josep M; Arostegui, Juan I; Rius, Josefa; Maso, Montserrat; Vives, Jordi; Yagüe, Jordi

    2004-01-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring short attacks of fever and serositis. Secondary AA amyloidosis is the worst complication of the disease and often determines the prognosis. The MEFV gene, on chromosome 16p13.3, is responsible for the disease and around 30 mutations have been reported to date. Colchicine is the standard FMF treatment today, and prevents both attacks and amyloid deposition in 95% of patients. Here we describe a three-generation Spanish kindred with five family members affected by a severe periodic inflammatory disorder associated with renal AA amyloidosis and colchicine unresponsiveness. Clinical diagnosis of definite FMF disease was made based on the Tel-Hashomer criteria set. Genetic analyses revealed that all subjects were heterozygous for the new H478Y MEFV variant, segregating with the disease. In addition, mutations in the TNFRSF1A and CIAS1/PYPAF1/NALP3 genes, related to the dominantly inherited autoinflammatory periodic syndromes, were ruled out. However, the dominant inheritance of the disease, the long fever episodes with a predominant joint involvement, and the resistance to colchicine in these patients raise the question of whether the periodic syndrome seen in this kindred is a true FMF disease with unusual manifestations or rather another MEFV-associated periodic syndrome. We conclude that the new H478Y MEFV mutation is the dominant pathological variant causing the inflammatory periodic syndrome in this kindred and that full-length analyses of the MEFV gene are needed to obtain an adequate diagnosis of patients with clinical suspicion of a hereditary periodic fever syndrome, especially those from non-ancestral populations.

  1. The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

    PubMed

    Ozantürk, Ayşegül; Marshall, Jan D; Collin, Gayle B; Düzenli, Selma; Marshall, Robert P; Candan, Şükrü; Tos, Tülay; Esen, İhsan; Taşkesen, Mustafa; Çayır, Atilla; Öztürk, Şükrü; Üstün, İhsan; Ataman, Esra; Karaca, Emin; Özdemir, Taha Reşid; Erol, İlknur; Eroğlu, Fehime Kara; Torun, Deniz; Parıltay, Erhan; Yılmaz-Güleç, Elif; Karaca, Ender; Atabek, M Emre; Elçioğlu, Nursel; Satman, İlhan; Möller, Claes; Muller, Jean; Naggert, Jürgen K; Özgül, Rıza Köksal

    2015-01-01

    Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations

  2. Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): Codon 178 mutation and codon 129 polymorphism

    SciTech Connect

    Medori, R.; Tritschler, H.J. )

    1993-10-01

    Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp) [yields] AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. The authors confirmed the 178[sup Asn] mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologic findings associated with 178[sup Asn] reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Straeussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129[sup Met/Val]. Moreover, of five 178[sup Asn] individuals who are above age-at-onset range and who are well, two have 129[sup Met] and three have 129[sup Met/Val], suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178[sup Asn] mutation. 32 refs., 5 figs., 1 tab.

  3. A systematic search for linkage with nonsyndromic recessive deafness in two large Middle Eastern inbred kindreds excludes more than 30% of the genome

    SciTech Connect

    Weiss, S.; Korostishevsky, M.; Frydman, M.

    1994-09-01

    It has been estimated that as many as 35 loci may individually cause autosomal recessive non-syndromic deafness. The extreme genetic heterogeneity, limited clinical differentiation and phenotypic assortative mating in many western countries make many families unsuitable for genetic linkage studies. Recently the first of those loci was mapped (to 13q) in two consanguineous families from northern Tunisia. We are studying two large highly consanguineous Middle Eastern kindreds (a total of 26 deaf in 98 sampled individuals). Examination in each family showed no evidence of clinical heterogeneity and indicated an uncomplicated profound bilateral sensorineural deafness. We have been able to exclude the 13q locus as the cause of deafness in each kindred and have also excluded such `candidate` loci as regions as those causing Usher`s syndrome type 1 (11q13)(11p), Usher`s syndrome type II (1q32-q41), Waardenburg syndrome type I (2q37), branchio-oto-renal syndrome (8q12-q13), Monge`s deafness (5q31), and Treacher Collins syndrome (5q31.3-q33.3). To date, no lod scores greater than 1 have been obtained in either kindred using 150 RFLT`s, VNTR`s and highly polymorphic microsatellite markers (CA repeats and tetranucleotides). By Morton`s criterion a minimum of 30% of the autosomal genome can be excluded for each kindred separately.

  4. Small nerve fibres, small hands and small feet: a new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel NaV1.7 mutation.

    PubMed

    Hoeijmakers, Janneke G J; Han, Chongyang; Merkies, Ingemar S J; Macala, Lawrence J; Lauria, Giuseppe; Gerrits, Monique M; Dib-Hajj, Sulayman D; Faber, Catharina G; Waxman, Stephen G

    2012-02-01

    The Na(V)1.7 sodium channel is preferentially expressed within dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. Gain-of-function variants of Na(V)1.7 have recently been described in patients with painful small fibre neuropathy and no other apparent cause. Here, we describe a novel syndrome of pain, dysautonomia, small hands and small feet in a kindred carrying a novel Na(V)1.7 mutation. A 35-year-old male presented with erythema and burning pain in the hands since early childhood, later disseminating to the feet, cheeks and ears. He also experienced progressive muscle cramps, profound sweating, bowel disturbances (diarrhoea or constipation), episodic dry eyes and mouth, hot flashes, and erectile dysfunction. Neurological examination was normal. Physical examination was remarkable in revealing small hands and feet (acromesomelia). Blood examination and nerve conduction studies were unremarkable. Intra-epidermal nerve fibre density was significantly reduced compared to age- and sex-matched normative values. The patient's brother and father reported similar complaints including distal extremity redness and pain, and demonstrated comparable distal limb under-development. Quantitative sensory testing revealed impaired warmth sensation in the proband, father and brother. Genetic analysis revealed a novel missense mutation in the SCN9A gene encoding sodium channel Na(V)1.7 (G856D; c.2567G > A) in all three affected subjects, but not in unaffected family members. Functional analysis demonstrated that the mutation hyperpolarizes (-9.3 mV) channel activation, depolarizes (+6.2 mV) steady-state fast-inactivation, slows deactivation and enhances persistent current and the response to slow ramp stimuli by 10- to 11-fold compared with wild-type Na(V)1.7 channels. Current-clamp analysis of dorsal root ganglion neurons transfected with G856D mutant channels demonstrated depolarized resting potential, reduced current threshold

  5. A family with Alport's syndrome

    PubMed Central

    Jain, P.

    1970-01-01

    Alport's syndrome has been diagnosed in members of four successive generations of one family. Renal biopsy was performed in two of these patients. The syndrome is briefly reviewed. ImagesFig. 2 PMID:5416510

  6. Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations.

    PubMed

    Behrens, Maria I; Brüggemann, Norbert; Chana, Pedro; Venegas, Pablo; Kägi, Marianne; Parrao, Teresa; Orellana, Patricia; Garrido, Cristian; Rojas, Cecilia V; Hauke, Jan; Hahnen, Eric; González, Rafael; Seleme, Nicolas; Fernández, Verónica; Schmidt, Alexander; Binkofski, Ferdinand; Kömpf, Detlef; Kubisch, Christian; Hagenah, Johann; Klein, Christine; Ramirez, Alfredo

    2010-09-15

    We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages ∼10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 ± 5.5 (mean ± SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation.

  7. Genetic and genealogic study of 33 Finnish HNPCC kindreds

    SciTech Connect

    Nystroem-Lahti, M; Peltomaeki, P.; Aaltonen, L.A.

    1994-09-01

    Two susceptibility loci for hereditary nonpolyposis colorectal cancer (HNPCC) have been identified: MSH2 on chromosome 2p and MLH1 on chromosome 3p. This study focuses on the role of the latter locus in 33 Finnish HNPCC kindreds. Of 9 families in which linkage studies were possible, 8 revealed linkage to markers on 3p. A haplotype of alleles from 9 loci extending 10 cM around MLH1 was conserved in 5 kindreds. All families with the shared large haplotype as well as two other 3p-linked families with different disease haplotypes showed an identical germline mutation of MLH1. The mutation consists of a heterozygous deletion of 165 bp corresponding to an exon. An additional 24 kindreds that could not be studied for linkage were tested for the presence of the above described deletion, and the mutation was found in 6. The ancestries of all kindreds were traced 3 to 13 generations back using data from the church parish registers. Of the 13 families with the 165 bp deletion in MLH1, 10 originated in a limited area in south-central Finland. At least 8 of these kindreds had a common ancestry. The remaining kindreds with the MLH1 mutation originated from another small region some 200 km away. The kindreds that did not show the characteristic germline mutation originated more evenly in different parts of the country. Our results suggest that a single MLH1 mutation is a widespread cause of HNPCC in the Finnish population.

  8. Deletion of exon 3 of the insulin receptor gene in a kindred with a familial form of insulin resistance

    SciTech Connect

    Wertheimer, E.; Barbetti, F.; Accili, D.; Taylor, S.I.; Litvin, Y.; Ebstein, R.P.; Bennet, E.R.

    1994-05-01

    Molecular scanning techniques, such as denaturing gradient gel electrophoresis (DGGE), greatly facilitate screening candidate genes for mutations. The authors have used DGGE to screen for mutations in the insulin receptor gene in a family in which four of five daughters were affected by type A insulin resistance in association with acanthosis nigricans and hyperandrogenism. DGGE did not detect mutations in any of the 22 exons of the insulin receptor gene. Nevertheless, Southern blot analysis suggested that there was a deletion of exon 3 in the other paternal allele of the insulin receptor gene. Analysis of the father`s cDNA confirmed that exon 3 was deleted from mRNA molecules derived from one of his two alleles of the insulin receptor gene. Furthermore, the father was found to be hemizygous for a polymorphic sequence (GAC{sup Asp} at codon 234) in exon 3 that was not inherited by any of the five daughters. Instead, all five daughters inherited the paternal allele with the deletion mutation. They did not detect mutations in the mother`s insulin receptor gene. Furthermore, the clinical syndrome did not segregate with either of the mother`s two alleles of the insulin receptor gene. Although the youngest daughter inherited the mutant allele from her father, she was not clinically affected. The explanation for the incomplete penetrance is not known. These results emphasize the importance of specifically searching for deletion mutations when screening candidate genes for mutations. Furthermore, the existence of apparently asymptomatic carriers of mutations in the insulin receptor gene, such as the father in the present study, suggests that the prevalence of mutations in the insulin receptor gene may be higher than would be predicted on the basis of the observed prevalence of patients with extreme insulin resistance. 34 refs., 6 figs., 1 tab.

  9. Familial Adrenocortical Carcinoma in Association With Lynch Syndrome

    PubMed Central

    Challis, Benjamin G.; Kandasamy, Narayanan; Powlson, Andrew S.; Koulouri, Olympia; Annamalai, Anand Kumar; Happerfield, Lisa; Marker, Alison J.; Arends, Mark J.; Nik-Zainal, Serena

    2016-01-01

    Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1–3) in the proband and her sister. Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes. PMID:27144940

  10. A novel truncating AIP mutation, p.W279*, in a familial isolated pituitary adenoma (FIPA) kindred.

    PubMed

    Cansu, Güven Barış; Taşkıran, Bengür; Trivellin, Giampaolo; Faucz, Fabio R; Stratakis, Constantine A

    2016-07-01

    Familial isolated pituitary adenomas (FIPA) constitute 2-3% of pituitary tumours. AIP is the most commonly mutated gene in FIPA. We herein report a novel germline mutation of the AIP gene in a family with FIPA. We present two patients, a father and his 12-year-old daughter, diagnosed clinically and using laboratory measures with acromegaly-gigantism. Both underwent transsphenoidal hypophyseal surgery for macroadenomas. We initially detected a novel heterozygous germline AIP mutation, c.836G>A (p.W279*), in the father's DNA. We then found the same mutation in his affected daughter. Pituitary adenomas associated with AIP mutations mostly present as FIPA (68%) at an early age (78% occur at <30 years old). They are often growth hormone (GH) - or prolactin - secreting macroadenomas (88%) that have already extended beyond the sella at the time of diagnosis. Acromegalic cases are resistant to somatostatin analogues and multimodal management is frequently essential to control the disease. Our patients had normalized GH/IGF-1 values soon after surgery, although enough time may not have elapsed to reach final cure. While penetrance of the disease can be as low as 10% in FIPA, especially children and young patients with somatotropinoma and prolactinoma should be surveyed for inactivating mutations or deletions in AIP. Determining the causative mutations may be of assistance in early diagnosis, treatment success, and genetic counseling.

  11. Current status of familial gastrointestinal polyposis syndromes

    PubMed Central

    Jung, Ioan; Gurzu, Simona; Turdean, Gligore Sabin

    2015-01-01

    Because of the rarity of familial gastrointestinal cancer-predisposing syndromes, their exploration in literature is not extensive. In this review, an update of the clinicopathological and molecular criteria of gastrointestinal familial polyposis syndromes with potential malignant transformation is performed. In addition, a guide for screening and surveillance was synthesized and a distribution of gene mutations according to the specific syndromes and geographic distribution was included. The following inherited polyposes syndromes were analyzed: familial adenomatous polyposis, the hamartomatous familial polyposes (Juvenile polyposis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, hereditary mixed polyposis syndrome, Gorlin syndrome, Birt-Hogg-Dube syndrome, neurofibromatosis type I and multiple endocrine neoplasia syndrome 2B), Li-Fraumeni syndrome, and MUTYH-associated adenomatous polyposis. For proper medical care, subspecialization of gastroenterologists, pathologists, and genticists in the field of familial diseases should be introduced in the medical curriculum. PMID:26600934

  12. Williams Syndrome: A Family's Journey.

    ERIC Educational Resources Information Center

    Sorrell, Adrian L.

    This paper describes Williams syndrome, a rare genetic disorder that results in mental retardation. An overview of this condition is presented from the perspective of a family who traveled through the many stages of the disability from infancy to young adulthood. The etiology and characteristics of the disability are discussed, including…

  13. Craniosynostosis suggestive of Saethre-Chotzen syndrome: Clinical description of a large kindred and exclusion of candidate regions on 7p

    SciTech Connect

    von Gernet, S.; Muehlbauer, W.; Fairley, J.

    1996-05-03

    We describe the clinical manifestations of an autosomal dominant form of craniosynostosis in a large family with eight affected relatives. Unilateral or bilateral coronal synostosis, low frontal hair line, strabismus, ptosis, and partial cutaneous syndactyly of fingers and toes are findings suggestive of the diagnosis of Saethre-Chotzen syndrome. The disease locus was excluded from the two adjacent Saethre-Chotzen candidate regions on 7p by linkage analysis with markers D7S664 and D7S507. This indicates heterogeneity of Saethre-Chotzen syndrome with a locus outside the candidate regions on 7p. 30 refs., 6 figs., 2 tabs.

  14. Legius Syndrome in Fourteen Families

    PubMed Central

    Denayer, Ellen; Chmara, Magdalena; Brems, Hilde; Kievit, Anneke Maat; van Bever, Yolande; Van den Ouweland, Ans MW; Van Minkelen, Rick; de Goede-Bolder, Arja; Oostenbrink, Rianne; Lakeman, Phillis; Beert, Eline; Ishizaki, Takuma; Mori, Tomoaki; Keymolen, Kathelijn; Van den Ende, Jenneke; Mangold, Elisabeth; Peltonen, Sirkku; Brice, Glen; Rankin, Julia; Van Spaendonck-Zwarts, Karin Y; Yoshimura, Akihiko; Legius, Eric

    2011-01-01

    Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome. © 2010 Wiley-Liss, Inc. PMID:21089071

  15. Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred

    SciTech Connect

    Andermann, F.; Andermann, E.; Carpenter, S.

    1994-09-01

    Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantly inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies have been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.

  16. The differential diagnosis of familial lentiginosis syndromes.

    PubMed

    Lodish, Maya B; Stratakis, Constantine A

    2011-09-01

    Cutaneous markers of systemic disease are vital for clinicians to recognize. This chapter outlines familial lentiginosis syndromes that include Peutz-Jeghers syndrome, Carney Complex, the PTEN hamartomatous syndromes, and LEOPARD/Noonan syndrome. The inheritance of these syndromes is autosomal dominant; they also share characteristic skin findings that offer a clue to their recognition and treatment. We will discuss the clinical presentation of these disorders, with a focus on the dermatological manifestations, and will provide an update on the molecular mechanisms involved. Recognition of cutaneous markers associated with these rare familial cancer syndromes provides the opportunity to pursue early surveillance for malignancies, as well as genetic counseling.

  17. Stress in Families of Young Children with Down Syndrome, Williams Syndrome, and Smith-Magenis Syndrome.

    ERIC Educational Resources Information Center

    Fidler, Deborah J.; Hodapp, Robert M.; Dykens, Elizabeth M.

    2000-01-01

    Compared stress levels in families of children with Down syndrome (DS), Williams syndrome (WS), or Smith-Magenis syndrome (SMS). Found that DS families experienced less Pessimism than others and less Parent and Family Problems than SMS families. Strongest predictors of Parent and Family Problems were maladaptive behavior in SMS, younger age in DS,…

  18. Waardenburg syndrome and myelomeningocele in a family.

    PubMed Central

    Chatkupt, S; Chatkupt, S; Johnson, W G

    1993-01-01

    We report the first family with Waardenburg syndrome type 1 and myelomeningocele in which more than one subject was affected with both disorders. The possible association is discussed. Prenatal screening for myelomeningocele is suggested for a family with Waardenburg syndrome type 1. Images PMID:8423616

  19. Muckle-Wells cryopyrinopathy: complex phenotyping and response to therapy in a new multiplex kindred.

    PubMed

    Headley, Alexander P; Cordingley, Frank; Hawkins, Phillip N; Riminton, D Sean

    2014-04-01

    Muckle-Wells syndrome (MWS) is a member of the cryopyrin-associated periodic syndrome family of auto-inflammatory diseases, originally described as a triad of urticaria, sensorineural deafness and amyloidosis. IL-1 blockade is a proven therapy for MWS. The clinical, laboratory and genotypic characteristics of a novel kindred of five individuals with Muckle-Wells syndrome are described. Response to IL-1 blockade therapy in the proband was evaluated. All five affected family members experienced symptoms of multi-organ inflammation. Lead time between symptom onset and diagnosis was approximately 30 years in the proband. Fever was not a universal feature in all affected family members. Anti-IL-1 therapy in the proband resulted in improvements in patient-reported symptoms, inflammatory markers, auditory acuity and reversal of her infertility. Muckle-Wells syndrome is a rare, multisystem, auto-inflammatory syndrome. Delay in diagnosis prevents effective treatment. We propose reversal of infertility to be among the potential benefits of IL-1 inhibition in this disease.

  20. Target gene analyses of 39 amelogenesis imperfecta kindreds

    PubMed Central

    Chan, Hui-Chen; Estrella, Ninna M. R. P.; Milkovich, Rachel N.; Kim, Jung-Wook; Simmer, James P.; Hu, Jan C-C.

    2012-01-01

    Previously, mutational analyses identified six disease-causing mutations in 24 amelogenesis imperfecta (AI) kindreds. We have since expanded the number of AI kindreds to 39, and performed mutation analyses covering the coding exons and adjoining intron sequences for the six proven AI candidate genes [amelogenin (AMELX), enamelin (ENAM), family with sequence similarity 83, member H (FAM83H), WD repeat containing domain 72 (WDR72), enamelysin (MMP20), and kallikrein-related peptidase 4 (KLK4)] and for ameloblastin (AMBN) (a suspected candidate gene). All four of the X-linked AI families (100%) had disease-causing mutations in AMELX, suggesting that AMELX is the only gene involved in the aetiology of X-linked AI. Eighteen families showed an autosomal-dominant pattern of inheritance. Disease-causing mutations were identified in 12 (67%): eight in FAM83H, and four in ENAM. No FAM83H coding-region or splice-junction mutations were identified in three probands with autosomal-dominant hypocalcification AI (ADHCAI), suggesting that a second gene may contribute to the aetiology of ADHCAI. Six families showed an autosomal-recessive pattern of inheritance, and disease-causing mutations were identified in three (50%): two in MMP20, and one in WDR72. No disease-causing mutations were found in 11 families with only one affected member. We conclude that mutation analyses of the current candidate genes for AI have about a 50% chance of identifying the disease-causing mutation in a given kindred. PMID:22243262

  1. Target gene analyses of 39 amelogenesis imperfecta kindreds.

    PubMed

    Chan, Hui-Chen; Estrella, Ninna M R P; Milkovich, Rachel N; Kim, Jung-Wook; Simmer, James P; Hu, Jan C-C

    2011-12-01

    Previously, mutational analyses identified six disease-causing mutations in 24 amelogenesis imperfecta (AI) kindreds. We have since expanded the number of AI kindreds to 39, and performed mutation analyses covering the coding exons and adjoining intron sequences for the six proven AI candidate genes [amelogenin (AMELX), enamelin (ENAM), family with sequence similarity 83, member H (FAM83H), WD repeat containing domain 72 (WDR72), enamelysin (MMP20), and kallikrein-related peptidase 4 (KLK4)] and for ameloblastin (AMBN) (a suspected candidate gene). All four of the X-linked AI families (100%) had disease-causing mutations in AMELX, suggesting that AMELX is the only gene involved in the aetiology of X-linked AI. Eighteen families showed an autosomal-dominant pattern of inheritance. Disease-causing mutations were identified in 12 (67%): eight in FAM83H, and four in ENAM. No FAM83H coding-region or splice-junction mutations were identified in three probands with autosomal-dominant hypocalcification AI (ADHCAI), suggesting that a second gene may contribute to the aetiology of ADHCAI. Six families showed an autosomal-recessive pattern of inheritance, and disease-causing mutations were identified in three (50%): two in MMP20, and one in WDR72. No disease-causing mutations were found in 11 families with only one affected member. We conclude that mutation analyses of the current candidate genes for AI have about a 50% chance of identifying the disease-causing mutation in a given kindred.

  2. IVIC syndrome: report of a second family.

    PubMed

    Sammito, V; Motta, D; Capodieci, G; Sanfilippo, S; Neri, G

    1988-04-01

    The IVIC syndrome derives its name from the Instituto Venezolano de Investigaciones Cientìficas, where it was described by Arias et al. [Am J Med Genet 6:25-59, 1980]. We report on several individuals in a family with the IVIC syndrome, the second described in the literature. In this family there are 3 affected individuals in 2 generations. This observation shows that the IVIC syndrome is not a private syndrome, and confirms that it is due to an autosomal dominant mutation.

  3. Modeling Family Adaptation to Fragile X Syndrome

    ERIC Educational Resources Information Center

    Raspa, Melissa; Bailey, Donald, Jr.; Bann, Carla; Bishop, Ellen

    2014-01-01

    Using data from a survey of 1,099 families who have a child with Fragile X syndrome, we examined adaptation across 7 dimensions of family life: parenting knowledge, social support, social life, financial impact, well-being, quality of life, and overall impact. Results illustrate that although families report a high quality of life, they struggle…

  4. Genetic linkage analysis in 26 families with Bardet-Biedl syndrome

    SciTech Connect

    Wright, A.F.; Bruford, E.A.; Mansfield, D.C.

    1994-09-01

    Bardet-Biedl syndrome is an autosomal recessive disorder characterized by polydactyly, obesity, hypogonadism, retinitis pigmentosa, renal anomalies and mental retardation. Clinical heterogeneity is quite marked both within and between families. Linkage has been reported between Bardet-Biedl syndrome and the D16408 marker in chromosomal region 16q21 in an extended Bedouin kindred and, more recently, in a subset of 17 out of 31 families using the PYGM/D11S913 markers in chromosomal region 11q13. We have analyzed linkage to the 16q21 and 11q13 regions and used markers covering chromosomes 2, 3, 17 and 18 in a set of 26 Bardet-Biedl families, each containing at least two affected individuals, with a total of 57 affected members. Evidence of linkage to the D11S527 locus has been identified assuming linkage homogeneity with a lod score of 2.72 at a recombination fraction of 0.11 (95% limits 0.03-0.25).

  5. Delayed Stress Response Syndrome: Family Therapy Indications

    ERIC Educational Resources Information Center

    Figley, Charles R.; Sprenkle, Douglas H.

    1978-01-01

    The delayed stress response syndrome is a form of chronic catastrophic stress disorder. The theoretical nature of the syndrome and its most characteristic symptoms are delineated within the context of treating Vietnam combat veterans. The paper outlines treatment implications within a family therapy program. (Author)

  6. Fraser syndrome: recurrence in a family.

    PubMed

    Singh, Renu; Tandon, Indu; Deo, Sujata

    2007-12-01

    Fraser syndrome is a rare, autosomal recessive condition with classical features of cryptophthalmos, syndactyly, ambiguous genitalia, genitourinary mal-formations and mental retardation. We report a family with affected child where the pregnant woman was referred at 24 weeks of gestation for termination of pregnancy. The aborted fetus showed typical findings suggestive of Fraser syndrome.

  7. A family with Wagner syndrome with uveitis and a new versican mutation

    PubMed Central

    Rothschild, Pierre-Raphaël; Brézin, Antoine P.; Nedelec, Brigitte; des Roziers, Cyril Burin; Ghiotti, Tiffany; Orhant, Lucie; Boimard, Mathieu

    2013-01-01

    Purpose To report the clinical and molecular findings of a kindred with Wagner syndrome (WS) revealed by intraocular inflammatory features. Methods Eight available family members underwent complete ophthalmologic examination, including laser flare cell meter measurements. Collagen, type II, alpha 1, versican (VCAN), frizzled family receptor 4, low density lipoprotein receptor-related protein 5, tetraspanin 12, and Norrie disease (pseudoglioma) genes were screened with direct sequencing. Results The index case was initially referred for unexplained severe and chronic postoperative bilateral uveitis following a standard cataract surgery procedure. Clinical examination of the proband revealed an optically empty vitreous with avascular vitreous strands and veils, features highly suggestive of WS. The systematic familial ophthalmologic examination identified three additional unsuspected affected family members who also presented with the WS phenotype, including uveitis for one of them. We identified a novel c.4004–6T>A nucleotide substitution at the acceptor splice site of intron 7 of the VCAN gene that segregated with the disease phenotype. Conclusions We present a family with WS with typical WS features and intraocular inflammatory manifestations associated with a novel splice site VCAN mutation. Beyond the structural role in the retinal-vitreous architecture, versican is also emerging as a pivotal mediator of the inflammatory response, supporting uveitis predisposition as a clinical manifestation of WS. PMID:24174867

  8. A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families.

    PubMed Central

    Price, J A; Wright, J T; Kula, K; Bowden, D W; Hart, T C

    1998-01-01

    Tricho-dento-osseous syndrome (TDO) is characterised by a variable clinical phenotype primarily affecting the hair, teeth, and bone. Different clinical features are observed between and within TDO families. It is not known whether the variable clinical features are the result of genetic heterogeneity or clinical variability. A gene for TDO was localised recently to chromosome 17q21 in four North Carolina families, and a 4 bp deletion in the human distal-less 3 gene (DLX3) was identified in all affected members. A previous genetic linkage study in a large Virginia kindred with TDO indicated possible linkage to the ABO, Gc, and Kell blood group loci. To examine whether TDO exhibits genetic heterogeneity, we have performed molecular genetic analysis to determine whether affected members of this Virginia kindred have the DLX3 gene deletion identified in North Carolina families. Results show that affected subjects (n=3) from the Virginia family have the same four nucleotide deletion previously identified in the North Carolina families. A common haplotype for three genetic markers surrounding the DLX3 gene was identified in all affected subjects in the North Carolina and Virginia families. These findings suggest that all people with TDO who have been evaluated have inherited the same DLX3 gene deletion mutation from a common ancestor. The variable clinical phenotype observed in these North Carolina and Virginia families, which share a common gene mutation, suggests that clinical variability is not the result of genetic heterogeneity at the major locus, but may reflect genetic heterogeneity at other epigenetic loci or contributing environmental factors or both. Images PMID:9783705

  9. Concordance of phenotypic expression and gender identity in a large kindred with a mutation in the androgen receptor.

    PubMed

    Hooper, H T; Figueiredo, B C; Pavan-Senn, C C; De Lacerda, L; Sandrini, R; Mengarelli, J K; Japp, K; Karaviti, L P

    2004-03-01

    A 14-year-old female presented to the Pediatric Endocrine Clinic, Universidade Federal o Parana Curitiba, Brazil, for obesity. A few years later, despite normal breast development, the patient had failed to menstruate and lacked pubic and axillary hair. Laboratory analyses revealed high levels of testosterone. Karyotype analysis was XY. Direct sequencing of her genomic DNA showed a G to T transition at nucleotide 2089 at exon 2 in the androgen receptor gene, resulting in a substitution of Phe for Cys at position 576. This mutation disrupts the first Zn finger critical to DNA binding and transcriptional activity and results in complete androgen-insensitivity syndrome (CAIS). This individual was part of 700-member multigenerational kindred of German origin living in small villages in Southern Brazil. Family members who gave informed consent were screened using a polymerase chain reaction-based method. Nineteen CAIS-affected individuals and carriers were identified. All presented with infertility and lack of or sparse pubic hair. The prevalence of common AIS within the kindred greatly exceeds that of the general population and is due in part to their isolated familial and community structures. All individuals are genuinely feminine in their appearance, sex behavior, gender identity, and integration within their communities. We conclude that CAIS leads to complete feminization of XY individuals and results in individuals who are psychologically and socially established and integrated as women within the familial and cultural contexts of their communities.

  10. Analysis of the CDKN2A and CDK4 genes and HLA-DR and HLA-DQ alleles in two Spanish familial melanoma kindreds.

    PubMed

    Nagore, E; Climent, J; Planelles, M D; Ledesma, E; Rubio-Moscardó, F; Fortea, J M; Oliver, V

    2000-01-01

    Some confusion exists in the literature about which criteria should be used to define familial melanoma. This could explain the different reported frequencies of mutations in predisposing genes, mostly CDKN2A, in these patients. This study evaluated the human leucocyte antigen (HLA) class II genotype and the presence of mutations in CDKN2A and CDK4 genes in 2 families with very different clinical features. The family with a germinal mutation in exon 2 of CDKN2A (Gly101Try) presented the following clinical features: 3 first-degree affected members, 1 of whom had 2 melanomas, and all the melanomas appearing before 35 years of age. In contrast, the second family did not present any mutation in the studied genes and included 2 first-degree affected members diagnosed at over 45 years of age. Neither family showed an association with HLA genotype. Other genes are also involved in familial melanoma but, when the CDKN2A gene is affected, some clinical features seem to be uniform.

  11. Family Demands, Social Support and Family Functioning in Taiwanese Families Rearing Children with Down Syndrome

    ERIC Educational Resources Information Center

    Hsiao, C-Y.

    2014-01-01

    Background: Down syndrome (DS) affects not only children but also their families. Much remains to be learned about factors that influence how families of children with DS function, especially families in non-Western populations. The purpose of this cross-sectional, correlational study was to examine how family demographics, family demands and…

  12. A kindred with alopecia, keratosis, pilaris, cataracts, and psoriasis.

    PubMed

    Appell, M L; Sherertz, E F

    1987-01-01

    Three members of a family with numerous ectodermal abnormalities are described. These anomalies primarily include patchy alopecia beginning in childhood, premature cataracts, widespread keratosis pilaris, and psoriasis. The alopecia and premature cataracts appear to follow an autosomal dominant inheritance pattern with incomplete penetrance and appear to be linked. Psoriasis also occurs in several members of this family and probably represents a separate but possibly related genodermatosis. This kindred has features of both keratosis follicularis spinulosa decalvans and ichthyosis follicularis, and the disorder seems to fit into the group of follicular hyperkeratosis disorders.

  13. Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

    PubMed Central

    Bai, M; Janicic, N; Trivedi, S; Quinn, S J; Cole, D E; Brown, E M; Hendy, G N

    1997-01-01

    Missense mutations have been identified in the coding region of the extracellular calcium-sensing receptor (CASR) gene and cause human autosomal dominant hypo- and hypercalcemic disorders. The functional effects of several of these mutations have been characterized in either Xenopus laevis oocytes or in human embryonic kidney (HEK293) cells. All of the mutations that have been examined to date, however, cause single putative amino acid substitutions. In this report, we studied a mutant CASR with an Alu-repetitive element inserted at codon 876, which was identified in affected members of families with the hypercalcemic disorders, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), to understand how this insertion affects CASR function. After cloning of the Alu-repetitive element into the wild-type CASR cDNA, we transiently expressed the mutant receptor in HEK293 cells. Expression of mutant and wild-type receptors was assessed by Western analysis, and the effects of the mutation on extracellular calcium (Ca2+(o)) and gadolinium (Gd3+(o)) elicited increases in the cytosolic calcium concentration (Ca2+(i)) were examined in fura-2-loaded cells using dual wavelength fluorimetry. The insertion resulted in truncated receptor species that had molecular masses some 30 kD less than that of the wild-type CASR and exhibited no Ca2+(i) responses to either Ca2+(o) or Gd3+(o). A similar result was observed with a mutated CASR truncated at residue 876. However, the Alu mutant receptor had no impact on the function of the coexpressed wild-type receptor. Interestingly, the Alu mutant receptor demonstrated decreased cell surface expression relative to the wild-type receptor, whereas the CASR (A877stop) mutant exhibited increased cell surface expression. Thus, like the missense mutations that have been characterized to date in families with FHH, the Alu insertion in this family is a loss-of-function mutation that produces hypercalcemia by

  14. Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer families: A genetic study of 15 185delAG-mutation kindreds

    SciTech Connect

    Berman, D.B.; Schultz, D.C.; Godwin, A.K.

    1996-06-01

    We screened 163 women from breast-ovarian cancer-prone families, as well as 178 individuals affected with breast and/or ovarian cancer but unselected for family history, for germ-line mutations in exon 2 of BRCA1, by SSCP analysis and direct sequencing. A total of 25 mutations were detected. Thirteen of 64 Jewish Ashkenazi women and 2 non-Jewish individuals were found to possess the 185delAG mutation. Haplotype data for all 15 individuals, with markers intragenic to BRCA1, suggest that the Jewish Ashkenazi individuals share a common ancestry that is distinct from the lineage shared by the other two women. These data provide the first evidence of two distinct lines of transmission for the 185delAG mutation, only one of which has its origins in the Jewish Ashkenazi population. Our screening also uncovered 10 affected individuals with an 11-bp deletion at nucleotide 188 of BRCA1 (188del11), 4 of whom are Ashkenazi Jews. This is only the third reported mutation detected within the Jewish Ashkenazi population and may represent the second most common alteration in BRCA1 found in Ashkenazi Jews in the United States. The observed overrepresentation of specific mutations within a subgroup of the general population may eventually contribute to the development of inexpensive and routine tests for BRCA1 mutations, as well as to the elucidation of other contributory factors (e.g., diet, environment, and chemical exposures) that may play a key role in cancer initiation and development. The implications of the mutational data, as well as the role that founder effect, demographic history, and penetrance play in the resulting observed phenomena, are discussed. 32 refs., 3 figs., 2 tabs.

  15. Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer families: a genetic study of 15 185delAG-mutation kindreds.

    PubMed Central

    Berman, D. B.; Wagner-Costalas, J.; Schultz, D. C.; Lynch, H. T.; Daly, M.; Godwin, A. K.

    1996-01-01

    We screened 163 women from breast-ovarian cancer-prone families, as well as 178 individuals affected with breast and/or ovarian cancer but unselected for family history, for germ-line mutations in exon 2 of BRCA1, by SSCP analysis and direct sequencing. A total of 25 mutations were detected. Thirteen of 64 Jewish Ashkenazi women and 2 non-Jewish individuals were found to possess the 185delAG mutation. Haplotype data for all 15 individuals, with markers intragenic to BRCA1, suggest that the Jewish Ashkenazi individuals share a common ancestry that is distinct from the lineage shared by the other two women. These data provide the first evidence of two distinct lines of transmission for the 185delAG mutation, only one of which has its origins in the Jewish Ashkenazi population. Our screening also uncovered 10 affected individuals with an 11-bp deletion at nucleotide 188 of BRCA1 (188del11), 4 of whom are Ashkenazi Jews. This is only the third reported mutation detected within the Jewish Ashkenazi population and may represent the second most common alteration in BRCA1 found in Ashkenazi Jews in the United States. The observed overrepresentation of specific mutations within a subgroup of the general population may eventually contribute to the development of inexpensive and routine tests for BRCA1 mutations, as well as to the elucidation of other contributory factors (e.g., diet, environment, and chemical exposures) that may play a key role in cancer initiation and development. The implications of the mutational data, as well as the role that founder effect, demographic history, and penetrance play in the resulting observed phenomena, are discussed. Images Figure 1 Figure 2 Figure 3 PMID:8651293

  16. Munchausen Syndrome by Proxy: A Family Affair.

    ERIC Educational Resources Information Center

    Mehl, Albert L.; And Others

    1990-01-01

    The article reports on a case of Munchausen syndrome by proxy in which chronic illicit insulin was administered to a one-year-old child by her mother. Factitious illnesses continued despite psychiatric intervention. Retrospective review of medical records suggested 30 previous episodes of factitious illness within the family. (DB)

  17. Down Syndrome May Not Be Big Financial Burden on Families

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_162595.html Down Syndrome May Not Be Big Financial Burden on Families ... HealthDay News) -- Although families with a child with Down syndrome do face extra medical expenses, they probably won' ...

  18. A novel keratin 12 mutation in a German kindred with Meesmann's corneal dystrophy

    PubMed Central

    Corden, L; Swensson, O; Swensson, B; Rochels, R; Wannke, B; Thiel, H; McLean, W

    2000-01-01

    AIM—To study a kindred with Meesmann's corneal dystrophy (MCD) to determine if a mutation within the cornea specific K3 or K12 genes is responsible for the disease phenotype.
METHODS—Slit lamp examination of the cornea in four members of the kindred was carried out to confirm the diagnosis of MCD. The region encoding the helix initiation motif (HIM) of the K12 polypeptide was polymerase chain reaction (PCR) amplified from genomic DNA derived from affected individuals in the kindred. PCR products generated were subjected to direct automated sequencing. Restriction enzyme analysis employing Ban I was used to confirm the presence of the mutation in affected individuals of the family.
RESULTS—Sequencing of the K12 gene in an affected individual from the family revealed a novel heterozygous missense mutation (413A→C), predicting the substitution of a proline for a glutamine at codon 130 (Q130P) in the HIM of the K12 protein. The mutation was excluded from 50 normal, unaffected individuals by restriction enyzme analysis and was therefore unlikely to be a common polymorphism.
CONCLUSION—A novel missense mutation in the K12 gene leads to MCD in a German kindred. Missense mutations have now been identified within the region encoding the helix initiation motif of the K12 protein in eight of 11 MCD kindreds analysed at the molecular level.

 PMID:10781519

  19. [Family medicine and functional somatic syndromes].

    PubMed

    Nago, Naoki

    2009-09-01

    Between psychosomatic medicine and psychiatry, FSS (functional somatic syndromes) patients are often visiting a family doctor. For FSS, the role of family physicians is large, but the family physicians are not required for the role of diagnosis and treatment of FSS. Rather, appropriate referral to a specialist to exclude organic disease is important and a role as the coordinator is large to the patient to refuse a psychiatric consultation. To serve as a role for such coordination, a family physician has to response the patient's emotional side and focus on the construction of the doctor-patient relationship and response. I also think of structuralism medicine approach to describe disease from the meta-level as a new procedure to the patient. This approach consists of 4 components, 'entity', 'phenomenon', 'words', and 'I'. This may be a useful approach to family physicians who coordinate the overall for FSS patients' management.

  20. The gene for Crouzon craniofacial dysostosis maps to a 7 centiMorgan region on chromosome 10q in three unrelated kindreds

    SciTech Connect

    Ehrlich, G.D.; Preston, R.A.; Aston, C.A.

    1994-09-01

    Crouzon craniofacial dysostosis (CFD, M.I.M. number 123500) is an autosomal dominant disorder of craniofacial development with complete penetrance and variable expressivity that is characterized by premature craniosynostosis, maxilary hypoplasia, and shallow orbits. We recently mapped CFD to a 21 centiMorgan (cM) region of chromosome 10q25-q26 in two unrelated families from North America. We now report the confirmation of this locus using a third large CFD kindred from South America and describe a refinement of the CFD gene map position. A recombination was observed in two members of the Argentinean kindred at marker D10S209, thereby redefining the centromeric limit of the CFD locus. In addition, a newly available Genethon microsatellite marker, D10S587, which maps between D10S216 and D10S209, proved to be informative for the original family and a recombination was observed at this marker in an unaffected family member, redefining the telomeric limit of the Crouzon syndrome locus. The finding of these obligate recombinants reduces the candidate region for the CFD gene locus to 7 cM. Multipoint linkage analysis (LINKAGE (ver 5.1)) carried out on the three pedigrees produced a maximal LOD score of 12.33 at a locus approximately 2 cM telomeric to D10S209. These findings suggest that CFD is a genetically homogeneous disorder caused by mutations in a gene located on chromosome 10q.

  1. A Korean Family with the Muenke Syndrome

    PubMed Central

    Yu, Jae Eun; Park, Dong Ha

    2010-01-01

    The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members. PMID:20592905

  2. A Korean family with the Muenke syndrome.

    PubMed

    Yu, Jae Eun; Park, Dong Ha; Yoon, Soo Han

    2010-07-01

    The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members.

  3. Description of a large kindred with autosomal dominant inheritance of branchial arch anomalies, hearing loss, and ear pits, and exclusion of the branchio-oto-renal (BOR) syndrome gene locus (chromosome 8q13.3).

    PubMed

    Stratakis, C A; Lin, J P; Rennert, O M

    1998-09-23

    It has been suggested that branchio-oculo-facial (BOF) syndrome, deafness with ear pits, and associated conditions [MIM nos. 125100, 120502], and branchio-oto-renal (BOR) [MIM no. 113650] or Melnick-Fraser syndrome represent phenotypic variants of the BOR syndrome, which is inherited in an autosomal dominant (AD) manner and has variable clinical expression. Recently, the BOR gene was mapped to chromosome region 8q13.3 and its sequence was identified as the human homolog of the Drosophila eyes absent (EYA1) gene. We studied an extended family with AD inheritance of branchial arch anomalies (BAA), hearing loss, and ear pits, whose phenotype differed from that of patients with BOR in that none of the affected members had renal abnormalities or lacrimal duct stenosis. Fifteen affected members were studied; ear pits were present in all of them, whereas hearing loss and other BAA were present in 40 and 20%, respectively. Blood was collected from 31 patients; DNA was extracted by standard methods and amplified using primers from microsatellite sequences flanking the BOR locus on chromosome 8q13.3 (D8S1807, D8S530, and D8S543). Linkage analysis was performed under two models of AD inheritance with different penetrance: 100% and 80%. In both cases, the logarithm of odds (LOD) scores produced were significantly less than -2; exclusion of the 8q13.3 locus was also confirmed by multipoint LOD score analysis. We conclude that, in one large family with AD inheritance of BAA, hearing loss and ear pits, the BOR locus was excluded. This represents the first documentation of heterogeneity in branchio-oto anomalies, syndromes with phenotypes similar to BOR syndrome.

  4. Idiopathic cholestasis of pregnancy in a large kindred.

    PubMed Central

    Reyes, H; Ribalta, J; González-Cerón, M

    1976-01-01

    A past history of idiopathic cholestasis of pregnancy (ICP) was detected in 10 out of the 32 multiparous women in the last two generations of a large kindred. The affected women are distributed in five family units, sharing Chilean-born great-grandparents.The connection between the ICP-affected women and the common trunk is given both by male and female parents. Five cases are concentrated in one family unit, where the mother and all her daughters have been affected by the disease. The role of genetic factors in the pathogenesis of ICP is supported by this study. It is proposed that the disease may be transmitted as a predisposing trait by individuals of either sex and that non-genetic factors may influence its expressivity. A reliable test to identify all the genetic carriers seems indispensable to define the pattern of inheritance in this disease. PMID:976812

  5. Fragile X syndrome in incestuous families

    SciTech Connect

    Seemanova, E.

    1996-11-11

    Reed suggested the investigation of children 219 from incestuous unions as a method for calculation of the detrimental heterozygosity of man. Some studies of latent genetics load in man have been based on the comparison of health status of incestuous children with their half-sibs born to the same mothers in matings with nonconsanguineous partners. These studies were limited to the detection of autosomal-recessive genes leading to abnormal phenotypes or mental deficiency in homozygotes. The highest coefficient of inbreeding in human beings is 1/4 in offspring of incestuous matings: hence, the high proportion of affected homozygotes and low incidence of affected individuals among their maternal half-sibs. Mental deficiency in incestuous children represents not only cases of simple recessive inheritance. Recently, we observed three incestuous families in which fragile X syndrome was detected. The fra(X) children were born to carriers from incestuous unions as well as to unrelated partners. Therefore, we recommend use of incestuous children and their maternal half-sibs as a control group for studies estimating latent genetic load after investigation for fra(X). The incidence of fra(X) syndrome is high, and mental retardation in heterozygotes is uncommon. Both of these factors can play a role in the occurrence of incest, and in pregnancy at young age, as well as in multiple partnerships. Families of heterozygotes for fragile X should be excluded from the material for the calculation of human latent detrimental (autosomal-recessive) genetic load. 3 refs., 3 figs.

  6. Parkinsonian syndrome in familial frontotemporal dementia.

    PubMed

    Siuda, Joanna; Fujioka, Shinsuke; Wszolek, Zbigniew K

    2014-09-01

    Parkinsonism in frontotemporal dementia (FTD) was first described in families with mutations in the microtubule-associated protein tau (MAPT) and progranulin (PRGN) genes. Since then, mutations in several other genes have been identified for FTD with parkinsonism, including chromosome 9 open reading frame 72 (C9ORF72), chromatin modifying protein 2B (CHMP2B), valosin-containing protein (VCP), fused in sarcoma (FUS) and transactive DNA-binding protein (TARDBP). The clinical presentation of patients with familial forms of FTD with parkinsonism is highly variable. The parkinsonism seen in FTD patients is usually characterized by akinetic-rigid syndrome and is mostly associated with the behavioral variant of FTD (bvFTD); however, some cases may present with classical Parkinson's disease. In other cases, atypical parkinsonism resembling progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) has also been described. Although rare, parkinsonism in FTD may coexist with motor neuron disease. Structural neuroimaging, which is crucial for the diagnosis of FTD, shows characteristic patterns of brain atrophy associated with specific mutations. Structural neuroimaging is not helpful in distinguishing among patients with parkinsonian features. Furthermore, dopaminergic imaging that shows nigrostriatal neurodegeneration in FTD with parkinsonism cannot discriminate parkinsonian syndromes that arise from different mutations. Generally, parkinsonism in FTD is levodopa unresponsive, but there have been cases where a temporary benefit has been reported, so dopaminergic treatment is worth trying, especially, when motor and non-motor manifestations can cause significant problems with daily functioning. In this review, we present an update on the clinical and genetic correlations of FTD with parkinsonism.

  7. Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation.

    PubMed

    Hauck, Fabian; Magerus-Chatinet, Aude; Vicca, Stephanie; Rensing-Ehl, Anne; Roesen-Wolff, Angela; Roesler, Joachim; Rieux-Laucat, Frédéric

    2013-04-01

    We describe a family with 12 members carrying a heterozygous germline FAS c.3G>T start codon mutation leading to FAS haploinsufficiency. One patient had autoimmune lymphoproliferative syndrome (ALPS), one had recovered from ALPS, and ten mutation-positive relatives (MPRs) were healthy. FAS-mediated apoptosis and surface expression of FAS in single-positive T cells were lower for MPRs but did not discriminate between them and the ALPS patient. However, double-negative (DN) T cells of the ALPS patient had no FAS expression due to somatic loss of heterozygosity. Our results in this kindred suggest that FAS haploinsufficiency does not cause ALPS-FAS, but that modifying genetic events are crucial for its pathogenesis. FAS surface expression on DN T cells should be assessed routinely and FAS haploinsufficient patients should be followed as its potential for lymphomagenesis is not well defined and a second hit might occur later on.

  8. Childhood cancers in families with and without Lynch syndrome

    PubMed Central

    Heath, John A.; Reece, Jeanette C.; Buchanan, Daniel D.; Casey, Graham; Durno, Carol A.; Gallinger, Steven; Haile, Robert W.; Newcomb, Polly A.; Potter, John D.; Thibodeau, Stephen N.; Le Marchand, Loïc; Lindor, Noralane M.; Hopper, John L.; Jenkins, Mark A.; Win, Aung Ko

    2015-01-01

    Background Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Materials and Methods Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-proficient colorectal cancer (non-Lynch syndrome families). Results There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24 %) and non-Lynch syndrome families (179/94,302; 0.19 %; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95 % CI 107–206) per million population per year in Lynch syndrome families and 115 (95 % CI 99.1–134) per million population per year in non-Lynch syndrome families. There was no evidence for a substantial increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families. Conclusion The risk of childhood cancers does not appear to be significantly increased in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families. PMID:25963852

  9. Recognizing Family Dynamics in the Treatment of Chronic Fatigue Syndrome

    ERIC Educational Resources Information Center

    Sperry, Len

    2012-01-01

    Chronic fatigue syndrome (CFS) is an increasingly common chronic medical condition that affects not only patients but also their families. Because family dynamics, particularly the family life cycle, can and does influence the disease process, those providing counseling to CFS patients and their families would do well to recognize these dynamics.…

  10. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.

    PubMed

    Sly, W S; Whyte, M P; Sundaram, V; Tashian, R E; Hewett-Emmett, D; Guibaud, P; Vainsel, M; Baluarte, H J; Gruskin, A; Al-Mosawi, M

    1985-07-18

    Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. In 1983, we reported a deficiency of carbonic anhydrase II, one of the isozymes of carbonic anhydrase, in three sisters with this disorder. We now describe our study of 18 similarly affected patients with this syndrome in 11 unrelated families of different geographic and ethnic origins. Virtual absence of the carbonic anhydrase II peak on high-performance liquid chromatography, of the esterase and carbon dioxide hydratase activities of carbonic anhydrase II, and of immunoprecipitable isozyme II was demonstrated on extracts of erythrocyte hemolysates from all patients studied. Reduced levels of isozyme II were found in obligate heterozygotes. These observations demonstrate the generality of the findings that we reported earlier in one family and provide further evidence that a deficiency of carbonic anhydrase II is the enzymatic basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. We also summarize the clinical findings in these families, propose mechanisms by which a deficiency of carbonic anhydrase II could produce this metabolic disorder of bone, kidney, and brain, and discuss the clinical evidence for genetic heterogeneity in patients from different kindreds with this inborn error of metabolism.

  11. Presence of Large Deletions in Kindreds with Autism

    PubMed Central

    Yu, Chang-En; Dawson, Geraldine; Munson, Jeffrey; D’Souza, Ian; Osterling, Julie; Estes, Annette; Leutenegger, Anne-Louise; Flodman, Pamela; Smith, Moyra; Raskind, Wendy H.; Spence, M. Anne; McMahon, William; Wijsman, Ellen M.; Schellenberg, Gerard D.

    2002-01-01

    Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from <5.9 kb to >260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis. PMID:12058345

  12. Coping with a child with Dravet syndrome: insights from families.

    PubMed

    Nolan, Kathleen; Camfield, Carol S; Camfield, Peter R

    2008-06-01

    Dravet syndrome is a truly catastrophic childhood-onset epilepsy. Families are faced with repeated episodes of status epilepticus, intractable seizures, mental handicap, behavior disorders, and a life of dependency; understandably, coping with Dravet syndrome is very difficult. Twenty-four families with a child with Dravet syndrome were interviewed and identified some practical suggestions to improve their daily life. These included inserting an indwelling venous access device, creating a portable microenvironment, writing an emergency department protocol, establishing emergency routines for the family, assigning a parent on call to lessen the effect on siblings, creating personal time to decrease parental stress, finding respite care, and contacting an Internet support group. Unresolved and common issues included transition to adult care, the utility of early diagnosis, and social isolation. These solutions and issues may be helpful to many families with a child with Dravet syndrome and possibly other severe childhood-onset epilepsies.

  13. Larsen syndrome in two generations of an Italian family.

    PubMed Central

    Ventruto, V; Festa, F; Sebastio, L; Sebastio, G

    1976-01-01

    This paper describes a familial case of Larsen syndrome. Typical anomalies were present in the propositus and 2 of his 6 daughters. In addition, all patients had progressive deafness and the 2 daughters had cleft palate. The certain exclusion of any consanguinity between the couple, suggests, in this instance, the dominant mode of transmission of the syndrome. Images PMID:1018317

  14. Asperger Syndrome: Familial and Pre- and Perinatal Factors

    ERIC Educational Resources Information Center

    Gillberg, Christopher; Cederlund, Mats

    2005-01-01

    Objective: Study familial and pre- and perinatal factors in Asperger Syndrome (AS). Methods: Hundred boys with AS had their records reviewed. "Pathogenetic subgroups" were defined according to presence of medical syndromes/chromosomal abnormalities, indices of familiarity, and pre- and perinatal risk factors predisposing to brain damage. Results:…

  15. Divorce in families of children with Down Syndrome or Rett Syndrome.

    PubMed

    Lederman, Vivian Renne Gerber; Alves, Bianca dos Santos; Negrão, Juliana; Maria, Juliana Negrão; Schwartzman, José Salomão; D'Antino, Maria Eloisa Famá; Brunoni, Decio

    2015-05-01

    This study evaluates the impact in the stability and management of the marriage of parents of a child with Down or Rett Syndrome. Morbidity of the syndromes and the marital status of the couples before and after the birth of the affected children were considered variables. The divorce rate in families with Down syndrome was 10%, similar to the Brazilian rate population. In Rett Syndrome, the divorce rate was significantly higher, 23.5%. The higher morbidity of Rett Syndrome, and the moment of diagnosis could be relevant factors for the increased divorce rate related to this syndrome.

  16. [Asperger's syndrome in family context--review of studies].

    PubMed

    Zmijewska, Anna

    2010-01-01

    In recent years in the face of still growing number of diagnosis of pervasive developmental disorders there has been an increase in number of research in the functioning of family of children with autism or Asperger's Syndrome. Studies concerning families of children with autism have been predominantly occupied with the stress-coping strategies and also with the therapeutic effect of interaction between disabled children and the rest of the family. New studies with families of children with Asperger's Syndrome, apart from the coping styles of parents and the received support, are also examining the properties of the system of these families, like: cohesion, adaptability, organisation, control, expressiveness or conflict. Such a perspective enables researchers to describe the circularity of influences in these families, on the other hand, however, some methodological deficiencies of this research, as well as the lack of longitudinal studies prevent researchers from creating a comprehensive picture of functioning of these families.

  17. Prenatal diagnosis and a donor splice site mutation in fibrillin in a family with Marfan syndrome

    SciTech Connect

    Godfrey, M.; Vandemark, N.; Wang, M.; Han, J.; Rao, V.H. ); Velinov, M.; Tsipouras, P. ); Wargowski, D.; Becker, J.; Robertson, W.; Droste, S. )

    1993-08-01

    The Marfan syndrome, an autosomal dominant connective tissue disorder, is manifested by abnormalities in the cardiovascular, skeletal, and ocular systems. Recently, fibrillin, an elastic-associated microfibrillar glycoprotein, has been linked to the Marfan syndrome, and fibrillin mutations in affected individuals have been documented. In this study, genetic linkage analysis with fibrillin-specific markers was used to establish the prenatal diagnosis in an 11-wk-gestation fetus in a four-generation Marfan kindred. At birth, skeletal changes suggestive of the Marfan syndrome were observed. Reverse transcription-PCR amplification of the fibrillin gene mRNA detected a deletion of 123 bp in one allele in affected relatives. This deletion corresponds to an exon encoding an epidermal growth factor-like motif. Examination of genomic DNA showed a G[yields]C transversion at the +1 consensus donor splice site. 45 refs., 7 figs.

  18. Hereditary leiomyomatosis and renal cell cancer syndrome: a family affair.

    PubMed

    Teh, Jiasian; Kinnear, Ned; Douglass-Molloy, Hannah; Hennessey, Derek Barrry

    2017-01-25

    A 49-year-old woman with cutaneous and uterine leiomyomas, flank pain and a family history of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome sought genetic testing. She was found to harbour a fumarate hydratase (FH) genetic mutation and a previously undetected renal tumour. The patient underwent radical nephrectomy, and remains well at follow-up. HLRCC syndrome is a rare autosomal dominant disease, with patients at increased risk for cutaneous leiomyomas, early-onset uterine leiomyomas and aggressive renal carcinoma. Although the syndrome may manifest life-threatening complications, outcomes may be improved by preventative family screening and surveillance, compelling early diagnosis.

  19. Familial IPEX syndrome: different glomerulopathy in two siblings.

    PubMed

    Park, Eujin; Chang, Hye Jin; Shin, Jae Il; Lim, Beom Jin; Jeong, Hyeon Joo; Lee, Kyoung Bun; Moon, Kyoung Chul; Kang, Hee Gyung; Ha, Il-Soo; Cheong, Hae Il

    2015-04-01

    Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (OMIM 304790) is a rare hereditary disorder of the immune regulatory system caused by FOXP3 mutations. The clinical features of this syndrome include a wide spectrum of severe autoimmune diseases and renal involvement, mostly due to tubulointerstitial diseases, in some patients. Glomerulopathy of membranous nephropathy (MN) and minimal change nephrotic syndrome (MCNS), however, have also been reported. We encountered two children with IPEX syndrome from the same family. Interestingly, they had different glomerular lesions: one had MN and the other had MCNS. Herein we describe the cases of these siblings and review the possible mechanisms for the development of two different renal lesions.

  20. Families of 30-35-Year Olds with Down's Syndrome

    ERIC Educational Resources Information Center

    Carr, Janet

    2005-01-01

    Background: The families of a population sample of people with Down's syndrome (DS), and of their non-disabled controls, have been followed since early childhood, and the families have now been seen again as their sons and daughters reached age 30 and 35 years. Methods: A semi-structured interview schedule was used, including items from the…

  1. Modeling Family Dynamics in Children with Fragile X Syndrome

    ERIC Educational Resources Information Center

    Hall, Scott S.; Burns, David D.; Reiss, Allan L.

    2007-01-01

    Few studies have examined the impact of children with genetic disorders and their unaffected siblings on family functioning. In this study, the reciprocal causal links between problem behaviors and maternal distress were investigated in 150 families containing a child with fragile X syndrome (FXS) and an unaffected sibling. Both children's…

  2. Family Therapy of Terroristic Trauma: Psychological Syndromes and Treatment Strategies.

    ERIC Educational Resources Information Center

    Miller, Laurence

    2003-01-01

    Reviews pertinent literature on terroristic trauma and combines this information with the author's experience in treating adults, children, and family victims and survivors of recent terrorist attacks. Describes the psychological syndromes resulting from terrorism and discusses the relevant individual and family therapy modalities for treating…

  3. [Tarsal-carpal coalition syndrome: a familial case].

    PubMed

    Caino, S; Dello Ruso, B; Fano, V; Obregón, M G

    2012-06-01

    Tarsal-carpal coalition syndrome (TCC, OMIM #186570) is an autosomal dominant disorder characterised by fusion of the carpals, tarsals, and phalanges, with the short first metacarpals causing brachydactyly and humeroradial fusion. Mutations in the NOG gene have been reported in many families. We describe a family with carpal tarsal fusion seen at a Skeletal Dysplasia Clinic and look at the differential diagnoses.

  4. The Liebenberg syndrome: in depth analysis of the original family.

    PubMed

    Mennen, U; Mundlos, S; Spielmann, M

    2014-11-01

    The Liebenberg syndrome was first described in 1973 in a five- generation family. A sixth generation was added in 2001, and in 2009 a hitherto unknown branch of the same family with similar anomalies extended the family tree significantly. This article describes the clinical findings and illustrates the abnormalities with radiographs and three-dimensional computed tomography scans. We discuss the genetic abnormality that causes Liebenberg syndrome, the genomic rearrangement at the PITX1 locus on chromosome 5.The structural variations seem to result in an ectopic expression of paired-like homeodomain transcription factor 1 (PITX1) in the forelimb causing a partial arm-to-leg transformation in these patients.

  5. Familial or genetic primary aldosteronism and Gordon syndrome.

    PubMed

    Stowasser, Michael; Pimenta, Eduardo; Gordon, Richard D

    2011-06-01

    Salt-sensitive forms of hypertension have received considerable renewed attention in recent years. This article focuses on 2 main forms of salt-sensitive hypertension (familial or genetic primary aldosteronism [PA] and Gordon syndrome) and the current state of knowledge regarding their genetic bases. The glucocorticoid-remediable form of familial PA (familial hyperaldosteronism type I) is dealt with only briefly because it is covered in depth elsewhere.

  6. Rare nonconservative LRP6 mutations are associated with metabolic syndrome.

    PubMed

    Singh, Rajvir; Smith, Emily; Fathzadeh, Mohsen; Liu, Wenzhong; Go, Gwang-Woong; Subrahmanyan, Lakshman; Faramarzi, Saeed; McKenna, William; Mani, Arya

    2013-09-01

    A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.

  7. Pfeiffer syndrome: clinical and genetic findings in five Brazilian families.

    PubMed

    Júnior, Hercílio-Martelli; de Aquino, Sibele-Nascimento; Machado, Renato-Assis; Leão, Letícia-Lima; Coletta, Ricardo-Della; Burle-Aguiar, Marcos-José

    2015-01-01

    Pfeiffer syndrome (PS) is mainly characterized by craniosysnostosis, midface hypoplasia, great toes with partial syndactyly of the digits, broad and medially deviated thumbs. It is caused by allelic mutations in the fibroblast growth factor receptor 1 and 2 (FGFR1 and 2) genes. This study describes the clinical and genetic features of five Brazilian families affected by PS. All patients exhibited the classical phenotypes related to PS. The genetic analysis was able to detect the mutations Cys278Phe, Cys342Arg, and Val359Leu in three of these families. Two mutations were de novo, with one familial. We identified pathogenic mutations in four PS cases in five Brazilian families by PCR sequencing of FGFR1 exon 5 and FGFR2 exons 5, 8, 10, 11, 15, and 16. The clinical and genetic aspects of these families confirm that this syndrome can be clinically variable, with different mutations in the FGFR2 responsible for PS.

  8. Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes

    SciTech Connect

    Farrer, L.A.; Hoth, C.; Arnos, K.S.; Asher, J.H. Jr.; Friedman, T.B.; Grundfast, K.M.; Lalwani, A.K.; Greenberg, J.; Diehl, S.R.

    1994-10-01

    Waardenburg syndrome (WS) is a dominantly inherited and clinically variable syndrome of deafness, pigmentary changes, and distinctive facial features. Clinically, WS type I (WS1) is differentiated from WS type II (WS2) by the high frequency of dystopia canthorum in the family. In some families, WS is caused by mutations in the PAX3 gene on chromosome 2q. We have typed microsatellite markers within and flanking PAX3 in 41 WS1 kindreds and 26 WS2 kindreds in order to estimate the proportion of families with probable mutations in PAX3 and to study the relationship between phenotypic and genotypic heterogeneity. Evaluation of heterogeneity in location scores obtained by multilocus analysis indicated that WS is linked to PAX3 in 60% of all WS families and in 100% of WS1 families. None of the WS2 families were linked. In those families in which equivocal lod scores (between -2 and +1) were found, PAX3 mutations have been identified in 5 of the 15 WS1 families but in none of the 4 WS2 families. Although preliminary studies do not suggest any association between the phenotype and the molecular pathology in 20 families with known PAX3 mutations and in four patients with chromosomal abnormalities in the vicinity of PAX3, the presence of dystopia in multiple family members is a reliable indicator for identifying families likely to have a defect in PAX3. 59 refs., 3 figs., 5 tabs.

  9. [The role of diagnostic neuropathology in familial tumour syndromes].

    PubMed

    Feiden, S; Sartorius, E; Feiden, W

    2010-10-01

    Inherited cancer syndromes often involve the central and peripheral nervous system. For the surgical neuropathologist the possibility in individual patients of a familial tumour syndrome needs to be considered in the case of special tumours such as malignant peripheral nerve sheath tumour (MPNST), medulloblastoma with extensive nodularity (MBEN) or even atypical teratoid/rhabdoid tumour (AT/RT) of the brain. Furthermore, tumour location and patient age may point to a familial tumour syndrome as in the case of neurofibromatosis type 2 (NF2) with typical bilateral vestibular schwannoma in young age. This short review discusses some of the diagnostic aspects in this field relating to neurofibromatosis type 1 and 2 (NF1, NF2), as well as the two rare tumors MBEN in Gorlin-Goltz syndrome and AT/RT in particular.

  10. Familial cryptic translocation in Angelman syndrome

    SciTech Connect

    Weyerts, L.K.; Wiley, J.E.; Loud, K.M.

    1994-09-01

    The majority of patients with Angelman syndrome have been shown to have a cytogenetic or molecular deletion on the maternally derived chromosome 15. We report on a case of Angelman syndrome in which this deletion occurs as an unbalanced cryptic translocation involving chromosomes 14 and 15. The proband was diagnosed clinically as having Angelman syndrome. Multiple cytogenetic studies were done without detecting any deletion. When DNA probes (Oncor) specific for the Prader Willi/Angelman locus became available, the patient was restudied and found to be deleted for {open_quotes}region A{close_quotes} (D15S11) but not for {open_quotes}region B{close_quotes} (GABRB3). No other abnormality was detected. The proband`s mother was then studied. The chromosome 15 marker probe and D15S11 were detected on different chromosomes. Using alpha-satellite probes, a cryptic 14;15 translocation was uncovered. This balanced translocation was also found to be carried by the sister of the proband. This case, along with a case presented at the 1993 ASHG meeting, illustrates the need for using acrocentric probes when studying Angelman syndrome patients. The proband was studied using additional probes specific for this region and found to be deleted for SNRPN but not for D15S10. The breakpoint of the translocation in this patient delineates the smallest deletion of the Angelman syndrome region reported to date and therefore may represent the specific gene involved.

  11. Autosomal dominant congenital Horner's syndrome in a Dutch family.

    PubMed Central

    Hageman, G; Ippel, P F; te Nijenhuis, F C

    1992-01-01

    A Dutch family is reported with congenital Horner's syndrome in five cases spanning five generations, with symptoms of varying degree but mainly ptosis and meiosis. Heterochromia iridium, anhidrosis, and enophthalmos were not present. The site of the lesion may be in the region between Gasser's ganglion and the short vertical segment of the internal carotid artery near the siphon. There are only four previous reports showing autosomal dominant inheritance of congenital Horner's syndrome. Images PMID:1548493

  12. Autosomal dominant congenital Horner's syndrome in a Dutch family.

    PubMed

    Hageman, G; Ippel, P F; te Nijenhuis, F C

    1992-01-01

    A Dutch family is reported with congenital Horner's syndrome in five cases spanning five generations, with symptoms of varying degree but mainly ptosis and meiosis. Heterochromia iridium, anhidrosis, and enophthalmos were not present. The site of the lesion may be in the region between Gasser's ganglion and the short vertical segment of the internal carotid artery near the siphon. There are only four previous reports showing autosomal dominant inheritance of congenital Horner's syndrome.

  13. Toxic Shock Syndrome: A Family Physician's Perspective

    PubMed Central

    Myhre, D. L.

    1982-01-01

    Although similar cases have been reported as far back as 1927, the term toxic shock syndrome was coined in 1978 to describe an acute fever involving Staph. aureus. The reported mortality rate in Canada is 3.8%, but may be much higher. Association with tampon use was made in 1980, but is still unclear. Treatment remains supportive and is aimed at reducing risk of recurrence, until the role of the exotoxin can be explained. This article reviews reported cases to date, listing diagnostic criteria, signs and symptoms. A high index of suspicion for this new syndrome is recommended. PMID:21286566

  14. A novel mutation in the SLC19A2 gene in a Tunisian family with thiamine-responsive megaloblastic anaemia, diabetes and deafness syndrome.

    PubMed

    Gritli, S; Omar, S; Tartaglini, E; Guannouni, S; Fleming, J C; Steinkamp, M P; Berul, C I; Hafsia, R; Jilani, S B; Belhani, A; Hamdi, M; Neufeld, E J

    2001-05-01

    Thiamine-responsive megaloblastic anaemia (TRMA) syndrome with diabetes and deafness was found in two patients from a Tunisian kindred. The proband was homozygous for a novel mutation, 287delG, in the high-affinity thiamine transporter gene, SLC19A2. We demonstrated that fibroblasts from this patient exhibited defective thiamine transport. These data confirm that the SLC19A2 gene is the high-affinity thiamine carrier and that this novel mutation is responsible for TRMA syndrome.

  15. Family Functioning in Families with a Child with Down Syndrome: A Mixed Methods Approach

    ERIC Educational Resources Information Center

    Povee, K.; Roberts, L.; Bourke, J.; Leonard, H.

    2012-01-01

    Background: This study aimed to explore the factors that predict functioning in families with a child with Down syndrome using a mixed methods design. The quantitative component examined the effect of maladaptive and autism-spectrum behaviours on the functioning of the family while the qualitative component explored the impact of having a child…

  16. Weismann-Netter-Stuhl syndrome: a family report.

    PubMed

    Alp, Hayrullah; Atabek, Mehmet Emre; Pirgon, Özgür

    2009-01-01

    Weismann-Netter-Stuhl (WNS) syndrome is a rare skeletal anomaly that affects the diaphyseal part of both the tibiae and fibulae with posterior cortical thickening and anteroposterior bowing. This anomaly is usually bilateral and symmetrical. The patients are generally of short stature. In some cases, a family history suggesting genetic transmission of a mutation with an unknown locus has been reported. In this paper we present an infant with WNS syndrome with bilateral involvement of the femur. Similar clinical findings were defined in three other family members.

  17. [Familial partial lipodystrophy type 1. A rare or underdiagnosed syndrome?].

    PubMed

    Soutelo, Jimena; Grüneisen, Mariana; Fritz, Clara; Sordo, Laura; Powazniak, Yanina; Lutfi, Rubén

    2015-01-01

    Familial partial lipodystrophy (FPL) type 1 is a syndrome characterized by loss of subcutaneous fat in arms and legs and an excess of body fat in face, neck, and torso. This rare syndrome is usually diagnosed when patients present cardiovascular complications or pancreatitis due to the severe metabolic abnormalities. Here we present the case of a 45 year old diabetic female without any pathological family history, a poor glycemic control (HbA1c 11.7%), hypertriglideridemia (3000 mg/dl), a body mass index (BMI) of 38, thin limbs, subcutaneous fat loss in gluteal area and ledge of fat above them, prominent veins in lower extremities, moon face, and acanthosis nigricans; as well as hypertension (150/100 mmHg) and subcutaneous folds measuring less than average were observed. Hypercortisolism was discarded and leptin levels were measured (16.8 mg/ml, VR: BMI > 30: 50 mg/ml). Due to these clinical and biochemical manifestations, and low leptin levels (16.8 mg/ml), Kobberling syndrome was suspected; however, LMNA mutation analysis was negative. Changes in lifestyle and treatment with fenofibrate, biphasic insulin 50/50, and enalapril were initiated showing a a significant metabolic improvement: HbA1c (7.8%) and TG (243 mg/dl). FPL type 1 is a familial disease, although there are spontaneous cases. No specific mutation is responsible for this syndrome. Due to its clinical manifestations, Cushing syndrome must be discarded.

  18. Mutation spectrum in South American Lynch syndrome families

    PubMed Central

    2013-01-01

    Background Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system. Methods We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included. Results Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia. Conclusion The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent. PMID:24344984

  19. Ellis-van Creveld Syndrome: Mutations Uncovered in Lebanese Families.

    PubMed

    Valencia, Maria; Tabet, Lara; Yazbeck, Nadine; Araj, Alia; Ruiz-Perez, Victor L; Charaffedine, Khalil; Fares, Farah; Badra, Rebecca; Farra, Chantal

    2015-01-01

    Background. Ellis-van Creveld (EvC) syndrome is a rare, autosomal recessive disorder characterized by short stature, short limbs, growth retardation, polydactyly, and ectodermal defects with cardiac anomalies occurring in around 60% of cases. EVC syndrome has been linked to mutations in EVC and EVC2 genes. Case Presentation. We report EvC syndrome in two unrelated Lebanese families both having homozygous mutations in the EVC2 gene, c.2653C>T (p.(Arg885(*))) and c.2012_2015del (p.(Leu671(*))) in exons 15 and 13, respectively, with the latter being reported for the first time. Conclusion. Although EvC has been largely described in the medical literature, clinical features of this syndrome vary. While more research is required to explore other genes involved in EvC, early diagnosis and therapeutic care are important to achieve a better quality of life.

  20. Pfeiffer syndrome: Clinical and genetic findings in five Brazilian families

    PubMed Central

    Júnior, Hercílio-Martelli; Machado, Renato-Assis; Leão, Letícia-Lima; Coletta, Ricardo- Della; Burle-Aguiar, Marcos-José

    2015-01-01

    Pfeiffer syndrome (PS) is mainly characterized by craniosysnostosis, midface hypoplasia, great toes with partial syndactyly of the digits and broad and medially deviated thumbs. It is caused by allelic mutations in the fibroblast growth factor receptor 1 and 2 (FGFR1 and 2) genes. This study describes the clinical and genetic features of five Brazilian families affected by PS. All patients exhibited the classical phenotypes related to PS. The genetic analysis was able to detect the mutations Cys278Phe, Cys342Arg, and Val359Leu in three of these families. Two mutations were de novo, with one familial. We identified pathogenic mutations in four PS cases in five Brazilian families by PCR sequencing of FGFR1 exon 5 and FGFR2 exons 5, 8, 10, 11, 15, and 16. The clinical and genetic aspects of these families confirm that this syndrome can be clinically variable, with different mutations in the FGFR2 responsible for PS. Key words:Craniosynostosis, Pfeiffer syndrome, mutation, FGFR2. PMID:25129254

  1. Genotype versus phenotype in families with androgen insensitivity syndrome.

    PubMed

    Boehmer, A L; Brinkmann, O; Brüggenwirth, H; van Assendelft, C; Otten, B J; Verleun-Mooijman, M C; Niermeijer, M F; Brunner, H G; Rouwé, C W; Waelkens, J J; Oostdijk, W; Kleijer, W J; van der Kwast, T H; de Vroede, M A; Drop, S L

    2001-09-01

    Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner

  2. Phenotype, hormonal profile and genotype of subjects with partial androgen insensitivity syndrome: report of a family with four adult males and one child with disorder of sexual differentiation.

    PubMed

    Kulshreshtha, B; Philibert, P; Eunice, M; Audran, F; Paris, F; Khurana, M L; Ammini, A C; Charles, S

    2009-08-01

    There is little information on the molecular basis of intrafamilial and inter-familial phenotypic heterogeneity with the same androgen receptor (AR) mutation in patients with partial androgen insensitivity syndrome. A genetic analysis was performed in a large kindred with ambiguous genitalia and the genotype-phenotype correlations were analysed. The index case was brought for sex assignment. Family history revealed four other affected members who had hypospadias and varying degrees of virilisation. All the affected males had hemizygous mutations in the third exon of the AR gene (A596T). One was also found to have a heterozygous mutation in the fourth exon of the 5 alpha reductase type 2 gene (G196S). This affected male with double mutations was better virilised compared with the other affected members with a single mutation. The degree of virilisation correlated with serum testosterone levels. Gynaecomastia was not present in any of these subjects. It is concluded that the subject with dual gene defects also had higher levels of testosterone and pubertal virilsation. Testosterone levels possibly govern the degree of pubertal virilisation in subjects with A596T gene defects. It is not clear whether the better pubertal virilsation and higher testosterone are in any way causally related to the SRD5A2 gene defect.

  3. Profuse congenital familial milia with absent dermatoglyphics (Basan's Syndrome): description of a new family.

    PubMed

    Luna, Paula Carolina; Larralde, Margarita

    2012-01-01

    Milia are common, small, keratin-containing cysts frequently seen in all age groups. They may arise spontaneously or develop after a variety of stimuli. They can be found alone or as part of syndromes. We present a female neonate born not only with profuse facial milia, but also with acral bullae and absent dermatoglyphics. Similar features were seen in several members of her family. These findings correspond to the syndrome known as Basan's syndrome, a rare autosomal-dominant inherited dermatosis characterized by profuse congenital milia, transient neonatal acral bullae, and absence of dermatoglyphics.

  4. Familial Gordon syndrome associated with a PIEZO2 mutation.

    PubMed

    Alisch, Franz; Weichert, Alexander; Kalache, Karim; Paradiso, Viola; Longardt, Ann Carolin; Dame, Christof; Hoffmann, Katrin; Horn, Denise

    2017-01-01

    Gordon syndrome or distal arthrogryposis type 3 is a rare autosomal dominant disorder characterized by contractures of upper and lower limbs. It is distinguishable from other forms of distal arthrogryposis by cleft palate and short stature. Recently, Gordon syndrome has been associated to heterozygous mutations in the piezo-type mechanosensitive ion channel component 2 gene (PIEZO2). Different mutations of this gene also cause distal arthrogryposis type 5 and Marden-Walker syndrome. Dysfunction of this ion channel provides pleiotropic effects on joints, ocular muscles, and bone development. Here, we present a family with three affected individuals exhibiting multiple contractures (metacarpo-phalangeal and interphalangeal joints as well as elbow, shoulder, knee, and ankle joints), clubfeet, short stature, bifid uvula/cleft palate, and a distinct facial phenotype including ptosis. In addition, mild intellectual disability and delay in psychomotor development are obvious. The multigenerational phenotypic spectrum of Gordon syndrome is present in the 37-year-old father, his 4-year-old son and a male neonate showing typical signs of arthrogryposis in the prenatal ultrasound examination already seen at 13 week of gestation. In all affected family members, we identified the PIEZO2 mutation c.8057G>A (p.Arg2686His) by Sanger sequencing. Our analysis indicated that mild delay in psychomotor development and intellectual disability could be part of the phenotypic spectrum of Gordon syndrome. © 2016 Wiley Periodicals, Inc.

  5. A large Turkish kindred with syndactyly type II (synpolydactyly). 1. Field investigation, clinical and pedigree data.

    PubMed Central

    Sayli, B S; Akarsu, A N; Sayli, U; Akhan, O; Ceylaner, S; Sarfarazi, M

    1995-01-01

    A very large Turkish family with syndactyly type II (synpolydactyly (SPD)) is described, which originated from and is mainly concentrated in the village of Derbent, Afyon. The kindred consists of 425 subjects over seven generations, of whom 182 are affected. It appears that a founder effect in this village has led to this extensive kindred. This condition is inherited as an autosomal dominant trait with variable expressivity and an estimated penetrance of 96%. Penetrance is different between the upper (96%) and lower (69.5%) extremities. No excess of affected males or females or other associated features were documented in this condition. Variations in the involvement of one or both hands, upper or lower extremities, bone and soft tissue, as well as variation in the affected subjects of two successive generations were documented. We also noted that metacarpal and metatarsal involvement and middle phalangeal hypoplasia of the feet are the consistent features of SPD and, therefore, should be considered as characteristic of this phenotype. We observed four different phenotypes in various branches of the Derbent kindred: (1) subjects presenting typical features of SPD; (2) subjects exhibiting both pre- and post-axial polydactyly simultaneously; (3) persons manifesting postaxial polydactyly type A; and (4) subjects born to two affected parents with severe hand and foot deformities that have not been previously described in any other SPD families (that is, homozygotes). A total of 27 affected offspring were born to two such affected parents, of whom seven are expected to be homozygous for the SPD gene. This group is presented in an accompanying paper in this issue of the Journal. A molecular study is currently under way to identify the chromosomal location of the defective gene. Images PMID:7666393

  6. Familial Kleine-Levin Syndrome: A Specific Entity?

    PubMed Central

    Nguyen, Quang Tuan Remy; Groos, Elisabeth; Leclair-Visonneau, Laurène; Monaca-Charley, Christelle; Rico, Tom; Farber, Neal; Mignot, Emmanuel; Arnulf, Isabelle

    2016-01-01

    Study Objectives: Kleine-Levin syndrome (KLS) is a rare, mostly sporadic disorder, characterized by intermittent episodes of hypersomnia plus cognitive and behavior disorders. Although its cause is unknown, multiplex families have been described. We contrasted the clinical and biological features of familial versus sporadic KLS. Methods: Two samples of patients with KLS from the United States and France (n = 260) were studied using clinical interviews and human leukocyte antigen (HLA) genotyping. A multiplex family contained two or more first- or second-degree affected relatives (familial cases). Results: Twenty-one patients from 10 multiplex families (siblings: n = 12, including two pairs of monozygotic twins; parent-child: n = 4; cousins: n = 2; uncle-nephews: n = 3) and 239 patients with sporadic KLS were identified, yielding to 4% multiplex families and 8% familial cases. The simplex and multiplex families did not differ for autoimmune, neurological, and psychiatric disorders. Age, sex ratio, ethnicity, HLA typing, karyotyping, disease course, frequency, and duration of KLS episodes did not differ between groups. Episodes were less frequent in familial versus sporadic KLS (2.3 ± 1.8/y versus 3.8 ± 3.7/y, P = 0.004). Menses triggered more frequently KLS onset in the nine girls with familial KLS (relative risk, RR = 4.12, P = 0.03), but not subsequent episodes. Familial cases had less disinhibited speech (RR = 3.44, P = 0.049), less combined hypophagia/hyperphagia (RR = 4.38, P = 0.006), more abrupt termination of episodes (RR = 1.45, P = 0.04) and less postepisode insomnia (RR = 2.16, P = 0.008). There was similar HLA DQB1 distribution in familial versus sporadic cases and no abnormal karyotypes. Conclusion: Familial KLS is mostly present in the same generation, and is clinically similar to but slightly less severe than sporadic KLS. Citation: Nguyen QT, Groos E, Leclair-Visonneau L, Monaca-Charley C, Rico T, Farber N, Mignot E, Arnulf I. Familial Kleine

  7. Genotype–phenotype correlation in long QT syndrome families

    PubMed Central

    Qureshi, Sameera Fatima; Ali, Altaf; Venkateshwari, Ananthapur; Rao, Hygriv; Jayakrishnan, M.P.; Narasimhan, Calambur; Shenthar, Jayaprakash; Thangaraj, Kumarasamy; Nallari, Pratibha

    2015-01-01

    Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction. Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1–4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of “anticipation” in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation. PMID:27479201

  8. The familial hyperchylomicronemia syndrome: New insights into underlying genetic defects

    SciTech Connect

    Santamarina-Fojo, S.; Brewer, H.B. )

    1991-02-20

    This case history reports the diagnosis of familial hyperchylomicronemia, a rare genetic syndrome inherited as an autosomal recessive trait. It is characterized by severe fasting hypertriglyceridemia and massive accumulations of chylomicrons in plasma. The two major molecular defects in the disease are a deficiency of lipoprotein lipase or of apo C-II. The location of the mutations in the human apolipoprotein (apo) C-II gene are identified.

  9. Mutations in keratin K9 in kindreds with epidermolytic palmoplantar keratoderma and epidemiology in Northern Ireland.

    PubMed

    Covello, S P; Irvine, A D; McKenna, K E; Munro, C S; Nevin, N C; Smith, F J; Uitto, J; McLean, W H

    1998-12-01

    Epidermolytic palmoplantar keratoderma (EPPK, MIM #144200) is an autosomal dominant disorder in which hyperkeratosis confined to the palms and soles is characterized histologically by cytolysis of suprabasal keratinocytes. Mutations in the keratin 9 gene (KRT9), a type 1 keratin expressed exclusively in the suprabasal keratinocytes of palmoplantar epidermis, have previously been demonstrated in this disorder. Here, we have studied four Northern Irish kindreds presenting with EPPK. By direct sequencing of polymerase chain reaction products, heterozygous missense mutations in exon 1 of KRT9 were detected in all the families. These included a novel mutation M156T; as well as M156V in two kindreds; and R162Q in the remaining family. All mutations were confirmed by reverse strand sequencing and restriction enzyme analysis. The point prevalence of EPPK in Northern Ireland was found to be 4.4 per 100,000. To date, all reported EPPK mutations occur in the helix initiation motif at the start of the central coiled-coil rod domain of K9.

  10. Diagnosis of cystic fibrosis in the kindred of an infant with CFTR-related metabolic syndrome: importance of follow-up that includes monitoring sweat chloride concentrations over time.

    PubMed

    Williams, Sophia N; Nussbaum, Eliezer; Chin, Terry W; Do, Paul C M; Singh, Kathryn E; Randhawa, Inderpal

    2014-03-01

    Newly implemented newborn screening (NBS) programs in California have resulted in a large subset of patients in whom at least two cystic fibrosis transmembrane conductance regulator (CFTR) mutations are identified, but subsequent sweat chloride analysis reveals normal or indeterminate values. These patients are diagnosed with CFTR-Related Metabolic Syndrome (CRMS). However, the natural progression and management of these patients are not clearly understood and frequently after the age of 1-year these patients are lost to follow-up with Cystic Fibrosis (CF) Centers. We present the first case of an infant who was referred to Miller Children's Hospital for a NBS positive for CF and subsequent discovery of identical mutations in six of his seven older brothers. Several siblings had positive sweat chloride results on repeat testing after the age of 3 years. We suggest the need for continued follow-up of CRMS in a CF center with diagnostic evaluation including repeat sweat chloride testing, beyond the currently recommended period.

  11. GLI3 mutations in syndromic and non-syndromic polydactyly in two Indian families.

    PubMed

    Patel, Rashmi; Singh, Chandra Bhan; Bhattacharya, Visweswar; Singh, Subodh Kumar; Ali, Akhtar

    2016-03-01

    The GLI3 protein is a zinc finger transcription factor, expressed early in development. The GLI3 gene exhibits allelic heterogeneity as mutations in this gene are associated with several developmental syndromic and non-syndromic polydactyly. The present study reports two cases: first, a familial case of Greig Cephalopolysyndactyly Syndrome (GCPS); the second is a sporadic case with both postaxial polydactyly (PAP) type A and B. Resequencing of GLI3 gene reveals a previously reported nonsense truncation mutation g.42007251G > A (p.R792X; rs121917714) in the GCPS family and a novel single nucleotide insertion g.42004239_42004240insA (p.E1478X) in the sporadic case of postaxial polydactyly (PAP). Both nonsense truncation mutations; p.R792X (GCPS) and p.E1478X (PAP) introduce a premature stop codon leading to loss of C-terminal domains.

  12. Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene.

    PubMed

    Pitteloud, Nelly; Acierno, James S; Meysing, Astrid U; Dwyer, Andrew A; Hayes, Frances J; Crowley, William F

    2005-03-01

    Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder. Recently, loss-of-function mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been shown to cause autosomal dominant KS. To date, the detailed reproductive phenotype of KS associated with mutations in the FGFR1 has yet to be described. We report a kindred comprising a male proband with KS and spontaneous reversibility, whose mother had delayed puberty and whose maternal grandfather isolated anosmia. The proband presented at age 18 yr with KS and was subsequently treated with testosterone (T) therapy. Upon discontinuation of T therapy, he recovered from his hypogonadotropic hypogonadism, as evidenced by a normal LH secretion pattern, sustained normal serum T levels, and active spermatogenesis. The three members of this single family harbor the same FGFR1 mutation (Arg(622)X) in the tyrosine kinase domain. This report demonstrates 1) the first genetic cause of the rare variant of reversible KS, 2) the reversal of hypogonadotropic hypogonadism in a proband carrying an FGFR1 mutation suggests a role of FGFR1 beyond embryonic GnRH neuron migration, and 3) a loss of function mutation in the FGFR1 gene causing delayed puberty.

  13. Divorce in Families of Children with Down Syndrome: A Population-Based Study

    ERIC Educational Resources Information Center

    Urbano, Richard C.; Hodapp, Robert M.

    2007-01-01

    In this study, we examined the nature, timing, and correlates of divorce in families of children with Down syndrome (647), other birth defects (10,283) and no identified disability (361,154). Divorce rates among families of children with Down syndrome were lower than in the other two groups. When divorce did occur in the Down syndrome group,…

  14. Effects of nephrotic syndrome on the family: a controlled study.

    PubMed

    Vance, J C; Fazan, L E; Satterwhite, B; Pless, I B

    1980-05-01

    The hypothesis that the parents and siblings of children with nephrotic syndrome are more likely to develop psychosocial problems than those of healthy children was tested. Seventy-nine siblings from 36 such families were compared with 79 healthy children from closely matched families using interviews, parent rating scales, teachers' reports, and psychological tests. Although few striking differences were found between the two groups, the findings suggest several areas of increased vulnerability among the parents and siblings of children with nephrosis. Parents often denied the existence of apparently stressful events, but the personality profiles of the siblings suggested decreased social confidence and a lesser degree of self-acceptance. Evidence of inhibition, such as less aggression and poorer academic performance, were also described in response to questions in the interview. These results should prove useful to clinicians in the management of families of children with this or other chronic illnesses.

  15. Familial Aggregation and Segregation Analysis in Families Presenting Autoimmunity, Polyautoimmunity, and Multiple Autoimmune Syndrome

    PubMed Central

    Castiblanco, John; Sarmiento-Monroy, Juan Camilo; Mantilla, Ruben Dario; Rojas-Villarraga, Adriana; Anaya, Juan-Manuel

    2015-01-01

    Studies documenting increased risk of developing autoimmune diseases (ADs) have shown that these conditions share several immunogenetic mechanisms (i.e., the autoimmune tautology). This report explored familial aggregation and segregation of AD, polyautoimmunity, and multiple autoimmune syndrome (MAS) in 210 families. Familial aggregation was examined for first-degree relatives. Segregation analysis was implemented as in S.A.G.E. release 6.3. Data showed differences between late- and early-onset families regarding their age, age of onset, and sex. Familial aggregation of AD in late- and early-onset families was observed. For polyautoimmunity as a trait, only aggregation was observed between sibling pairs in late-onset families. No aggregation was observed for MAS. Segregation analyses for AD suggested major gene(s) with no clear discernible classical known Mendelian transmission in late-onset families, while for polyautoimmunity and MAS no model was implied. Data suggest that polyautoimmunity and MAS are not independent traits and that gender, age, and age of onset are interrelated factors influencing autoimmunity. PMID:26697508

  16. Clinical variability in KBG syndrome: report of three unrelated families.

    PubMed

    Maegawa, Gustavo Henrique Boff; Leite, Júlio Cesar Loguercio; Félix, Têmis Maria; da Silveira, Heraldo Luís Dias; da Silveira, Heloísa Emília

    2004-12-01

    The KBG syndrome is characterized by short stature, macrodontia, a specific combination of minor anomalies, developmental delay, and/or mental retardation. We reported on four patients from three unrelated families. The most frequent clinical findings were: atypical face, long/flat philtrum, thin upper lip, macrodontia, dental malposition, enamel hypoplasia, and cleft teeth. Skeletal anomalies such as cervical ribs and vertebral abnormalities were also noted. Hand anomalies were observed in three patients. Mental retardation and developmental delay were present in three of the four patients. There is wide clinical variability in the expression of this syndrome. The males are usually more severely affected then the females, suggesting possible X-linked inheritance in some cases.

  17. Familial hypopituitarism associated with mosaic form of Turner syndrome.

    PubMed

    Lomna-Bogdanov, Elzbieta; Bolanowski, Marek; Slezak, Ryszard; Sokolska, Violetta; Pałczyiński, Bogusław; Spring, Adam; Demissie, Marek

    2005-01-01

    We present herein an unusual coincidence of familial hypopituitarism associated with a mosaic form of Turner syndrome in two adult sisters (51 and 43 years old). Both patients had hypopituitarism diagnosed in childhood. They have never been administered growth hormone, and remained short in stature. They were not given long-term estrogen-progestin treatment, despite lack of menstruation. Early in childhood both received thyroid hormone substitution. Pituitary imaging revealed pituitary hypoplasia with partial empty sella in one sister, and pituitary hypoplasia in the other. Very recently, during endocrinological evaluation, they were diagnosed with a mosaic form of Turner syndrome, additionally to their hypopituitarism. In this paper, we place special emphasis on the results of hormonal analyses and discuss the differential diagnosis.

  18. PDGFRA-mutant syndrome.

    PubMed

    Ricci, Riccardo; Martini, Maurizio; Cenci, Tonia; Carbone, Arnaldo; Lanza, Paola; Biondi, Alberto; Rindi, Guido; Cassano, Alessandra; Larghi, Alberto; Persiani, Roberto; Larocca, Luigi M

    2015-07-01

    Germline PDGFRA mutations cause multiple heterogeneous gastrointestinal mesenchymal tumors. In its familial form this disease, which was formerly termed intestinal neurofibromatosis/neurofibromatosis 3b (INF/NF3b), has been included among familial gastrointestinal stromal tumors (GISTs) because of its genotype, described when GIST was the only known PDGFRA-mutant gastrointestinal tumor. Shortly afterwards, however, inflammatory fibroid polyps also revealed PDGFRA mutations. Subsequently, gastrointestinal CD34+ 'fibrous tumors' of uncertain classification were described in a germline PDGFRA-mutant context. Our aim was to characterize the syndrome produced by germline PDGFRA mutations and establish diagnostic criteria and management strategies for this hitherto puzzling disease. We studied a kindred displaying multiple gastrointestinal mesenchymal tumors, comparing it with published families/individuals with possible analogous conditions. We identified a novel inherited PDGFRA mutation (P653L), constituting the third reported example of familial PDGFRA mutation. In adult mutants we detected inflammatory fibroid polyps, gastric GISTs and gastrointestinal fibrous tumors of uncertain nosology. We demonstrate that the syndrome formerly defined as INF/NF3b (exemplified by the family reported herein) is simplistically considered a form of familial GIST, because inflammatory fibroid polyps often prevail. Fibrous tumors appear variants of inflammatory fibroid polyps. 'INF/NF3b' and 'familial GIST' are misleading terms which we propose changing to 'PDGFRA-mutant syndrome'. In this condition, unlike KIT-dependent familial GIST syndromes, if present, GISTs are stomach-restricted and diffuse Cajal cell hyperplasia is not observed. This restriction of GISTs to the stomach in PDGFRA-mutant syndrome: (i) focuses oncological concern on gastric masses, as inflammatory fibroid polyps are benign; (ii) supports a selective role of gastric environment for PDGFRA mutations to elicit GISTs

  19. Exclusion of linkage between the serotonin2 receptor and schizophrenia in a large Swedish kindred.

    PubMed

    Hallmayer, J; Kennedy, J L; Wetterberg, L; Sjögren, B; Kidd, K K; Cavalli-Sforza, L L

    1992-03-01

    Family, twin, and adoption studies suggest that genetic factors play an important role in the etiology of schizophrenia. Detection of single gene(s) involved in a higher susceptibility to a hereditary disease is possible with linkage analysis. The effects of serotonin2-receptor antagonists on symptoms of schizophrenia suggest that a mutation in the gene coding for this receptor subtype might be involved in the pathophysiology of this disease. Recently a copy DNA encoding the serotonin 5-HT2 receptor has been isolated and with a human 5-HT2 receptor copy DNA probe the HTR2 locus has been mapped to chromosome 13. Using multipoint linkage analysis between schizophrenia and genetic markers spanning the region of the HTR2 locus, we were able to exclude linkage between this candidate gene and schizophrenia in a Swedish kindred. Given this result, we conclude that the serotonin 5-HT2 receptor gene itself is not a major susceptibility gene for schizophrenia in this family.

  20. Towards identification of an epilepsy gene in a large family with idiopathic generalized epilepsy

    SciTech Connect

    Roussear, M.; Lopes-Cendes, I.; Berkovic, S.F.

    1994-09-01

    To identify the disease gene in a large, multiplex family segregating an autosomal dominant form of idiopathic generalized epilepsy (IGE). The IGEs have been recognized for several decades as being genetically determined. However, large pedigrees with a clear Mendelian inheritance are not commonly available. This, and the presence of locus heterogeneity have been obstacles to the identification of linkage in several IGE syndromes. We have identified a large IGE kindred with fifty-eight living individuals, including 26 affecteds, showing a clear autosomal dominant inheritance with incomplete penetrance. Forty-fur informative individuals, including 23 affecteds, were selected for the linkage studies. We have chosen 200 polymorphic microsatellite markers, about 20 cM apart, throughout the human autosomes as a genome-search linkage strategy. To date, 47 markers, representing 30% of the human genome, have been excluded for linkage in the Australian kindred. As our study progresses, we will report up-to-date results.

  1. Factors influencing uptake of familial long QT syndrome genetic testing.

    PubMed

    Burns, Charlotte; McGaughran, Julie; Davis, Andrew; Semsarian, Christopher; Ingles, Jodie

    2016-02-01

    Ongoing challenges of clinical assessment of long QT syndrome (LQTS) highlight the importance of genetic testing in the diagnosis of asymptomatic at-risk family members. Effective access, uptake, and communication of genetic testing are critical for comprehensive cascade family screening and prevention of disease complications such as sudden cardiac death. The aim of this study was to describe factors influencing uptake of LQTS genetic testing, including those relating to access and family communication. We show those who access genetic testing are overrepresented by the socioeconomically advantaged, and that although overall family communication is good, there are some important barriers to be addressed. There were 75 participants (aged 18 years or more, with a clinical and/or genetic diagnosis of LQTS; response rate 71%) who completed a survey including a number of validated scales; demographics; and questions about access, uptake, and communication. Mean age of participants was 46 ± 16 years, 20 (27%) were males and 60 (80%) had genetic testing with a causative gene mutation in 42 (70%). Overall uptake of cascade testing within families was 60% after 4 years from proband genetic diagnosis. All participants reported at least one first-degree relative had been informed of their risk, whereas six (10%) reported at least one first-degree relative had not been informed. Those who were anxious or depressed were more likely to perceive barriers to communicating. Genetic testing is a key aspect of care in LQTS families and intervention strategies that aim to improve equity in access and facilitate effective family communication are needed.

  2. FOXL2 mutations in Chinese families with Blepharophimosis syndrome (BPES).

    PubMed

    Fan, Jia-Yan; Wang, Ye-Fei; Han, Bing; Ji, Yong-Rong; Song, Huai-Dong; Fan, Xian-Qun

    2011-01-01

    Blepharophimosis syndrome (BPES) is a rare, autosomal dominant disease. Two clinical types of BPES have been distinguished. In BPES type I, an eyelid malformation is associated with infertility in affected females as a result of premature ovarian failure. In BPES type II, eyelid anomalies alone are observed. Mutations of FOXL2, which is a gene encoding a forkhead transcription factor, have recently been shown to cause both types of BPES. Here, we report 1 novel duplication mutation of the FOXL2 gene identified in a large Chinese family affected by type II BPES and 1 less recurrent 17-bp duplication in a large Chinese family affected by BPES of an undetermined type. These new cases give additional support to the previously reported genotype-phenotype correlations and our findings have expanded the spectrum of known mutations of the FOXL2 gene.

  3. Affected Kindred Analysis of Human X Chromosome Exomes to Identify Novel X-Linked Intellectual Disability Genes

    PubMed Central

    Niranjan, Tejasvi S.; Skinner, Cindy; May, Melanie; Turner, Tychele; Rose, Rebecca; Stevenson, Roger; Schwartz, Charles E.; Wang, Tao

    2015-01-01

    X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders. PMID:25679214

  4. Affected kindred analysis of human X chromosome exomes to identify novel X-linked intellectual disability genes.

    PubMed

    Niranjan, Tejasvi S; Skinner, Cindy; May, Melanie; Turner, Tychele; Rose, Rebecca; Stevenson, Roger; Schwartz, Charles E; Wang, Tao

    2015-01-01

    X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders.

  5. Blau syndrome (familial granulomatous arthritis, iritis, and rash) in an african-american family.

    PubMed

    Cuesta, I A; Moore, E C; Rabah, R; Bawle, E V

    2000-02-01

    Blau syndrome (familial granulomatous arthritis, iritis, and rash) was originally described in 1985, in 11 members of a family of Dutch ancestry. Inheritance is autosomal dominant. Several more Caucasian families have been described since. Skin and synovial biopsy specimens show noncaseating sarcoid like granulomas, but the lung is not involved as in classic sarcoidosis. This report describes 3 members of an African American family with Blau syndrome. It is important to differentiate this genetic disorder from other childhood arthritides, such as, juvenile rheumatoid arthritis, juvenile spondyloarthropathies, and early-onset sarcoidosis, because of the need for genetic counseling, treatment and differing potential for selective involvement of other organs (eye, skin, and tendons/joints). All children of an affected individual have a 50% chance of inheriting the disease. Unaffected children do not have to be concerned about subsequent generations being affected. The response to conventional treatments used in juvenile rheumatoid arthritis and to etanercept in our patients has not been satisfactory. Joint disease responds to corticosteroids, but these agents are not suitable for a disease that is lifelong. The eye involvement is aggressive and can lead to blindness. These patients need close follow-up by an ophthalmologist.

  6. Recognizing, naming, and measuring a family intensive care unit syndrome.

    PubMed

    Netzer, Giora; Sullivan, Donald R

    2014-03-01

    Most major decisions in the intensive care unit (ICU) regarding goals of care are shared by clinicians and someone other than the patient. Multicenter clinical trials focusing on improved communication between clinicians and these surrogate decision makers have not reported consistently improved outcomes. We suggest that acquired maladaptive reasoning may contribute importantly to failure of the intervention strategies tested to date. Surrogate decision makers often suffer significant psychological morbidity in the form of stress, anxiety, depression, and post-traumatic stress disorder. Family members in the ICU also suffer cognitive blunting and sleep deprivation. Their decision-making abilities are eroded by anticipatory grief and cognitive biases, while personal and family conflicts further impact their decision making. We propose recognizing a family ICU syndrome to describe the morbidity and associated decision-making impairment experienced by many family members of patients with acute critical illness (in the ICU) and chronic critical illness (in the long-term, acute care hospital). Research rigorously using models of compromised decision making may help elucidate both mechanisms of impairment and targets for intervention. Better quantifying compromised decision making and its relationship to poor outcomes will allow us to formulate and advance useful techniques. The use of decision aids and improving ICU design may provide benefit now and in the near future. In measuring interventions targeting cognitive barriers, clinically significant outcomes, such as time to decision, should be considered. Statistical approaches, such as survival models and rank statistic testing, will increase our power to detect differences in our interventions.

  7. Discovering fragile X syndrome: family experiences and perceptions.

    PubMed

    Bailey, Donald B; Skinner, Debra; Sparkman, Karen L

    2003-02-01

    We used surveys from 274 families who had at least 1 child with fragile X syndrome (FXS) to determine their experiences in discovering FXS, factors associated with the timeliness of discovery, and the perceived consequences of obtaining this information. For families of male children who were born in the last decade, someone first became concerned about the child's development at an average age of 13 months. Professional confirmation of a developmental delay did not occur until an average age of 21 months, and a FXS diagnosis occurred at an average age of nearly 32 months. Families reported several barriers to discovering FXS and frustration with the process. Many families had additional children with FXS without knowing reproductive risk. A range of perceived benefits and challenges associated with the discovery were reported. We conclude that selected pediatric practices could promote earlier identification but in only a limited way and predict that disorders such as FXS will continue to challenge current criteria for determining viable candidate disorders for newborn screening.

  8. Familial primary antiphospholipid syndrome: A report of co-occurrence in three Malaysian family members.

    PubMed

    Islam, Md Asiful; Wong, Kah Keng; Sasongko, Teguh Haryo; Gan, Siew Hua; Wong, Jin Shyan

    2016-09-01

    Here we present a case report of three familial primary antiphospholipid syndrome (PAPS) patients from Malaysia. The three familial patients comprised two females and one male with a mean age of 26.3 years. The first diagnosis was made between 2005 and 2009, and all patients demonstrated deep vein thrombosis, high levels of IgM and IgG anticardiolipin antibodies, and received warfarin treatment international normalized ratio (INR) 2.0-3.0. The patients ceased to show clinical symptoms after treatment. Recently (August 2014), we investigated whether the levels of antiphospholipid antibodies remained elevated, and we found that seronegativity occurred in the patients. We suspect that prolonged anticoagulant treatment might be one of the causes of reduced levels of antiphospholipid antibodies in these familial PAPS patients.

  9. Familial Binswanger encephalopathy in the absence of hypertension; a new family with the CADASIL syndrome

    SciTech Connect

    Schanen, N.C.; Glusker, P.; Chung, M.

    1994-09-01

    Binswanger encephalopathy is a clinicopathologic entity characterized by deep white matter ischaemic lesions associated with hypertension and arteriosclerosis; but a rare inherited form, termed CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) has been recently described with earlier onset in the absence of hypertension. This syndrome has been linked to markers in chromosome band 19q12 in of two unrelated French families. We have identified a family of Central American heritage with a similar syndrome also demonstrating an autosomal dominant pattern of inheritance. Clinically, the onset of symptoms is between 19-53 years of age with variable progression in loss of neurologic function. Numerous lesions are visible on MRI involving the deep white matter including the corpus callosum as well as basal ganglia. None of the family members has had significant hypertension. Extensive evaluations of metabolic, infectious and inflammatory origin of disease have been noncontributory. In the two patients whose brains were examined pathologically, multiple cystic lesions, frequently centered around blood vessels, were present in the deep white matter and basal ganglia with diffuse loss of myelin and relative preservation of the neurons. The media of large and small parenchymal arteries shows hyaline and hydropic degeneration with replacement of the smooth muscle by a slate-grey amorphous substance on trichrome staining, corresponding to granular osmiophilic material on ultrastructural examination. There was no evidence of amyloid or atherosclerosis in the vessels. Phenotypically, this family appears to have the CADASIL syndrome. We are currently pursuing linkage analysis with chromosome 19 markers to investigate the genetic homogeneity of the disorder. Thirty-three individuals spanning three generations and including seven clinically affected patients are potentially available for study.

  10. Syncope in genotype-negative long QT syndrome family members.

    PubMed

    Olde Nordkamp, Louise R A; Ruwald, Martin H; Goldenberg, Ilan; Wieling, Wouter; McNitt, Scott; Polonsky, Bronislava; Wilde, Arthur A M; van Dijk, Nynke; Moss, Arthur J

    2014-10-15

    Unaffected long-QT syndrome family members (FMs) frequently experience syncope. The aims of this study were to test the hypothesis that syncope events in FMs are benign events and to compare clinical characteristics, triggers eliciting the syncope events, and long-term outcomes between FMs and those with LQT1 or LQT2 mutations from the international Long QT Syndrome Registry. A total of 679 FMs, 864 LQT1 patients, and 782 LQT2 patients were included. Seventy-eight FMs (11%) experienced cardiovascular events. Almost all cardiovascular events were nonfatal syncope; only 1 FM, with an additional mitral valve prolapse, experienced aborted cardiac arrest during exercise. The mean age at first syncope in FMs was 17 years, and female FMs experienced syncope more frequently than male FMs (14% vs 9%, p = 0.027). Syncope was more frequently triggered by exercise in LQT1 patients (43% in LQT1 patients vs 5% in FMs, p <0.001), while syncope triggered by a variety of other triggers was more frequent in FMs (54% in FMs vs 22% in LQT1 patients and 30% in LQT2 patients, p <0.001 for both). None of the FMs experienced aborted cardiac arrest or sudden cardiac death after the first syncopal episode. In conclusion, syncope is frequently present in FMs, and these syncopal events occurred more frequently in female than in male FMs, with an increased incidence in midadolescence. Triggers eliciting the syncopal events were different between FMs and patients with long-QT syndrome mutations. Hence, the type of trigger is useful in distinguishing between high- and low-risk syncope. These data indicate that FMs from families with LQTS have a benign form of syncope, most likely related to vasovagal syncope and not ventricular tachyarrhythmic syncope.

  11. Hypoadrenocorticism in a kindred of Pomeranian dogs.

    PubMed

    Mooney, Erin T; Hammond, Tara N; Mahony, Orla M

    2015-01-01

    Three adult Pomeranian dogs, full siblings from 2 litters, were diagnosed with primary hypoadrenocorticism following onset of hypoadrenal crisis. Review of the family history revealed the dogs' maternal grandmother also had hypoadrenocorticism. All 4 dogs were pedigree-certified by the American Kennel Club. An inherited basis for hypoadrenocorticism is proposed in these Pomeranian dogs.

  12. Families of children with Down syndrome: responding to "a change in plans" with resilience.

    PubMed

    Van Riper, Marcia

    2007-04-01

    The purpose of the present investigation, which was guided by the Resiliency Model of Family Stress, Adjustment, and Adaptation, was twofold: (a) to describe maternal perceptions of parental and family adaptation in families raising a child with Down syndrome, and (b) to examine linkages between family demands, family resources, family problem solving and coping, and family adaptation in families of children with Down syndrome. Seventy-six mothers completed mailed questionnaires. Seventy percent of the mothers rated their family's overall functioning as either a 4 or a 5 on a 5-point scale (1 = poor; 5 = excellent). In their written comments, most mothers reported that their family was doing well or very well. Three family variables (i.e., family demands, family resources, and family problem-solving communication) were significantly associated with family adaptation. These results provide support for the belief that many families of children with Down syndrome respond to "a change of plans" with resilience. That is, they are able to endure, survive, and even thrive in the face of ongoing challenges associated with raising a child with Down syndrome.

  13. Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

    ERIC Educational Resources Information Center

    Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

    2012-01-01

    We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth…

  14. Familial gigantiform cementoma with Ehlers - Danlos syndrome: A report of 2 cases

    PubMed Central

    2015-01-01

    Ehlers-Danlos syndrome is an autosomal dominant hereditary disorder of connective tissue, while familial gigantiform cementoma is a condition that usually manifests as multiple radiopaque cementum-like masses throughout the jaws. This case report discusses the oral management and prosthetic rehabilitation of two patients presenting familial gigantiform cementoma with Ehlers-Danlos Syndrome. PMID:25932318

  15. Experiences of Supporting People with Down Syndrome and Alzheimer's Disease in Aged Care and Family Environments

    ERIC Educational Resources Information Center

    Carling-Jenkins, Rachel; Torr, Jennifer; Iacono, Teresa; Bigby, Christine

    2012-01-01

    Background: Research addressing the experiences of families of adults with Down syndrome and Alzheimer's disease in seeking diagnosis and gaining support is limited. The aim of this study was to gain a greater understanding of these processes by exploring the experiences of families and carers in supporting people with Down syndrome and…

  16. Familial pattern of large vestibular aqueduct syndrome in a Chinese family

    PubMed Central

    Hazmi, Mohd; Ab Aziz, A.; Asma, A.

    2013-01-01

    Large Vestibular Aqueduct Syndrome (LVAS) is the most common radiographic malformation in children with early onset of hearing loss. Usually its occurrence is non-familial, however intriguingly a portion of patients with LVAS is found to have evidence of genetic predisposition. We described cases of LVAS in two siblings of a Chinese family. The elder sister first presented with reduced hearing since childhood and her brother has a similar complaint upon further questioning. Their hearing test showed bilateral sensorineural hearing loss (SNHL) and computed tomography (CT) of temporal bone showed enlarged vestibular aqueduct in both patients. We described an approach to diagnosis of LVAS and highlight the importance of hearing assessment in genetic link hearing loss. PMID:27034633

  17. Familial juvenile nephronophthisis, Jeune's syndrome, and associated disorders.

    PubMed Central

    Donaldson, M D; Warner, A A; Trompeter, R S; Haycock, G B; Chantler, C

    1985-01-01

    Fourteen patients with familial juvenile nephronophthisis are described, eight of whom displayed one or more additional disorders. One boy with short limbed dwarfism and an abnormal chest was considered to have Jeune's syndrome; review of the published reports supports the view that nephronophthisis is the principal cause of renal failure in this disorder. Another patient with renal failure and retinitis pigmentosa at presentation developed progressive neurological and neuromuscular impairment leading to the discovery of ragged red fibre disease (mitochondrial cytopathy). Cardiomyopathy was present in this and one other patient. Tapeto-retinal degeneration, hepatic fibrosis, cerebellar ataxia, and oculomotor apraxia were among the other disorders encountered. Three patients presented in extremis with acute heart failure and irreversible oligo-anuria and this complication developed in another child who was already known to have nephronophthisis. Awareness of this disease and its associations is important for early diagnosis and appropriate management. Images Fig. 1 Fig. 2 Fig. 3 PMID:4015147

  18. [Clinical symptoms of branchio-oto-renal syndrome in a family with a positive test for EYA1 gene].

    PubMed

    Markova, T G

    2006-01-01

    Three families with branchio-oto-renal syndrome (BOR syndrome) were examined. In one of the families all its members with BOR syndrome had deletion of cytosine in position 759 (759delC) in DNA sequence of EYA1 gene in exone 8. Clinical characteristics of BOR syndrome in the family are given. Molecular-genetic analysis confirmed the diagnosis clinically in case of all signs of the syndrome presence among the members of the family. Rare cases of hereditary syndromes with hearing problems provide more knowledge about structure of hereditary hypoacusis forms in the population. The syndromal forms reflect a complex genetic basis of the processes of sound perception.

  19. Marfan syndrome in a large family: response of family members to a screening programme.

    PubMed

    Bridges, A B; Faed, M; Boxer, M; Gray, J R; Bundy, C; Murray, A

    1992-02-01

    Reaction to medical, social, and genetic implications of Marfan syndrome was evaluated by means of two questionnaires, the first after various tests before discussion of the diagnosis, the second after full discussion of the patient's diagnosis. Thirty-seven members of a family known to be at risk for Marfan syndrome attended for both questionnaires. All patients claimed to be satisfied with the way they were informed of the results of screening; 41% of patients were more worried about their health and 48% were more worried about the future after diagnosis. Apart from 50% of the smokers reducing or stopping their intake of cigarettes there were only very minor changes in lifestyle over the first month despite the increased level of expressed anxiety. If a definitive screening test was available, 96% of patients claimed they would have chosen it, 45% felt it would have an influence on their future plans, and 78% would choose to use a method of prenatal diagnosis for Marfan syndrome if it were available.

  20. Behaviour Problems, Maternal Internalising Symptoms and Family Relations in Families of Adolescents and Adults with Fragile X Syndrome

    ERIC Educational Resources Information Center

    Baker, J. K.; Seltzer, M. M.; Greenberg, J. S.

    2012-01-01

    Background: Studies have linked the behaviour problems of children with fragile X syndrome (FXS) to maternal well-being, but less is known about how behaviour problems relate to important family factors such as marital satisfaction and family cohesion. Methods: Married mothers of 115 adolescents and adults with FXS completed questionnaires and…

  1. Gestational, perinatal and family findings of patients with Patau syndrome

    PubMed Central

    Rosa, Rafael Fabiano M.; Sarmento, Melina Vaz; Polli, Janaina Borges; Groff, Daniela de Paoli; Petry, Patrícia; de Mattos, Vinícius Freitas; Rosa, Rosana Cardoso M.; Trevisan, Patrícia; Zen, Paulo Ricardo G.

    2013-01-01

    OBJECTIVE: To describe gestational, perinatal and family findings of patients with Patau syndrome (PS). METHODS: The study enrolled patients with PS consecutively evaluated during 38 years in a Clinical Genetics Service of a pediatric referral hospital in Southern Brazil. The clinical data and the results of cytogenetic analysis were collected from the medical records. For statistical analysis, the two-tailed Fisher's exact test and the chi-square test with Yates' correction were used, being significant p<0.05. RESULTS: The sample was composed of 27 patients, 63% were male, with a median age of nine days at the first evaluation. Full trisomy of chromosome 13 was the main cytogenetic finding (74%). Only six patients were submitted to obstetric ultrasound and none had prenatal diagnosis of PS. The patients' demographic characteristics, compared to born alive infants in the same Brazilian state showed a higher frequency of: mothers with 35 years old or more (37.5%); multiparous mothers (92.6%); vaginal delivery (77%); preterm birth (34.6%); birth weight <2500g (33.3%), and Apgar scores <7 in the 1st (75%) and in the 5th minute (42.9%). About half of them (53%) died during the first month of life. CONCLUSIONS: The understanding of the PS patients' gestational, perinatal and family findings has important implications, especially on the decision about the actions to be taken in relation to the management of these patients. PMID:24473950

  2. Familial Recurrence of 3MC Syndrome in Consanguineous Families: A Clinical and Molecular Diagnostic Approach With Review of the Literature.

    PubMed

    Gardner, Olivia K; Haynes, Karla; Schweitzer, Daniela; Johns, Alexis; Magee, William P; Urata, Mark M; Sanchez-Lara, Pedro A

    2016-06-29

    We report four individuals from two unrelated consanguineous families with 3MC syndrome. In the first family, chromosome microarray data revealed that the two affected sisters, born to first-cousin parents, shared a unique homozygous C-terminal deletion in the COLEC11 gene. Two affected brothers from a second family, also born to first-cousin parents, shared a region of homozygosity that included the second gene known to cause the 3MC syndrome, MASP1. We discuss the diagnostic approach of craniofacial disorders born to consanguineous parents and highlight a literature search and reference a helpful dysmorphology solution powered by FDNA (Facial Dysmorphology Novel Analysis) technology.

  3. Familial Aggregation of Acute Myeloid Leukemia and Myelodysplastic Syndromes

    PubMed Central

    Goldin, Lynn R.; Kristinsson, Sigurdur Y.; Liang, Xueying Sharon; Derolf, Åsa R.; Landgren, Ola; Björkholm, Magnus

    2012-01-01

    Purpose Apart from rare pedigrees with multiple cases of acute myeloid leukemia (AML), there is limited data on familial aggregation of AML and myelodysplastic syndromes (MDSs) in the population. Patients and Methods Swedish population-based registry data were used to evaluate risk of AML, MDS, and other malignancies among 24,573 first-degree relatives of 6,962 patients with AML and 1,388 patients with MDS compared with 106,224 first-degree relatives of matched controls. We used a marginal survival model to calculate familial aggregation. Results AML and/or MDS did not aggregate significantly in relatives of patients with AML. There was a modest risk ratio (RR, 1.3; 95% CI, 0.9 to 1.8) in myeloproliferative/myeloid malignancies combined. The risks for any hematologic or any solid tumor were modestly but significantly increased. Relatives of patients with MDS did not show an increased risk for any hematologic tumors. In contrast, we found a significantly increased risk (RR, 6.5; 95% CI, 1.1 to 38.0) of AML/MDS and of all myeloid malignancies combined (RR, 3.1; 95% CI, 1.0 to 9.8) among relatives of patients diagnosed at younger than age 21 years. Conclusion We did not find evidence for familial aggregation of the severe end of the spectrum of myeloid malignancies (AML and MDS). The risks of myeloproliferative neoplasms were modestly increased with trends toward significance, suggesting a possible role of inheritance. In contrast, although limited in sample size, relatives of young patients with AML were at increased risk of AML/MDS, suggesting that germline genes may play a stronger role in these patients. The increased risk of all hematologic malignancies and of solid tumors among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared. PMID:22162584

  4. The Importance of Older Family Members in Providing Social Resources and Promoting Cancer Screening in Families with a Hereditary Cancer Syndrome

    ERIC Educational Resources Information Center

    Ashida, Sato; Hadley, Donald W.; Goergen, Andrea F.; Skapinsky, Kaley F.; Devlin, Hillary C.; Koehly, Laura M.

    2011-01-01

    Purpose: This study evaluates the role of older family members as providers of social resources within familial network systems affected by an inherited cancer susceptibility syndrome. Design and Methods: Respondents who previously participated in a study that involved genetic counseling and testing for Lynch syndrome and their family network…

  5. Acceptance of Genetic Testing for Hereditary Breast Ovarian Cancer Among Study Enrollees from an African American Kindred

    PubMed Central

    Simonsen, Sara Ellis; Baty, Bonnie Jeanne; Mandal, Diptasri; Neuhausen, Susan L; Seggar, Kate; Holubkov, Rich; Smith, Ken

    2008-01-01

    Clinical availability of genetic testing for cancer predisposition genes is generating a major challenge for U.S. health care systems to provide relevant genetic services to underserved populations. Here we present rates of study enrollment and utilization of genetic testing in a research study on BRCA1 testing acceptance in one large kindred. We also present data on baseline access to genetic information as well as enabling and obstructing factors to study enrollment. The study population included female and male members of an African-American kindred based in the rural southern United States with an identified BRCA1 mutation. A combination of quantitative and qualitative data were collected and analyzed. Of the 160 living, eligible and locatable kindred members, 105 (66%) enrolled in the study. Family, personal, and educational motivations were the most commonly endorsed reasons for study participation. The most commonly cited reasons for refusal to participate in the study were: lack of interest, time constraints, and negative experiences with prior participation in genetic research. Eighty three percent of the participants underwent BRCA1 testing. In multiple logistic regression analysis, age 40-49 (odds ratio (OR) = 6.9; 95% confidence interval (CI) = 1.2-39.5), increased perceived cancer risk (OR = 4.1; 95% CI = 1.1-14.6), and high cancer genetics knowledge levels (OR = 1.5; 95% CI = 1.1-2.3) were associated with BRCA1 testing acceptance. The results of this study indicate that cognitive and demographic factors may influence genetic research participation and genetic testing decisions among African Americans who are at increased risk of carrying a deleterious BRCA1 mutation. PMID:16523520

  6. Report of a kindred with x-linked (or autosomal dominant sex-limited) 46, XY partial gonadal dysgenesis

    SciTech Connect

    Fechner, P.Y.; Marcantonio, S.M.; Ogata, T.; Rosales, T.O.; Smith, K.D.; Goodfellow, P.N.; Migeon, C.J.; Berkovitz, G.D. )

    1993-05-01

    The condition termed 46, XY complete gonadal dysgenesis is characterized by the lack of testicular determination with resulting streak gonads, normal Mullerian structures, and female external genitalia. In the partial form, there is incomplete testicular determination with a wide range in the degree of ambiguous genitalia and sexual duct development. The authors evaluated a kindred in which a partial form of 46, XY gonadal dysgenesis occurred in four subjects from two generations. Pedigree analysis indicated an X-linked or possibly an autosomal sex-limited mode of inheritance. All affected subjects were ascertained because of ambiguous genitalia with minimal virilization. At 10 days of age, the proband had a subnormal plasma level of testosterone, and at 4 months, there was no rise in plasma T after stimulation with hCG. At laparotomy, a dysgenetic gonad was found on the right side, but no gonad was found on the left side. A vas deferens was present on the right, indicating the presence of functional leydig cells early in fetal life. In the other affected subjects, gonadal tissue was also limited to one side of the abdomen and showed poorly developed seminiferous tubules. The sex-determining region Y gene, which encodes the testis-determining factor, was present and unaltered in the genomic DNA of all affected subjects. Duplication of the distal short arm of the X-chromosome has been associated with 46, XY complete gonadal dysgenesis in some patients. In the authors studies, Southern blot analysis revealed that sequences of the distal short arm of the X-chromosome were present in single copy, excluding a large duplication in this area of the X. Several kindreds with familial 46, XY complete gonadal dysgenesis have been reported; five of them had evidence of an X-linked mode of inheritance. The authors study of a kindred with 46, XY partial gonadal dysgenesis further supports the role of an X chromosome gene in testicular determination. 44 refs., 1 fig., 3 tabs.

  7. Premenstrual syndrome. Evidence-based treatment in family practice.

    PubMed Central

    Douglas, Sue

    2002-01-01

    OBJECTIVE: To evaluate the strength of evidence for treatments for premenstrual syndrome (PMS) and to derive a set of practical guidelines for managing PMS in family practice. QUALITY OF EVIDENCE: An advanced MEDLINE search was conducted from January 1990 to December 2001. The Cochrane Library and personal contacts were also used. Quality of evidence in studies ranged from level I to level III, depending on the intervention. MAIN MESSAGE: Good scientific evidence shows that calcium carbonate (1200 mg/d) and selective serotonin reuptake inhibitors are effective treatments for PMS. The most commonly used therapies (including vitamin B6, evening primrose oil, and oral contraceptives) are based on inconclusive evidence. Other treatments for which there is inconclusive evidence include aerobic exercise, stress reduction, cognitive therapy, spironolactone, magnesium, nonsteroidal anti-inflammatory drugs, various hormonal regimens, and a complex carbohydrate-rich diet. Although evidence for them is inconclusive, it is reasonable to recommend healthy lifestyle changes given their overall health benefits. Progesterone and bromocriptine, which are still widely used, are ineffective. CONCLUSION: Calcium carbonate should be recommended as first-line therapy for women with mild-to-moderate PMS. Selective serotonin reuptake inhibitors can be considered as first-line therapy for women with severe affective symptoms and for women with milder symptoms who have failed to respond to other therapies. Other therapies may be tried if these measures fail to provide adequate relief. PMID:12489244

  8. Xp22. 3 deletions in isolated familial Kallmann's syndrome

    SciTech Connect

    Hardelin, J.P.; Levilliers, J.; Legouis, R.; Petit, C. ); Young, J.; Pholsena, M.; Schaison, G. ); Kirk, J.; Bouloux, P. )

    1993-04-01

    Several familial cases of Kallmann's syndrome (KS) have been reported, among which the X-chromosome-linked mode of inheritance is the most frequent. The gene responsible for the X-linked KS has been localized to the terminal part of the X-chromosome short arm (Xp22.3 region), immediately proximal to the steroid sulfatase gene responsible for X-linked ichthyosis. Large deletions of this region have been previously shown in patients affected with both X-linked ichthyosis and KS. The authors report here the search for Xp22.3 deletions in 20 unrelated males affected with isolated X-linked KS. Only 2 deletions were found using Southern blot analysis, indicating that large deletions are uncommon in patients affected with KS alone. Both deletions were shown to include the entire KAL gene responsible for X-linked KS. The patients carrying these deletions exhibit additional clinical anomalies, which are discussed: unilateral renal aplasia, unilateral absence of vas deferens, mirror movements, and sensory neural hearing loss. 47 refs., 2 figs., 1 tab.

  9. Exclusion mapping of a third HNPCC locus in a large Lynch I kindred

    SciTech Connect

    Morasse, J.; Khandjian, E.W.; Rousseau, F.

    1994-09-01

    Hereditary Non-Polyposis Colorectal Cancer (HNPCC) accounts for 5-10% of all the cases of colorectal cancers. HNPCC can be classified in two clinical forms: (1) Hereditary Site-Specific Colorectal Cancer (HSSCC or Lynch I) and (2) colon cancer associated with extracolonic cancers (Lynch II). Segregation analyses show an autosomal dominant mode of inheritance. In order to identify the HNPCC gene involved in a large Canadian kindred, we performed linkage analysis using microsatellites spanning 9 candidate regions. For all loci tested, the lod score data obtained were negative. Our results demonstrate that the genes hMSH1 and hMLH1 recently reported in HNPCC are not linked in this family. Five loci frequently altered in colorectal tumor cells, APC, MCC, K-ras, p53 and DCC and the DRA gene whose expression is confined to the colon mucosa cells and deregulated in colonic adenomas, are also unlinked to HNPCC susceptibility in this family. We have also excluded chromosomes 4, 5, 8, 11 and 17 as containing the cancer predisposition gene in this family.

  10. A Family with Axenfeld-Rieger Syndrome: Report of the Clinical and Genetic Findings

    PubMed Central

    Yang, Hee Jung; Lee, You Kyung; Joo, Choun-Ki; Moon, Jung Il; Mok, Jee Won

    2015-01-01

    Purpose To describe clinical findings in a Korean family with Axenfeld-Rieger syndrome. Methods A retrospective review of clinical data about patients with diagnosed Axenfeld-Rieger syndrome. Five affected members of the family underwent a complete ophthalmologic examination. We screened the forkhead box C1 gene and the pituitary homeobox 2 gene in patients. Peripheral blood leukocytes and buccal mucosal epithelial cells were obtained from seven members of a family with Axenfeld-Rieger syndrome. DNA was extracted and amplified by polymerase chain reaction, followed by direct sequencing. Results The affected members showed iris hypoplasia, iridocorneal adhesions, posterior embryotoxon, and advanced glaucoma in three generation. None had systemic anomalies. Two mutations including c.1362_1364insCGG and c.1142_1144insGGC were identified in forkhead box C1 in four affected family members. Conclusions This study may help to understand clinical findings and prognosis for patients with Axenfeld-Rieger syndrome. PMID:26240509

  11. Factors Predicting Mortality in Midlife Adults with and without Down Syndrome Living with Family

    ERIC Educational Resources Information Center

    Esbensen, A. J.; Seltzer, M. M.; Greenberg, J. S.

    2007-01-01

    Background: Little is known about the mortality of individuals with Down syndrome who have lived at home with their families throughout their lives. The current study evaluates the predictors, causes and patterns of mortality among co-residing individuals in midlife with Down syndrome as compared with co-residing individuals with ID owing to other…

  12. Syndrome Specificity and Behavioural Disorders in Young Adults with Intellectual Disability: Cultural Differences in Family Impact

    ERIC Educational Resources Information Center

    Blacher, J.; McIntyre, L. L.

    2006-01-01

    Background: This study examined whether behaviour problems and adaptive behaviour of low functioning young adults, and well-being of their families, varied by diagnostic syndrome intellectual disability (ID) only, cerebral palsy, Down syndrome, autism, as well as by cultural group. Methods: Behaviour disorders in young adults with moderate to…

  13. Tel-Hashomer camptodactyly syndrome with hirsuitism in an Indian family.

    PubMed

    Patel, Zareen M; Adhia, Rashmi A

    2004-10-01

    Two new cases with the Tel-Hashomer camptodactyly syndrome have been ascertained in an Indian family. This report emphasizes the autosomal recessive nature of disease and documents an additional feature of hirsuitism not previously described. The gene for Tel-Hashomer camptodactyly syndrome is present in all populations around the world.

  14. Exploring the genetic basis of 3MC syndrome: Findings in 12 further families.

    PubMed

    Urquhart, Jill; Roberts, Rebecca; de Silva, Deepthi; Shalev, Stavit; Chervinsky, Elena; Nampoothiri, Sheela; Sznajer, Yves; Revencu, Nicole; Gunasekera, Romesh; Suri, Mohnish; Ellingford, Jamie; Williams, Simon; Bhaskar, Sanjeev; Clayton-Smith, Jill

    2016-05-01

    The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome.

  15. Like Father, Like Daughter-inherited cutis aplasia occurring in a family with Marfan syndrome: a case report.

    PubMed

    Islam, Yasmin Florence Khodeja; Williams, Charles A; Schoch, Jennifer Jane; Andrews, Israel David

    2017-01-01

    We present the case of a newborn with co-occurrence of Marfan syndrome and aplasia cutis congenita (ACC) and a family history significant for Marfan syndrome and ACC in the father. This case details a previously unreported mutation in Marfan syndrome and describes a novel coinheritance of Marfan syndrome and ACC.

  16. Divorce in families of children with Down syndrome: a population-based study.

    PubMed

    Urbano, Richard C; Hodapp, Robert M

    2007-07-01

    In this study, we examined the nature, timing, and correlates of divorce in families of children with Down syndrome (647), other birth defects (10,283) and no identified disability (361,154). Divorce rates among families of children with Down syndrome were lower than in the other two groups. When divorce did occur in the Down syndrome group, however, a higher proportion occurred within the first 2 years after the child's birth. Mothers and fathers of children with Down syndrome were much more likely to divorce if they were younger, had not graduated from high school, and if fathers were less educated and lived in a rural area. Few effects on divorce were noted for a variety of family structure variables.

  17. Tourniquet Syndrome: Interest of a Systematic Analysis of Families' Social Conditions to Detect Neglect Situations

    ERIC Educational Resources Information Center

    Claudet, Isabelle; Pasian, Nicolas; Debuisson, Cecile; Salanne, Sophie; Rekhroukh, Hocine

    2009-01-01

    Objective: Describe the correlates of tourniquet syndromes, analyze family social situation to detect neglectful behaviors and analyze the tracking of subsequent Pediatric Emergency Department (PED) admissions to identify at risk families. Material and methods: From January 1, 2003 to December 31, 2007 all patients admitted to the PED for…

  18. Use of Equipment and Respite Services and Caregiver Health among Australian Families Living with Rett Syndrome

    ERIC Educational Resources Information Center

    Urbanowicz, Anna; Downs, Jenny; Bebbington, Ami; Jacoby, Peter; Girdler, Sonya; Leonard, Helen

    2011-01-01

    This study assessed factors that could influence equipment and respite services use among Australian families caring for a girl/woman with Rett syndrome and examined relationships between use of these resources and the health of female caregivers. Data was sourced from questionnaires completed by families (n=170) contributing to the Australian…

  19. Parents of Children with Asperger Syndrome or with Learning Disabilities: Family Environment and Social Support

    ERIC Educational Resources Information Center

    Heiman, Tali; Berger, Ornit

    2008-01-01

    The study examined the family environment and perceived social support of 33 parents with a child diagnosed with Asperger syndrome and 43 parents with a child with learning disability, which were compared to 45 parents of children without disabilities as a control group. Parents completed the Family Environment Scale and Social Support Scale…

  20. Williams Syndrome: Daily Challenges and Positive Impact on the Family

    ERIC Educational Resources Information Center

    Scallan, Susan; Senior, Joyce; Reilly, Colin

    2011-01-01

    Background: Despite the distinctive physical, cognitive, personality and behavioural characteristics associated with Williams syndrome, few studies to date have examined parental experiences of raising a child with this genetic syndrome. Methods: This explorative pilot study employed predominantly qualitative methodologies via face-to-face…

  1. Genetic and functional analysis of a Li Fraumeni syndrome family in China.

    PubMed

    Hu, Huaying; Liu, Jingping; Liao, Xinbin; Zhang, Shuju; Li, Haibo; Lu, Renbin; Li, Xianfeng; Lin, Wei; Liu, Minji; Xia, Zanxian; Qing, Guoliang; Li, Jia-Da

    2016-01-28

    Li Fraumeni syndrome (LFS) is a rare familial cancer predisposition syndrome with autosomal-dominant inheritance, occurring as frequently as one in 5,000-20,000 individuals. However, no LFS case has been reported from mainland China although it constitutes one quarter of population on earth. In this study, we identified, to our best knowledge, the first Li Fraumeni syndrome family in China. Six family members were affected with various tumors. A TP53 mutation (c.730G > A; p.G244S) co-segregated with the tumor phenotype within this family. Functional analysis indicated that G244S mutation disrupted the transactivity, DNA-binding and cell growth inhibition activity of p53 protein. Two available tumor samples (medulloblastoma and choroid plexus papilloma) underwent large rearrangement in the chromosomes and loss of wild-type TP53. Our data warranted further studies on the prevalence of germline TP53 mutation in various tumor patients in China.

  2. Latino families with a child with Prader-Willi syndrome: exploring needs for support.

    PubMed

    Chaij, Carina; Han, Meekyung; Graziano, Lisa

    2014-01-01

    Prader-Willi syndrome (PWS) is a complex, genetically based disorder; caring for a family member with a disability such as PWS brings significant challenges to the whole family. However, no research has been conducted focusing on the impact of PWS in the dynamics of Latino families. This qualitative study explored the challenges and need for support services among Latino families of children with PWS. Findings of the study suggest the need for support services geared toward the whole family unit to help members cope with daily challenges at home.

  3. Subtle familial translocation t(11;22)(q24.2;q13.33) resulting in Jacobsen syndrome and distal trisomy 22q13.3: further details of genotype-phenotype maps.

    PubMed

    Jamsheer, Aleksander; Smyk, Marta; Wierzba, Jolanta; Kołowska, Jolanta; Woźniak, Anna; Skołozdrzy, Joanna; Fischer, Maria; Latos-Bieleńska, Anna

    2008-01-01

    We report on 3 kindred patients with terminal 11q monosomy and distal 22q trisomy involving the SHANK3 gene, resulting from a subtle familial translocation t(11;22)(q24.2;q13.33). The patients presented with the characteristic symptoms of Jacobsen syndrome (JBS), including: mental retardation, short stature, and craniofacial dysmorphism in all 3 cases; cardiac defects in 2 cases; and thrombocytopenia, brain abnormality, eye coloboma, recurrent infections, cryptorchidism and toe anomalies in single cases. The oldest patient also had Hashimoto disease and diabetes mellitus type 2. So far, these 2 conditions have not been reported in adult patients with JBS. Features typical for distal 22q trisomy in our patients include muscular hypotonia and prenatal failure to thrive, seen in 2 and 1 cases, respectively. We also present a family member with 11q24.2-qter trisomy and 22q13.33-qter monosomy, whose clinical phenotype is partially overlapping with several dysmorphic features of JBS. In addition, multiple pregnancy losses and infantile deaths occurred in this family, suggesting that these chromosomal imbalances may produce a lethal phenotype. FISH with a panel of BAC probes determined the accurate sizes of the deletion 11q (9.9 Mb) and trisomy 22q (0.8 Mb). To date, only 5 cases of submicroscopic 22q13.3-qter trisomy have been reported. A detailed clinical description of our patients, along with a precise cytogenetic designation of chromosomal breakpoints, allow further refinement of genotype-phenotype correlation for distal imbalances in 11q and 22q.

  4. Cancer anorexia-cachexia syndrome: psychological effect on the patient and family.

    PubMed

    McClement, Susan

    2005-01-01

    The majority of patients with advanced cancer experience weight loss, reduced appetite, fatigue, and weakness. Chronic nausea and early satiety may also occur. This constellation of symptoms is known as the cancer anorexia-cachexia syndrome. Together with cancer pain, cancer anorexia-cachexia syndrome has been identified as 1 of the 2 most frequent and devastating problems affecting individuals with advanced malignancies. Research examining the issue of cancer anorexia-cachexia syndrome has been conducted; however, such work is largely biomedical in orientation. In contrast, the psychologic dimensions of the cancer anorexia-cachexia syndrome experience from the perspective of terminally ill patients and their family members is less well explored or described. The ability to provide psychosocial support to patients and families requires that caregivers appreciate the psychologic effect of cancer anorexia and cachexia on these individuals. This article examines that effect in light of existing knowledge and discusses the clinical implications arising from this work.

  5. Familial pancreatic cancer: Concept, management and issues

    PubMed Central

    Matsubayashi, Hiroyuki; Takaori, Kyoichi; Morizane, Chigusa; Maguchi, Hiroyuki; Mizuma, Masamichi; Takahashi, Hideaki; Wada, Keita; Hosoi, Hiroko; Yachida, Shinichi; Suzuki, Masami; Usui, Risa; Furukawa, Toru; Furuse, Junji; Sato, Takamitsu; Ueno, Makoto; Kiyozumi, Yoshimi; Hijioka, Susumu; Mizuno, Nobumasa; Terashima, Takeshi; Mizumoto, Masaki; Kodama, Yuzo; Torishima, Masako; Kawaguchi, Takahisa; Ashida, Reiko; Kitano, Masayuki; Hanada, Keiji; Furukawa, Masayuki; Kawabe, Ken; Majima, Yoshiyuki; Shimosegawa, Toru

    2017-01-01

    Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, “anticipation” is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society. PMID:28246467

  6. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome

    PubMed Central

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V.P.; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-01-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak-like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811-812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the

  7. Response to IL-1-receptor antagonist in a child with familial cold autoinflammatory syndrome.

    PubMed

    O'Connell, Susan M; O'Regan, Grainne M; Bolger, Turlough; Hoffman, Hal M; Cant, Andrew; Irvine, Alan D; Watson, Rosemarie M

    2007-01-01

    Familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic, cutaneous, articular syndrome are related disorders associated with mutations in the CIAS1 gene. They appear to represent a continuum of one disease characterized by IL-1-mediated inflammation. Until recently, these conditions have been difficult to treat; however, with the advent of IL-1-receptor antagonist therapy, many reports of successful treatment of patients with these autoinflammatory diseases have emerged in the past 2 years. We describe an 8-year-old girl, diagnosed with Familial cold auto-inflammatory syndrome, confirmed by presence of a novel CIAS1 mutation, who was refractory to symptomatic treatment. As frequent attacks of urticaria and associated arthralgia had a debilitating effect on the child's lifestyle, a trial of IL-1-receptor antagonist (anakinra) was instituted. Dramatic sustained clinical improvement was evident within days and serum amyloid and C-reactive protein levels normalized within a month. Although several authors have reported successful use of this agent in children with chronic infantile neurologic, cutaneous, articular syndrome, we believe ours is the first report of successful treatment with anakinra in a young child with familial cold auto-inflammatory syndrome.

  8. Dual Familial Roles: An Asperger's Syndrome Case Story

    ERIC Educational Resources Information Center

    Ivey, Julie K.; Ward, A. Kris

    2010-01-01

    Sibling interactions are challenges that all families face on a daily basis. These interactions are significantly more difficult when one child has autism. With the apparent increase in diagnoses of autism, there are more families each year who are dealing with issues of relationships. Children learn, as part of the growing up experience, how to…

  9. [Gardner syndrome. A report of 3 cases in members of the same family].

    PubMed

    Bertoni, F; Bacchini, P; Marchetti, C; Fagioli, S; Campobassi, A

    1990-03-01

    The aim of the present report is to describe the overall mandibular and extramandibular lesions correlated to Gardner's syndrome which were found in the same family (mother and two daughters). In two cases (mother and one daughter) mandibular lesions consisted of osteoma. In the latter, these were associated with composite odontoma. In the other daughter the lesions consisted of desmoid fibroma. The two daughters revealed single colonic polyposis whereas the mother was affected by multiple colonic polyposis and subcutaneous lipoma. Such a constellation of lesions may be attributed to Gardner's syndrome, a Mendelian hereditary syndrome which is often incomplete. In fact, intestinal polyposis can only be associated with one of the various extraintestinal manifestations of the syndrome. The recognition of the syndrome is important given the high percentage of intestinal polyp-adenocarcinoma associations.

  10. Parents of children with Asperger syndrome or with learning disabilities: family environment and social support.

    PubMed

    Heiman, Tali; Berger, Ornit

    2008-01-01

    The study examined the family environment and perceived social support of 33 parents with a child diagnosed with Asperger syndrome and 43 parents with a child with learning disability, which were compared to 45 parents of children without disabilities as a control group. Parents completed the Family Environment Scale and Social Support Scale questionnaires. The comparison revealed significant differences for expressiveness and family system organization and for social support. Parents with an Asperger child perceived their family's expressive feelings as lower and the family organization as higher, and perceived their friendships and other support as lower than the other groups of parent. Parents of the control group reported the highest family support. The study highlighted the need for additional social support for parents with a child with special needs, and accentuated the importance of developing awareness and intervention programs to facilitate parents' coping abilities and their family interactions.

  11. Lung transplantation for Williams-Campbell syndrome with a probable familial association.

    PubMed

    Burguete, S Rodrigo; Levine, Stephanie M; Restrepo, Marcos I; Angel, Luis F; Levine, Deborah J; Coalson, Jacqueline J; Peters, Jay I

    2012-09-01

    Williams-Campbell syndrome is a rare disorder characterized by deficiency of subsegmental bronchial cartilage and development of airway collapse and bronchiectasis that may subsequently progress to respiratory failure and death. There are only 2 published reports suggesting a familial association, and only one report of lung transplantation being used as a therapeutic modality. Due to postoperative airway complications, transplantation has not been recommended for this disease. We report the first lung transplant with prolonged survival, approaching 10 years, in a patient with Williams-Campbell syndrome, and provide further evidence to support a familial association.

  12. Lung Transplantation for Williams-Campbell Syndrome With a Probable Familial Association

    PubMed Central

    Burguete, S Rodrigo; Levine, Stephanie M; Restrepo, Marcos I; Angel, Luis F; Levine, Deborah J; Coalson, Jacqueline J; Peters, Jay I

    2014-01-01

    Williams-Campbell syndrome is a rare disorder characterized by deficiency of subsegmental bronchial cartilage and development of airway collapse and bronchiectasis that may subsequently progress to respiratory failure and death. There are only 2 published reports suggesting a familial association, and only one report of lung transplantation being used as a therapeutic modality. Due to postoperative airway complications, transplantation has not been recommended for this disease. We report the first lung transplant with prolonged survival, approaching 10 years, in a patient with Williams-Campbell syndrome, and provide further evidence to support a familial association. PMID:22348466

  13. DICER1 mutation and tumors associated with a familial tumor predisposition syndrome: practical considerations.

    PubMed

    Bardón-Cancho, Eduardo J; Haro-Díaz, Ana; Alonso-García-de la Rosa, Francisco J; Huerta-Aragonés, Jorge; García-Morín, Marina; González-Martínez, Felipe; Garrido-Colino, Carmen

    2017-04-01

    The familial tumor predisposition syndrome known as DICER1-pleuropulmonary blastoma (PPB) or DICER1 tumor predisposition syndrome was first described in 2009, and it involves an increased risk in the occurrence of various tumors, like cystic nephroma and PPB. Here is presented a girl with a cystic nephroma and two cystic lung lesions who was diagnosed years later with the DICER1 gene mutation. This mutation was also found in one of her parents. Thus, the screening for the DICER1 gene mutation may be important in children with certain/multiple tumors and their families.

  14. Intrafamilial and interfamilial variability of phenotype in familial velo-cardio-facial syndrome

    SciTech Connect

    Hajianpour, M.J.; Covle, M.

    1994-09-01

    Two half-sisters and their mother from one family, and two full-brothers and their mother from another family presented with features of velo-cardio-facial syndrome (VCSF)/DiGeorge syndrome (DS) with intrafamilial and interfamilial variability of phenotypic expression. None of these patients had an apparent cleft palate. Cardiac anomaly, jejunal atresia and hypocalcemia were present only in the newborn patient. Fluorescence in situ hybridization for VCFS/DS with probe D22S75 showed a deletion in the 22q11.2 region in patients available for the study.

  15. Fetal Alcohol Syndrome: A Guide for Families and Communities.

    ERIC Educational Resources Information Center

    Streissguth, Ann

    The 14 chapters of this book review the research and offer guidelines for intervention with infants and children having fetal alcohol syndrome or fetal alcohol effects (FAS/FAE). Chapters are grouped into five sections on the diseases of fetal alcohol, the science of FAS, a life-span approach to FAS, preparing people with FAS for life in the…

  16. Down Syndrome, Birth to Adulthood: Giving Families an EDGE.

    ERIC Educational Resources Information Center

    Rynders, John E.; Horrobin, J. Margaret

    This updated book provides a collection of longitudinal perspectives on experiences of individuals with Down Syndrome, from birth to adulthood. The book is an outgrowth of a federally funded early intervention study called Project EDGE (Expanding Developmental Growth through Education). Contents cover the following topics: historical review of…

  17. Family influences on adaptive development in young children with Down syndrome.

    PubMed

    Hauser-Cram, P; Warfield, M E; Shonkoff, J P; Krauss, M W; Upshur, C C; Sayer, A

    1999-01-01

    In this study we investigated the extent to which the family environment predicted differences in trajectories of adaptive development in young children with Down syndrome. The sample was comprised of 54 children with Down syndrome and their families who were studied from infancy through the age of 5 years as part of a longitudinal study of children with disabilities. Hierarchical linear modeling (HLM) was used to estimate the parameters of hierarchical growth models in domains of adaptive development. Results indicated that growth in communication, daily living skills, and socialization domains were predicted by measures of the family environment (i.e., family cohesion and mother-child interaction) above and beyond that predicted by maternal education. Further, Bayley MDI measures during infancy did not predict changes in adaptive development in any of the domains. The results are discussed in terms of implications for service provision and for expanding theoretical frameworks to include the development of children with disabilities.

  18. A severe case of Pfeiffer syndrome associated with stub thumb on the maternal side of the family.

    PubMed

    Kreiborg, S; Cohen, M M

    1993-01-01

    We report a severe case of Pfeiffer syndrome with an early demise. The mother and her own father had unilateral stub thumb, which was inherited as a coincidental autosomal dominant trait. Although the affected thumb was short, it was not broad and neither family member had any features of Pfeiffer syndrome. We conclude that our patient represents a new Pfeiffer syndrome mutation.

  19. Maternal Parenting Stress in Families with a Child with Angelman Syndrome or Prader-Willi Syndrome

    ERIC Educational Resources Information Center

    Wulffaert, Josette; Scholte, Evert M.; Van Berckelaer-Onnes, Ina A.

    2010-01-01

    Background: Parenting stress was investigated in mothers with a child with Angelman syndrome (AS) or Prader-Willi syndrome (PWS), which are genetically related. Method: Mothers of 24 children with AS and 23 children with PWS (2-12 years) completed the Nijmegen Parenting Stress Index-Short, Developmental Behaviour Checklist, and Vineland Screener…

  20. Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome.

    PubMed

    Hanninen, Mikael; Klein, George J; Laksman, Zachary; Conacher, Susan S; Skanes, Allan C; Yee, Raymond; Gula, Lorne J; Leong-Sit, Peter; Manlucu, Jaimie; Krahn, Andrew D

    2015-08-01

    The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score ≥3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p = 0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotype-negative (1.7 vs. 3.1, p = 0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p = 0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted.

  1. Familial testicular germ cell tumor: no associated syndromic pattern identified

    PubMed Central

    2014-01-01

    Background Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT. Methods We evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies. Results The prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected. Conclusions Overall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility. PMID:24559313

  2. Phenotypic variability and diffuse arterial lesions in a family with Loeys-Dietz syndrome type 4.

    PubMed

    Mazzella, J-M; Frank, M; Collignon, P; Langeois, M; Legrand, A; Jeunemaitre, X; Albuisson, J

    2017-03-01

    Syndromic thoracic aortic aneurysm and dissection (TAAD) can suggest Marfan, vascular Ehlers-Danlos or Loeys-Dietz (LDS) syndromes. Several of the TGFβ-pathway-related genes predispose to different types of LDS. Heterozygous loss-of-function variations in TGFβ2 have been shown to be responsible for a novel form of syndromic TAAD associated with an impairment of the mitral valve and cerebrovascular disease called Loeys-Dietz syndrome type 4 (LDS4). We report the clinical characterization of a LDS4 French family with sudden deaths and diffuse vascular lesions, caused by a frameshift mutation in TGFβ2 gene: c.[995del]; p.(Leu332TrpfsTer27). Clinical characteristics include aneurysm of aortic sinus, skeletal and cutaneous features compatible with a syndromic form of TAAD (joint hypermobility, scoliosis, and easy bruises), intracranial aneurysms and rare mitral valve involvement. Iliac aneurysms, systemic medium caliber arteries dissections, and mild developmental delay were present in the family, and have not been described in LDS4. Phenotypic variability was also an important finding, including absence of clinical vascular events at advanced age in one case. Our data expand the phenotype of LDS4: we confirm that TGFβ2 mutations are responsible for true LDS syndrome with non-specific features of connective tissue disorders and diffuse vascular lesions. Adapted vascular follow up and prevention has to be proposed for these patients.

  3. Genotype by energy expenditure interaction with metabolic syndrome traits: the Portuguese healthy family study.

    PubMed

    Santos, Daniel M V; Katzmarzyk, Peter T; Diego, Vincent P; Souza, Michele C; Chaves, Raquel N; Blangero, John; Maia, José A R

    2013-01-01

    Moderate-to-high levels of physical activity are established as preventive factors in metabolic syndrome development. However, there is variability in the phenotypic expression of metabolic syndrome under distinct physical activity conditions. In the present study we applied a Genotype X Environment interaction method to examine the presence of GxEE interaction in the phenotypic expression of metabolic syndrome. A total of 958 subjects, from 294 families of The Portuguese Healthy Family study, were included in the analysis. Total daily energy expenditure was assessed using a 3 day physical activity diary. Six metabolic syndrome related traits, including waist circumference, systolic blood pressure, glucose, HDL cholesterol, total cholesterol and triglycerides, were measured and adjusted for age and sex. GxEE examination was performed on SOLAR 4.3.1. All metabolic syndrome indicators were significantly heritable. The GxEE interaction model fitted the data better than the polygenic model (p<0.001) for waist circumference, systolic blood pressure, glucose, total cholesterol and triglycerides. For waist circumference, glucose, total cholesterol and triglycerides, the significant GxEE interaction was due to rejection of the variance homogeneity hypothesis. For waist circumference and glucose, GxEE was also significant by the rejection of the genetic correlation hypothesis. The results showed that metabolic syndrome traits expression is significantly influenced by the interaction established between total daily energy expenditure and genotypes. Physical activity may be considered an environmental variable that promotes metabolic differences between individuals that are distinctively active.

  4. Genotype by Energy Expenditure Interaction with Metabolic Syndrome Traits: The Portuguese Healthy Family Study

    PubMed Central

    Santos, Daniel M. V.; Katzmarzyk, Peter T.; Diego, Vincent P.; Souza, Michele C.; Chaves, Raquel N.; Blangero, John; Maia, José A. R.

    2013-01-01

    Moderate-to-high levels of physical activity are established as preventive factors in metabolic syndrome development. However, there is variability in the phenotypic expression of metabolic syndrome under distinct physical activity conditions. In the present study we applied a Genotype X Environment interaction method to examine the presence of GxEE interaction in the phenotypic expression of metabolic syndrome. A total of 958 subjects, from 294 families of The Portuguese Healthy Family study, were included in the analysis. Total daily energy expenditure was assessed using a 3 day physical activity diary. Six metabolic syndrome related traits, including waist circumference, systolic blood pressure, glucose, HDL cholesterol, total cholesterol and triglycerides, were measured and adjusted for age and sex. GxEE examination was performed on SOLAR 4.3.1. All metabolic syndrome indicators were significantly heritable. The GxEE interaction model fitted the data better than the polygenic model (p<0.001) for waist circumference, systolic blood pressure, glucose, total cholesterol and triglycerides. For waist circumference, glucose, total cholesterol and triglycerides, the significant GxEE interaction was due to rejection of the variance homogeneity hypothesis. For waist circumference and glucose, GxEE was also significant by the rejection of the genetic correlation hypothesis. The results showed that metabolic syndrome traits expression is significantly influenced by the interaction established between total daily energy expenditure and genotypes. Physical activity may be considered an environmental variable that promotes metabolic differences between individuals that are distinctively active. PMID:24260389

  5. Family Health and Characteristics in Chronic Fatigue Syndrome, Juvenile Rheumatoid Arthritis, and Emotional Disorders of Childhood.

    ERIC Educational Resources Information Center

    Rangel, Luiza; Garralda, M. Elena; Jeffs, Jim; Rose, Gillian

    2005-01-01

    Objective: To compare family health and characteristics in children with chronic fatigue syndrome (CFS), in juvenile rheumatoid arthritis (JRA), and emotional disorders. Method: Parents of 28 children and adolescents aged 11 to 18 years with CFS, 30 with JRA, and 27 with emotional disorders (i.e., anxiety and/or depressive disorders) were…

  6. Stress and Family Functioning in Parents of Girls with Rett Syndrome.

    ERIC Educational Resources Information Center

    Perry, Adrienne; And Others

    1992-01-01

    This survey of parents of 29 girls with Rett syndrome found that subjects reported more stress, lower marital satisfaction, and certain adaptations in family functioning compared to norms. However, most parents scored in the normal range. Scores were not related to socioeconomic status or characteristics of the affected child. (DB)

  7. The Adolescent with Down's Syndrome: Life for the Teenager and for the Family.

    ERIC Educational Resources Information Center

    Buckley, Sue; Sacks, Ben

    The book presents the results of a survey of the daily life and attitudes of 90 English families with an adolescent with Down Syndrome (DS). The first chapter reviews the typical development of DS children. Chapter 2 provides demographic data including schooling (94% attended schools for children with severe learning difficulties), residence (83%…

  8. Family and Professional Congruence in Communication Assessments of Preschool Boys with Fragile X Syndrome.

    ERIC Educational Resources Information Center

    Jackson, Sandra C.; Roberts, Joanne E.

    1999-01-01

    A study compared family and professional assessment of the communication skills of 34 preschool males with Fragile X syndrome. Moderate agreement was found for expressive communication ratings, whereas agreement for receptive communication ratings was low to moderate. Parents rated their children significantly higher than did professionals for…

  9. Using an Epidemiological Approach to Examine Outcomes Affecting Young Children with Down Syndrome and Their Families

    ERIC Educational Resources Information Center

    Hodapp, Robert M.; Urbano, Richard C.; So, Stephanie A.

    2006-01-01

    In this paper, we utilise an approach drawn from the field of epidemiology to explore what is known and unknown about young children with Down syndrome and their families. After describing what we mean by an epidemiological approach, we review basic findings for children with intellectual disabilities, as well as challenges to performing such…

  10. The Impact of Tourette's Syndrome in the School and the Family: Perspectives from Three Stakeholder Groups

    ERIC Educational Resources Information Center

    Rivera-Navarro, Jesús; Cubo, Esther; Almazán, Javier

    2014-01-01

    This article analyzes the perceptions of Spanish health professionals, children with Tourette's Syndrome (TS) and their parents about social, school and family problems related to the disorder. A qualitative research methodology was used involving Focus Groups (FGs) made up of children with TS (× 2 FGs), parents/caregivers of persons with TS (× 2…

  11. [Ocular symptoms in a family with pseudo-Ullrich-Turner syndrome].

    PubMed

    Förster, W; Lenz, W; Busse, H

    1991-11-01

    We report on a family with some features of the Pseudo-Ullrich-Turner-Syndrome, so-called Noonan-Syndrome. Besides low-set ears, microgenia, short neck, pterygium colli, low-anterior hair line and small stature as well as partial scoliosis, partial cubitus valgus and camptodactylia, retinal detachment, disturbances of the eye motility, keratoconus, unilateral ptosis and antimongoloid slant of the palpebral fissures in different expression are described. The caryotype was normal. Some of the features can be seen within at least 2 generations of the family. It seems to be an autosomal genetic mode of transmission. Differences and common characteristics in comparison to the literature are shown. Differential diagnostic aspects are described. A definite relation to a syndrome already described is not possible.

  12. A family with Townes-Brocks syndrome with congenital hypothyroidism and a novel mutation of the SALL1 gene.

    PubMed

    Choi, Won Ik; Kim, Ji Hye; Yoo, Han Wook; Oh, Sung Hee

    2010-12-01

    Townes-Brocks syndrome (TBS) is a rare autosomal dominant congenital disorder caused by mutations in the SALL1 gene. Its signs and symptoms overlap with other genetic syndromes, including VACTERL association, Pendred syndrome, Baller-Gerold syndrome, and cat eye syndrome. Structural vertebral abnormalities, hypoplasia of the thumb, and radial bone abnormalities, which are not usually associated with TBS, help in the differential diagnosis of these syndromes. We report the case of a family whose members were diagnosed with TBS with congenital hypothyroidism and had a novel SALL1 gene mutation.

  13. Irritable bowel syndrome. Strategy for the family physician.

    PubMed Central

    Thompson, W. G.

    1994-01-01

    Irritable bowel syndrome is one of the most common reasons for disability and health care seeking. A sensible strategy for management incorporates a confident diagnosis based upon history, physical examination, and pertinent tests. The physician can then reassure the patient, offer dietary and stress management advice, and recommend bran to relieve constipation and to evoke the placebo response. Patients who do not respond could require supportive psychotherapy or a drug for the dominant symptom. A few require careful referral, but overall responsibility should remain with the primary physician. Images Figures 1-2 PMID:8130678

  14. Comparison Groups in Autism Family Research: Down Syndrome, Fragile X Syndrome, and Schizophrenia

    ERIC Educational Resources Information Center

    Seltzer, Marsha Mailick; Abbeduto, Leonard; Krauss, Marty Wyngaarden; Greenberg, Jan; Swe, April

    2004-01-01

    This paper examines methodological challenges inherent in conducting research on families of children with autism and in comparing these families with others who are coping with different types of disabilities or who have nondisabled children. Although most comparative research has contrasted families whose child has autism with those whose child…

  15. Osteochondritis dissecans and Osgood Schlatter disease in a family with Stickler syndrome

    PubMed Central

    Al Kaissi, Ali; Klaushofer, Klaus; Grill, Franz

    2009-01-01

    Purpose Stickler syndrome is among the most common autosomal dominant connective tissue disorders but is often unrecognised and therefore not diagnosed by clinicians. Despite much speculation, the cause of osteochondrosis in general and osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) in particular remain unclear. Etiological understanding is essential. We describe a pair of family subjects presented with OCD and OSS as a symptom complex rather than a diagnosis. Methods Detailed clinical and radiographic examinations were undertaken with emphasis on the role of MRI imaging. Magnetic resonance imaging may allow early prediction of articular lesion healing potential in patients with Stickler syndrome. Results The phenotype of Stickler syndrome can be diverse and therefore misleading. The expectation that the full clinical criteria of any given genetic disorder such as Stickler syndrome will always be present can easily lead to an underestimation of these serious inheritable disorders. We report here two family subjects, a male proband and his aunt (paternal sister), both presented with the major features of Stickler syndrome. Tall stature with marfanoid habitus, astigmatism/congenital vitreous abnormality and submucus cleft palate/cleft uvula, and enlarged painful joints with early onset osteoarthritis. Osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) were the predominating joint abnormalities. Conclusion We observed that the nature of the articular and physeal abnormalities was consistent with a localised manifestation of a more generalised epiphyseal dysplasia affecting the weight-bearing joints. In these two patients, OCD and OSS appeared to be the predominant pathologic musculoskeletal consequences of an underlying Stickler's syndrome. It is empirical to consider generalised epiphyseal dysplasia as a major underlying causation that might drastically affect the weight-bearing joints. PMID:19193224

  16. Clinical characterization and mutation spectrum in Hispanic families with adenomatous polyposis syndromes

    PubMed Central

    Cruz-Correa, Marcia; Diaz-Algorri, Yaritza; Mendez, Vanessa; Vazquez, Pedro Juan; Lozada, Maria Eugenia; Freyre, Katerina; Lathroum, Liselle; Gonzalez-Pons, Maria; Hernandez-Marrero, Jessica; Giardiello, Francis; Rodriguez-Quilichini, Segundo

    2013-01-01

    Background Several genetically defined hereditary CRC syndromes are associated with colonic polyposis including familial adenomatous polyposis (FAP) and MUTYH adenomatous polyposis (MAP). Limited data exists on the clinical characterization and genotypic spectrum of polyposis syndromes among Hispanics. Purpose To describe the phenotype and genotype of Puerto Rican Hispanic patients with FAP and MUTYH and compare with other ethnic and racial groups. Methods Probands were identified from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Recruited individuals completed risk factors, medical, and family history questionnaires and underwent genetic testing for genotype analysis. Frequency analysis, chi-square, Fisher’s exact test and Wilcoxon rank-sum test were used for statistical analysis methods. Results A total of 31 FAP (from 19 families) and 13 MAP (from 13 families) Hispanic patients recruited from the Puerto Rico Familiar Colorectal Cancer Registry were evaluated. Among the FAP cases, mean age at diagnosis was 27.6 (range 9–71 years); 67.7% cases had more than 100 polyps and 41.9% had upper gastrointestinal polyps. Among the 19 FAP families, there were 77 affected FAP individuals and 26 colorectal cancer cases. Genetic mutations were available for 42.2% of FAP families; all mutations identified were unique. Surgeries were reported in 31 cases; 14 (45.2%) prophylactic surgeries and 6 (19.4%) therapeutic surgeries for management of CRC. Among MAP cases, mean age at diagnosis was 53 (range 34–76 years) and genetic analysis revealed homozygous biallelic mutations (G382D) in 53.8%, compound heterozygous mutations (G382/Y165C) in 23%, and non-G382/Y165C monoallelic mutations in 23%. Conclusions Familial cancer registries should be promoted as vehicles for detection, education and follow up of families at-risk of acquiring familial cancers. PURIFICAR is the first and only familial cancer registry in Puerto Rico providing these services to families

  17. Familial Uncombable Hair Syndrome: Ultrastructural Hair Study and Response to Biotin.

    PubMed

    Boccaletti, V; Zendri, E; Giordano, G; Gnetti, L; De Panfilis, G

    2007-01-01

    We report a family affected to the fourth generation by uncombable hair syndrome. This syndrome is characterized by unruly, dry, blond hair with a tangled appearance. The family pedigree strongly supports the hypothesis of autosomal dominant inheritance; some members of the family had, apart from uncombable hair, minor signs of atopy and ectodermal dysplasia, such as abnormalities of the nails. The diagnosis was confirmed by means of extensive scanning electron microscopy. A trial with oral biotin 5 mg/day was started on two young patients with excellent results as regards the hair appearance, although scanning electron microscopy did not show structural changes in the hair. After a 2-year-period of follow-up, hair normality was maintained without biotin, while nail fragility still required biotin supplementation for control.

  18. Hadju-Cheney syndrome. Report of a non-familial case.

    PubMed

    Kawamura, J; Matsubayashi, K; Ogawa, M

    1981-01-01

    The case of a 24-year-old man with Hadju-Cheney syndrome is reported. No similar disease occurred in his family. Inverted and bullous tips of fingers were noted at age 9 and protruded occipital bone at age 10. He complained on left facial spasm and facial tics for 1 year. Examination revealed a man of short stature, with a brachycephalic skull and hypertelorism. Radiologically there was an extreme degree of basilar impression with the basal angle of 180 degrees, demineralized spinal vertebrae, and acro-osteolysis. Both bone and CT scans demonstrated the abnormalities of the skull clearly. The basilar artery ran almost horizontally on angiography. He gradually deteriorated neurologically with bulbar, pyramidal and cerebellar signs and symptoms. Review of the literature revealed at least ten non-familial and nine familial cases of this disorder. It is considered that this syndrome is a genetically determined generalized dysplastic bone disorder.

  19. Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families

    PubMed Central

    Kondo, Daiki; Harada, Kouji H.; Youssefian, Shohab; Shioi, Hirotomo; Kabata, Risako; Domon, Yuki; Kubota, Kazufumi; Kitano, Yutaka; Takayama, Yasunori; Hitomi, Toshiaki; Ohno, Kousaku; Saito, Yoshiaki; Asano, Takeshi; Tominaga, Makoto

    2016-01-01

    Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8–9 weeks old; n = 10–12 for each group) and mature (36–38 weeks old; n = 5–6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8–9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations

  20. Primary familial hypomagnesemia syndrome: a new approach in treatment.

    PubMed

    Nesibe, Andiran; Sinasi, Ozsoylu

    2012-01-01

    Primary familial hypomagnesemia is a rare genetically determined disorder characterized by a selective defect in magnesium (Mg) absorption. Mutations of the transient receptor potential melastatin 6 (TRPM6) gene, which codes for TRPM6, the basic channel for intestinal Mg absorption and a new member of the transient receptor potential (TRP) family of cation channels, result in primary hypomagnesemia. Here we present a 14-year-old Turkish girl whose first symptoms manifested as neonatal tetany at 17 days old. During her follow-up, she was mainly taking high-dose oral Mg therapy. However, intravenous Mg and calcium (Ca) therapies were given during symptomatic attacks. When her requirements for Ca and Mg were increased during the pubertal growth period, which overlapped with increased loss of Mg during the summer, oral Ca and active vitamin D (calcitriol, Rocaltrol) were added. Calcitriol is needed because hypomagnesemia results in decreased production and resistance to the actions of active vitamin D, which leads to the disturbance of intracellular signal transmission. Although high-dose oral Mg is reported as a sufficient therapy in most of the patients with primary familial hypomagnesemia, addition of active vitamin D to the usual oral Mg and Ca therapy seems very useful, as in this patient.

  1. Prevalence of metabolic syndrome in the family members of women with polycystic ovary syndrome from North India

    PubMed Central

    Shabir, Iram; Ganie, Mohd Ashraf; Zargar, Mohd Afzal; Bhat, Dilafroz; Mir, Mohd Muzzafar; Jan, Aleem; Shah, Zaffar Amin; Jan, Vicar; Rasool, Riyaz; Naqati, Andleeb

    2014-01-01

    Background: Polycystic ovary syndrome (PCOS) is the most complex and common endocrine disorder of women in reproductive years. In addition to irregular menstrual cycles, chronic anovulation and hyperandrogenism, it has many metabolic manifestations such as obesity, hyperlipidemia, hyperinsulinemia, insulin resistance, dysglycemia, increased risk of cardiovascular disease or possibly endometrial cancer. Familial clustering of PCOS in consistence with the genetic susceptibility has been described. Materials and Methods: The present study assessed the clinical, biochemical and hormonal parameters including prevalence of metabolic syndrome by two different criteria in the first- degree relatives of patients with PCOS. Results: The average age of 37 index patients was 23 ± 3.6 years, with the mean age of menarche as 13.3 ± 1.2 years. The mean age and age of menarche in mothers (n = 22) was 48.8 ± 5.1 and 13 ± 1.3 years, respectively, whereas as it was 23.5 ± 4.7 and 13.3 ± 1.2 years in sisters (n = 22), respectively. Metabolic syndrome (MS) defined by International Diabetes Federation (IDF) criteria was present in 10 index patients, 1 brother, 4 sisters, 17 mothers and 15 fathers while as by Adult Treatment Panel III (ATP III) it was in 8 index patients, 5 sisters, 16 mothers and 11 fathers. Conclusion: The presence of MS or related metabolic derangements is high in the family members of women with PCOS. PMID:24944933

  2. Autoimmune lymphoproliferative syndrome (ALPS). Case report and family history.

    PubMed

    Ries, F; Ferster, A; Rieux-Laucat, F; Biwer, A; Dicato, M

    2010-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease caused by defective lymphocyte apoptosis and is characterized by non-malignant lymphoproliferation, hepatosplenomegaly, autoimmune manifestations and increased risk of both Hodgkin's and non-Hodgkin's lymphoma. Most forms of the disease are due to germ line mutations of the FAS gene and manifest during the first years of life with fluctuating lymphadenopathies, hemolysis, immune thrombocytopenia. During the second decade of life disease manifestations improve spontaneously but autoimmune problems still occur and there is an increased risk of lymphoproliferative malignancy. We describe a typical case of ALPS in a now 44 year old man, followed since the age of 2 for disease manifestations that were unclear at the beginning.

  3. Severe Gardner Syndrome in Families with Mutations Restricted to a Specific Region of the APC Gene

    PubMed Central

    Davies, D. Rhodri; Armstrong, John G.; Thakker, Nalin; Horner, Keith; Guy, Simon P.; Clancy, Tara; Sloan, Phil; Blair, Val; Dodd, Chris; Warnes, Tom W.; Harris, Rodney; Evans, D. Gareth R.

    1995-01-01

    Familial adenomatous polyposis (FAP) is associated with a number of extraintestinal manifestations, which include osteomas, epidermoid cysts, and desmoid tumors, often referred to as “Gardner syndrome.” Recent studies have suggested that some of the phenotypic features of FAP are dependent on the position of the mutation within the APC gene. In particular, the correlation between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and APC genotype indicates that affected families may be divided into distinct groups. We have investigated the association between the dento-osseous features of GS on dental panoramic radiographs (DPRs) and APC genotype in a regional cohort of FAP families. DPRs were performed on 84 affected individuals from 36 families, and the dento-osseous features of FAP were quantified by a weighted scoring system. Significant DPR abnormalities were present in 69% of affected individuals. The APC gene mutation was identified in 27 of these families, and for statistical analysis these were subdivided into three groups. Group 1 comprised 18 affected individuals from seven families with mutations 5' of exon 9; these families (except one) did not express CHRPE. Groups 2 comprised 38 individuals from 16 families with mutations between exon 9 and codon 1444, all of whom expressed CHRPE. Group 3 comprised 11 individuals from four families with mutations 3' of codon 1444, none of whom expressed CHRPE. Families with mutations 3' of codon 1444 had significantly more lesions on DPRs (P < .001) and appeared to have a higher incidence of desmoid tumors. These results suggest that the severity of some of the features of Gardner syndrome may correlate with genotype in FAP. ImagesFigure 2 PMID:7485167

  4. Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes.

    PubMed Central

    Reis, A.; Dittrich, B.; Greger, V.; Buiting, K.; Lalande, M.; Gillessen-Kaesbach, G.; Anvret, M.; Horsthemke, B.

    1994-01-01

    The D15S9 and D15S63 loci in the Prader-Willi/Angelman syndrome region on chromosome 15 are subject to parent-of-origin-specific DNA methylation. We have found two Prader-Willi syndrome families in which the patients carry a maternal methylation imprint on the paternal chromosome. In one of these families, the patients have a small deletion encompassing the gene for the small nuclear ribonucleoprotein polypeptide N, which maps 130 kb telomeric to D15S63. Furthermore, we have identified a pair of nondeletion Angelman syndrome sibs and two isolated Angelman syndrome patients who carry a paternal methylation imprint on the maternal chromosome. These Angelman and Prader-Willi syndrome patients may have a defect in the imprinting process in 15q11-13. We propose a model in which a cis-acting mutation prevents the resetting of the imprinting signal in the germ line and thus disturbs the expression of imprinted genes in this region. Images Figure 2 Figure 3 PMID:8178815

  5. Quantitative and qualitative insights into the experiences of children with Rett syndrome and their families.

    PubMed

    Downs, Jenny; Leonard, Helen

    2016-09-01

    Rett syndrome is a rare neurodevelopmental disorder caused by a mutation in the MECP2 gene. It is associated with severe functional impairments and medical comorbidities such as scoliosis and poor growth. The population-based and longitudinal Australian Rett Syndrome Database was established in 1993 and has supported investigations of the natural history of Rett syndrome and effectiveness of treatments, as well as a suite of qualitative studies to identify deeper meanings. This paper describes the early presentation of Rett syndrome, including regression and challenges for families seeking a diagnosis. We discuss the importance of implementing strategies to enhance daily communication and movement, describe difficulties interpreting the presence of pain and discomfort, and argue for a stronger evidence base in relation to management. Finally, we outline a framework for understanding quality of life in Rett syndrome and suggest areas of life to which we can direct efforts in order to improve quality of life. Each of these descriptions is illustrated with vignettes of child and family experiences. Clinicians and researchers must continue to build this framework of knowledge and understanding with efforts committed to providing more effective treatments and supporting the best quality of life for those affected.

  6. Imprinting mutations suggested by abnormal DNA methylation patterns in familial angelman and Prader-Willi syndromes

    SciTech Connect

    Reis, A. ); Dittrich, B.; Buiting, K.; Gillessen-Kaesbach, G.; Horsthemke, B. ); Greger, V.; Lalande, M. ); Anvret, M. )

    1994-05-01

    The D15S9 and D15S63 loci in the Prader-Willi/Angelman syndrome region on chromosome 15 are subject to parent-of-origin-specific DNA methylation. The authors have found two Prader-Willi syndrome families in which the patients carry a maternal methylation imprint on the paternal chromosome. In one of these families, the patients have a small deletion encompassing the gene for the small nuclear ribonucleoprotein polypeptide N, which maps 130 kb telomeric to D15S63. Furthermore, they have identified a pair of nondeletion Angelman syndrome sibs and two isolated Angelman syndrome patients who carry a paternal methylation imprint on the maternal chromosome. These Angelman and Prader-Willi syndrome patients may have a defect in the imprinting process in 15q11-13. The authors propose a model in which a cis-acting mutation prevents the resetting of the imprinting signal in the germ line and thus disturbs the expression of imprinted genes in this region. 39 refs., 4 figs., 1 tab.

  7. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome.

    PubMed

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V P; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-09-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak‑like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811‑812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of

  8. [Unusual complications of the Peutz-Jeghers-syndrome in two consecutive generations of the same family].

    PubMed

    Lazaridis, Ch; Papaziogas, B; Atmatzidis, K; Kalaitzis, E; Pavlidis, T; Papaziogas, T

    2002-02-01

    The Peutz-Jeghers syndrome is an autosomal dominant inherited disease, characterized by the presence of hamartomatous polyposis of the gastrointestinal tract and perioral mucocutaneous pigmentation. The incidence of surgical complications in these patients is relatively rare, and correlates with the size and location of the polyps. We report on two complications of the Peutz-Jeghers syndrome which occurred in two generations of the same family. There was a perforation and an invagination of the small intestine. Both cases were treated by resection of the small intestine.

  9. Anakinra induces complete remission of nephrotic syndrome in a patient with familial mediterranean fever and amyloidosis.

    PubMed

    Sevillano, Ángel M; Hernandez, Eduardo; Gonzalez, Esther; Mateo, Isabel; Gutierrez, Eduardo; Morales, Enrique; Praga, Manuel

    2016-01-01

    Renal amyloidosis is one of the most severe complications of familial Mediterranean fever (FMF). Colchicine has reduced the incidence of this complication, which now only appears in untreated, under-treated and resistant patients, but it is usually ineffective in patients with advanced amyloidosis. Here we report a patient with FMF and biopsy-proven amyloidosis who presented with nephrotic syndrome despite colchicine treatment. Anakinra (an interleukin-1β inhibitor) was started and a dramatic complete remission of nephrotic syndrome was observed in the following months. Anakinra can be an effective treatment for FMF patients with severe secondary amyloidosis.

  10. Waardenburg syndrome type I: Dental phenotypes and genetic analysis of an extended family

    PubMed Central

    de Aquino, Sibele-Nascimento; Paranaíba, Lívia-Maris-R.; Gomes, Andreia; dos-Santos-Neto, Pedro; Coletta, Ricardo-D.; Cardoso, Aline-Francoise; Frota, Ana-Cláudia; Martelli-Júnior, Hercílio

    2016-01-01

    Background The aim of this study was to describe the pattern of inheritance and the clinical features in a large family with Waardenburg syndrome type I (WS1), detailing the dental abnormalities and screening for PAX3 mutations. Material and Methods To characterize the pattern of inheritance and clinical features, 29 family members were evaluated by dermatologic, ophthalmologic, otorhinolaryngologic and orofacial examination. Molecular analysis of the PAX3 gene was performed. Results The pedigree of the family,including the last four generations, was constructed and revealed non-consanguineous marriages. Out of 29 descendants, 16 family members showed features of WS1, with 9 members showing two major criteria indicative of WS1. Five patients showed white forelock and iris hypopigmentation, and four showed dystopia canthorum and iris hypopigmentation. Two patients had hearing loss. Dental abnormalities were identified in three family members, including dental agenesis, conical teeth and taurodontism. Sequencing analysis failed to identify mutations in the PAX3 gene. Conclusions These results confirm that WS1 was transmitted in this family in an autosomal dominant pattern with variable expressivity and high penetrance. The presence of dental manifestations, especially tooth agenesis and conical teeth which resulted in considerable aesthetic impact on affected individuals was a major clinical feature. Clinical relevance: This article reveals the presence of well-defined dental changes associated with WS1 and tries to establish a possible association between these two entities showing a new spectrum of WS1. Key words:Waardenburg syndrome, hearing loss, oral manifestations, mutation. PMID:27031059

  11. Employment Impact and Financial Burden for Families of Children with Fragile X Syndrome: Findings from the National Fragile X Survey

    ERIC Educational Resources Information Center

    Ouyang, L.; Grosse, S.; Raspa, M.; Bailey, D.

    2010-01-01

    Background: The employment impact and financial burden experienced by families of children with fragile X syndrome (FXS) has not been quantified in the USA. Method: Using a national fragile X family survey, we analysed data on 1019 families with at least one child who had a full FXS mutation. Out-of-pocket expenditures related to fragile X were…

  12. Non-Syndromic Familial Keratocystic Odontogenic Tumour: A Rare Case Report in Japanese Identical Twins

    PubMed Central

    Maruoka, Yutaka; Yamaji, Iena; Kawai, Shigeo

    2016-01-01

    Keratocystic Odontogenic Tumour (KCOT) is unicystic or multicystic intraosseous benign tumour of odontogenic origin that recurs due to locally destructive behaviour. KCOTs are usually the first manifestation of Nevoid Basal Cell Carcinoma Syndrome (NBCCS), an autosomal dominant disorder also known as Gorlin’s syndrome and they are most frequently observed familial symptom regardless of patients’ nationality. In addition, the recurrence rate and multiplicity of KCOTs is relatively high as compared to that of other sporadic carcinomas. KCOT has been considered as a non-hereditary lesion and its familial onset is an extremely rare event in non-NBCCS cases. Here, we describe previously unreported non-syndromic multiple KCOT cases in identical twins in a Japanese family. The subjects were female Japanese identical twins who were 26 and 27 years old, respectively, at the time of diagnosis for KCOT. They had no major or minor features of NBCCS other than KCOT. Although there were lesions that were likely to be dentigerous cysts based on radiographic findings, one of them was KCOT. This case report highlights the importance of precise diagnosis, choice of surgical method and careful observation for multiplicity or familial onset in sporadic KCOT cases without NBCCS. PMID:27656582

  13. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome.

    PubMed

    Schell, U; Hehr, A; Feldman, G J; Robin, N H; Zackai, E H; de Die-Smulders, C; Viskochil, D H; Stewart, J M; Wolff, G; Ohashi, H

    1995-03-01

    Pfeiffer syndrome (PS) is an autosomal dominant skeletal disorder which affects the bones of the skull, hands and feet. Previously, we have mapped PS in a subset of families to chromosome 8cen by linkage analysis and demonstrated a common mutation in the fibroblast growth factor receptor-1 (FGFR1) gene in the linked families. Here we report a second locus for PS on chromosome 10q25, and present evidence that mutations in the fibroblast growth factor receptor-2 (FGFR2) gene on 10q25 cause PS in an additional subset of familial and sporadic cases. Three different point mutations in FGFR2, which alter the same acceptor splice site of exon B, were observed in both sporadic and familial PS. In addition, a T to C transition in exon B predicting a cysteine to arginine substitution was identified in three sporadic PS individuals. Interestingly, this T to C change is identical to a mutation in FGFR2 previously reported in Crouzon syndrome, a phenotypically similar disorder but one lacking the hand and foot anomalies seen in PS. Our results highlight the genetic heterogeneity in PS and suggest that the molecular data will be an important complement to the clinical phenotype in defining craniosynostosis syndromes.

  14. FGFR2 mutation in a Chinese family with unusual Crouzon syndrome

    PubMed Central

    Li, Zi-Li; Chen, Xue; Zhuang, Wen-Juan; Zhao, Wei; Liu, Ya-Ni; Zhang, Fang-Xia; Ha, Ruo-Shui; Wu, Jin-Hua; Zhao, Chen; Sheng, Xun-Lun

    2016-01-01

    AIM To describe the clinical characteristics with genetic lesions in a Chinese family with Crouzon syndrome. METHODS All five patients from this family were included and received comprehensive ophthalmic and systemic examinations. Direct sequencing of the FGFR2 gene was employed for mutation identification. Crystal structure analysis was applied to analyze the structural changes associated with the substitution. RESULTS All patients presented typical Crouzon features, including short stature, craniosynostosis, mandibular prognathism, shallow orbits with proptosis, and exotropia. Intrafamilial phenotypic diversities were observed. Atrophic optic nerves were exclusively detected in the proband and her son. Cranial magnetic resonance imaging (MRI) implied a cystic lesion in her sellar and third ventricular regions. A missense mutation, FGFR2 p.Cys342Trp, was found as disease causative. This substitution would generate conformational changes in the extracellular Ig-III domain of the FGFR-2 protein, thus altering its physical and biological properties. CONCLUSION We describe the clinical presentations and genotypic lesions in a Chinese family with Crouzon syndrome. The intrafamilial phenotypic varieties in this family suggest that other genetic modifiers may also play a role in the pathogenesis of Crouzon syndrome. PMID:27803855

  15. Familial 16q24.3 microdeletion involving ANKRD11 causes a KBG-like syndrome.

    PubMed

    Sacharow, Stephanie; Li, Deling; Fan, Yao Shan; Tekin, Mustafa

    2012-03-01

    Haploinsufficiency of ANKRD11 encoding ankyrin repeat domain-containing protein 11 was recently reported as the cause of a syndrome due to microdeletion, characterized by intellectual disability with minor facial anomalies and short stature. Most recently, intragenic mutations of ANKRD11 were found in a cohort of patients with KBG syndrome. KBG is an autosomal dominant intellectual disability syndrome characterized by short stature, characteristic facial appearance, macrodontia, and skeletal anomalies. It remains unknown if deletion of the entire ANKRD11 causes KBG syndrome. We present a mother and child with a heterozygous 365 Kb deletion at 16q24.3 containing ANKRD11, ZNF778, and SPG7 genes. The child presented with developmental delay, facial anomalies, hand anomalies, and a congenital heart defect. The mother has short stature, facial anomalies, macrodontia, hand anomalies, and learning disability. Both individuals had many findings reported in KBG syndrome and the family met the suggested diagnostic criteria. However, typical macrodontia with fused incisors, costovertebral anomalies, and delayed bone age were not present. We conclude that microdeletions involving ANKRD11 result in a phenotype similar to that of KBG syndrome. © 2012 Wiley Periodicals, Inc.

  16. Congenital heart defects in two siblings in an Axenfeld-Rieger syndrome family.

    PubMed

    Akkus, Mehmet Necdet; Argin, Atilla

    2010-04-01

    Axenfeld-Rieger syndrome is a genetically heterogeneous, autosomal dominant disorder characterized by anomalies of the anterior segment of the eye, face, teeth, and umbilicus. Many other extraocular findings, including congenital heart defects, have been reported in association with this syndrome. It has been suggested by some investigators that the coexistence of Axenfeld-Rieger syndrome and congenital heart defects is not a chance event but it represents a distinct entity. We report a family in which four members in three generations have typical ocular features of Axenfeld-Rieger syndrome. Two of them, who are siblings, also have congenital heart defects. The congenital heart defect was bicuspid aortic valve anomaly with severe stenosis and mild regurgitation in one sibling and ostium secundum atrial septal defect in the other. To our knowledge, the combination of congenital heart defects with Axenfeld-Rieger syndrome in siblings has not been reported previously. Our observation further strengthens the notion that Axenfeld-Rieger syndrome associated with congenital heart defects is not a chance event.

  17. All in the family? Analyzing the impact of family history in addition to genotype on medullary thyroid carcinoma aggressiveness in MEN2A patients.

    PubMed

    Long, Kristin L; Etzel, Carol; Rich, Thereasa; Hyde, Samuel; Perrier, Nancy D; Graham, Paul H; Lee, Jeffrey E; Hu, Mimi I; Cote, Gilbert J; Gagel, Robert; Grubbs, Elizabeth G

    2017-04-01

    Several guidelines for patients with multiple endocrine neoplasia 2A (MEN2A) take into account genotype and family history of medullary thyroid carcinoma (MTC) disease aggressiveness. We sought to determine if an association exists independent of genotype, which could provide important information for counseling MEN2A patients in management of their MTC. Pedigrees of patients with ≥5 family members with MEN2A were retrospectively reviewed. Analysis was performed among kindreds with the most frequently observed codon mutation (RET 634). Familial MTC disease aggressiveness was evaluated using: (1) mean age at diagnosis of MTC, (2) current mean age of carriers without MTC, (3) proportion of kindred with MTC with metastatic disease at diagnosis, (4) proportion of kindred with MTC with metastasis/death from MTC as worst outcome, and (5) proportion of kindred with disease progression. 170 affected patients from 12 different MEN2A kindreds met inclusion criteria. The number of affected family members available for study per kindred ranged from 8 to 43 individuals. A difference in mean age of MTC diagnosis was found in screened patients (p = 0.01); mean age of MTC-free patients did not differ (p = 0.93). No differences were noted among kindreds in disease stage at presentation, worst outcome, or progression; marked variation in these measures was noted within families. In conclusion, a difference in age of MTC diagnosis among different RET 634 kindreds was identified. In contrast, notable intra-familial variability in disease aggressiveness was observed. Based on these findings, we recommend counseling patients with codon 634 mutations that their MTC disease course cannot be predicted by that of their relatives.

  18. CYLD GeneticTesting for Brooke-Spiegler Syndrome, Familial Cylindromatosis and Multiple Familial Trichoepitheliomas

    PubMed Central

    Dubois, Anna; Wilson, Valerie; Bourn, David; Rajan, Neil

    2015-01-01

    The clinical presentation of multiple, rare, skin appendage tumours called cylindromas has been attributed to germline mutations in the tumour suppressor gene CYLD (OMIM 605018). Brooke-Spiegler Syndrome (BSS), familial cylindromatosis (FC) and multiple familial trichoepitheliomas (MFT) (OMIM #605041, #132700, #601606 respectively) differ due to the types of other skin appendage tumour seen together with cylindroma, such as spiradenoma and trichoepithelioma. Previously thought to be separate entities, they are now viewed as allelic variants with overlapping phenotypes, supported by mutation analysis of CYLD . The conditions display autosomal dominant inheritance and affected individuals develop multiple benign skin tumours most commonly on the head and neck. CYLD testing can be performed using PCR and Sanger sequencing for patients with: 1. Multiple cylindromas, spiradenomas or trichoepitheliomas. 2. A single cylindroma, spiradenoma or trichoepithelioma and an affected first-degree relative with any of these tumours. 3. An asymptomatic family member at 50% risk with a known mutation in the family. PMID:25737804

  19. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome.

    PubMed

    Tsigos, C; Arai, K; Latronico, A C; DiGeorge, A M; Rapaport, R; Chrousos, G P

    1995-07-01

    Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, usually without mineralocorticoid deficiency. Occasionally, the disorder is associated with alacrima and achalasia of the esophagus (triple A syndrome), suggesting potential heterogeneity in its etiology. Mutations in the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in 1 other family with IGD and 2 families with triple A syndrome. The proband with IGD was a homozygote for an A-->G substitution, changing tyrosine 254 to cysteine in the third extracellular loop of the receptor protein, probably interfering with ligand binding. Both of her parents were heterozygotes for this mutation, which was not detected in 100 normal alleles. No mutations were identified in the entire coding area of the ACTH receptor in the 2 families with triple A syndrome, supporting the idea of a developmental or postreceptor defect in this syndrome.

  20. [Considerations on family dynamics and the malnutrition syndrome in Mexican children].

    PubMed

    Vásquez-Garibay, Edgar Manuel; González-Rico, José Luis; Romero-Velarde, Enrique; Sánchez-Talamantes, Eva; Navarro-Lozano, María Eugenia; Nápoles-Rodríguez, Francisco

    2015-01-01

    Since the early 1990s we noted that family dysfunction was more common in children with severe primary malnutrition than in children admitted to the hospital without malnutrition. Defects on feeding habits during the first year of life, especially early weaning and inadequate complementary feeding were more common in dysfunctional families. We also observed that chronic malnutrition in preschool children, and overweight and obesity in schoolchildren were more common in children from dysfunctional families. Once the association between dysfunctional family dynamics and obesity in schoolchildren was demonstrated, it was observed that low education of fathers and mothers increased twofold the possibility of family dysfunction: OR: 2.06; 95% CI: 1.37-3.10 and OR: 2.47; 95% CI: 1.57-3.89, respectively. In addition, the low-income and the lower purchasing power of foods were associated to family dysfunction (p<0.05). A remaining task is to explore how to assess family dysfunction in composite, extended, single-parent families where there exist other persons vulnerable to the different entities of malnutrition syndrome and indeed depend on adults for their care, food and nutrition.

  1. [Molecular genetics of familial tumour syndromes of the central nervous system].

    PubMed

    Murnyák, Balázs; Szepesi, Rita; Hortobágyi, Tibor

    2015-02-01

    Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications.

  2. Spinal fusion in girls with Rett syndrome: postoperative recovery and family experiences

    PubMed Central

    Marr, Caitlin; Leonard, Helen; Torode, Ian; Downs, Jenny

    2015-01-01

    Background Rett syndrome is a severe neurodevelopmental disorder mainly affecting females and scoliosis is a common comorbidity. Spinal fusion may be recommended if the scoliosis is progressive. This qualitative study investigated recovery of girls with Rett syndrome during the first 12 postoperative months and explored family perspectives and coping around the time of surgery. Method Parents registered with the population-based Australian Rett Syndrome Database were recruited to this study if their daughter had a confirmed pathogenic MECP2 mutation and spinal fusion between 2006 and 2012. Twenty-five interviews were conducted to determine their daughter’s recovery and parental stresses and coping. Themes in the interview data were identified with content analysis and the regaining of gross motor skills over the first 12 postoperative months were described with time-to-event (survival) analysis. Results Pain and energy levels, appetite, mood and coinciding health issues influenced their daughter’s postoperative recovery. The majority of girls recovered preoperative sitting (88%), standing (81%) and walking (80%) by 12 months. The decision to proceed with surgery was associated with feelings of fear, obligation, relief and guilt for families. Development of complications, poor support and feelings of isolation increased their emotional burden whilst adequate information and discharge preparation, confidence in self and staff, and balancing personal needs with their daughter’s care relieved this burden. Interpretation Our study identified clinical practice issues in relation to families whose daughter with Rett syndrome undergoes spinal fusion, issues that are also relevant to other severe disabilities. Return of wellness and gross motor skills following spinal fusion in girls with Rett syndrome occurred within the first 12 postoperative months in most cases. Parents require information and practical support to alleviate their emotional burden. PMID:25752500

  3. GDNF Gene Is Associated With Tourette Syndrome in a Family Study

    PubMed Central

    Huertas-Fernández, Ismael; Gómez-Garre, Pilar; Madruga-Garrido, Marcos; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Martín-Rodríguez, Juan Francisco; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Carrillo, Fátima; Pascual, Alberto; Tischfield, Jay A.; King, Robert A.; Heiman, Gary A.; Mir, Pablo

    2016-01-01

    Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line–derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. PMID:26096985

  4. PFAPA syndrome mimicking familial Mediterranean fever: report of a Turkish child.

    PubMed

    Ataş, Bülent; Caksen, Hüseyin; Arslan, Sükrü; Tuncer, Oğuz; Kirimi, Ercan; Odabaş, Dursun

    2003-11-01

    The PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitidis) syndrome is characterized by periodic fever, adenitis, pharyngitis, and aphthous stomatitis. Herein, we present a Turkish child with PFAPA syndrome mimicking familial Mediterranean fever because of a rare presentation. A 9-year-old boy was admitted with recurrent fever, aphthous stomatitis, sore throat, headache, and general body pains, lasting 2 to 3 days since 3.5 years of age. He was completely symptom-free between the attacks. He was diagnosed as having familial Mediterranean fever according to the clinical findings when he was 6 years of age and Colchicum tablet was administrated. Despite colchicines therapy for 8 months, his attacks did not subside; therefore, the drug was discontinued. He had high fever, a painful cervical lymphadenopathy, aphthous stomatitis, and tonsillo-pharyngitis. The patient was then diagnosed as having PFAPA syndrome. He was given a single dose of prednisolone (0.35 mg/kg/dose). His complaints dramatically and completely disappeared 3 h after administration of the drug. During the 8th month of follow-up, a similar febrile attack lasting only 1 day was noted and it was controlled with a single dose of prednisolone (0.5 mg/kg/day). At this writing the patient is in the 12th month of follow-up, and there have been no symptoms after the second attack. In conclusion, our patient shows that PFAPA syndrome can be confused with familial Mediterranean fever. We also would like to emphasize that the typical PFAPA syndrome can be easily diagnosed by detailed history-taking and physical findings.

  5. Aarskog syndrome: report of a family with review and discussion of nosology.

    PubMed

    Teebi, A S; Rucquoi, J K; Meyn, M S

    1993-06-15

    Five individuals in one family, including dizygotic male twins, a half brother and their mother, had Aarskog syndrome (AS). Phenotypic variability is wide not only between mother and sons but also between sibs. Collectively, the affected relatives have the full spectrum of findings seen in AS. Based on analysis of this family and others from the literature, we derive primary and secondary diagnostic criteria for AS. Primary criteria include: short stature, hypertelorism, short nose with anteverted nares, maxillary hypoplasia, a crease below the lower lip, mild interdigital webbing with short and broad hands, short fifth finger with clinodactyly, and shawl scrotum. Secondary criteria include: abnormal auricles with fleshy lobules, posteriorly angulated ears, widow's peak, ptosis, downward slant of palpebral fissures, joint hyperextensibility, broad feet with bulbous toes, cryptorchidism, inguinal hernia, and prominent umbilicus. Literature pertaining to the clinical manifestations and genetics of AS is reviewed and nosology of similar syndromes is discussed.

  6. Loeys-Dietz syndrome: life threatening aortic dissection diagnosed on routine family screening

    PubMed Central

    Martin, Claire A; Clowes, Virginia E; Cooper, John P

    2014-01-01

    A 52-year-old man was found to have a severely dilated aortic root and a Stanford type A dissection on familial screening echocardiography, following diagnosis of a dilated aorta in his son. The dissection required urgent surgical repair. Clinical examination suggested features of Loeys-Dietz syndrome type II, and subsequent demonstration of a mutation in the TGFBR1 gene in the patient and his son confirmed the diagnosis. This article highlights the high prevalence of inherited conditions in dilated aortic root presentations and the importance of family screening and surveillance to allow early surgical intervention. PMID:24495977

  7. C596G mutation in FBN1 causes Marfan syndrome with exotropia in a Chinese family

    PubMed Central

    Li, Bo; Lan, Lan; Li, Lin

    2015-01-01

    Purpose To screen mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS). Methods Patients and unaffected family members were given ophthalmic, cardiovascular, and physical examinations with a 5-year follow-up. Genomic DNA was extracted from the leukocytes of venous blood from all patients and their relatives. The entire coding region of the FBN1gene was screened with an ABI 9700 GeneAmp PCR System. The mutation identified was screened in 100 healthy and ethnically unrelated Chinese individuals. Results Mutation screening in FBN1 identified a T>G transition at position c.1786 in exon 14, leading to substitution of cysteine for glycine at codon 596 (C596G) in this four-generation Chinese family. The C596G mutation was associated with the disease phenotypes in all six patients but not found in 14 unaffected family members or the 100 ethnically unrelated and healthy controls. Conclusions A C596G mutation in FBN1 was identified in a Chinese family with MFS. Our results expand the spectrum of FBN1 mutations and contribute to the understanding of the role of FBN1 in the pathogenesis of Marfan syndrome. PMID:25729264

  8. The "military family syndrome" revisited: "by the numbers".

    PubMed

    Jensen, P S; Xenakis, S N; Wolf, P; Bain, M W

    1991-02-01

    Because concerns have been raised about high levels of psychopathology in military children, the authors used standardized psychopathology rating scales to survey 213 six-to twelve-year-old children of military parents and their parents. Results from children's symptom self-reports, as well as from teachers' ratings of children, indicated that children's symptom levels were at levels consistent with national norms. In contrast, parents' (especially mothers') ratings of children were significantly higher than national norms, as were parents' ratings of their own symptoms. Also, parents' own symptom reports showed somewhat stronger relationships with life stressors presumably affecting the child than did the children's and teachers' reports. Results suggest that parents' reports of children's symptoms may be mediated by the effects of military life stressors on the parents, but these stressors do not necessarily result in higher symptoms in the children. Overall results do not support the notion that levels of psychopathology are greatly increased in children of military parents. Further studies of military families should address the effects of rank and socioeconomic status, housing, and the current impact of life stressors on the parents as well as the children in order to avoid drawing erroneous conclusions about parts or all of the military community.

  9. [Familial posterior cortical atrophy with visual agnosia and Bálint's syndrome].

    PubMed

    Otsuki, M; Soma, Y; Tanaka, M; Tanaka, K; Tanno, Y; Uesugi, Y; Tsuji, S

    1995-12-01

    We report a patient of posterior cortical atrophy with progressive visual agnosia, Bálint's syndrome and dementia in which posterior cortical atrophy with similar characteristics on CT and progressive dementia were found in a sister. The patient was a 75-year-old woman who noted the onset of a progressive visual disorder at the age of 70, and whose family first noticed disoriented behavior at around the same period. Ophthalmologic examinations revealed mild cataract but no evidence of peripheral optic nerve or retinal lesions. Neuropsychological examination showed right homonymous hemianopia, visual agnosia, Bálint's syndrome, mild transcortical sensory aphasia, Gerstmann's syndrome, constructional apraxia, mild ideomotor apraxia and memory disorder. MRI showed marked dilatation of both lateral ventricles, especially the posterior horns, and severe atrophy of the occipital lobes, hippocampus, and the parahippocampal gyrus. Assessment of regional cerebral blood flow by IMP-SPECT revealed a generalized decrease in the temporo-parieto-occipital region bilaterally. The patient's sister began to show evidence of progressive dementia at 80 years of age and CT of the brain revealed marked atrophy, predominantly in the occipital lobes, similar to that of the patient. We believe this to be the first report of posterior cortical atrophy with a positive family history, suggesting the possibility of a hereditary syndrome.

  10. Growth hormone deficiency and pituitary malformation in a recurrent Cat-Eye syndrome: a family report.

    PubMed

    Jedraszak, Guillaume; Braun, Karine; Receveur, Aline; Decamp, Matthieu; Andrieux, Joris; Rabbind Singh, Amrathlal; Copin, Henri; Bremond-Gignac, Dominique; Mathieu, Michèle; Rochette, Jacques; Morin, Gilles

    2015-10-01

    Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter-22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated.

  11. A novel FOXL2 mutation in a Chinese family with blepharophimosis, ptosis, epicanthus inversus syndrome.

    PubMed

    Tan, Hu; Yang, Pu; Li, Haoxian; Pan, Qian; Liang, Desheng; Wu, Lingqian

    2015-01-01

    Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disease characterized by a narrowed horizontal palpehral aperture, ptosis, epicanthus inversus and telecanthus with or without premature ovarian failure. Mutations in the forkhead transcription factor 2 (FOXL2) have been shown to be responsible for BPES. We performed direct sequencing of the FOXL2 gene for molecular investigation of a Chinese family with BPES. A novel duplication mutation (c.858_868dup), resulting in a truncated protein, was detected.

  12. Familial translocation resulting in Wolf-Hirschhorn syndrome in two related unbalanced individuals: Clinical evaluation of a 39-year-old man with Wolf-Hirschhorn syndrome

    SciTech Connect

    Wheeler, P.G.; Weaver, D.D.; Palmer, C.G.

    1995-02-13

    A chromosomal translocation between chromosomes 4 and 8 resulting in Wolf-Hirschhorn syndrome in 2 individuals has been traced through 4 generations of a family. Ascertainment of the family was through a newborn infant with evident Wolf-Hirschhorn syndrome who had an unbalanced chromosomal translocation (46,XY,-4,+der(4),t(4;8) (p15.32;p22)). Discussion with the family documented a paternal great-uncle who also had a similar phenotype and profound mental retardation. Subsequently this individual was found to have the same unbalanced chromosome constitution as the propositus. The 39-year-old great-uncle is the oldest reported individual with the Wolf-Hirschhorn syndrome. The importance of chromosome evaluation of older individuals with mental retardation syndromes is emphasized. 4 refs., 6 figs.

  13. The phenotypic spectrum of Schaaf-Yang syndrome – 18 new affected individuals from 14 families

    PubMed Central

    Fountain, Michael D.; Aten, Emmelien; Cho, Megan T.; Juusola, Jane; Walkiewicz, Magdalena A.; Ray, Joseph W.; Xia, Fan; Yang, Yaping; Graham, Brett H.; Bacino, Carlos A.; Potocki, Lorraine; van Haeringen, Arie; Ruivenkamp, Claudia A.L.; Mancias, Pedro; Northrup, Hope; Kukolich, Mary K.; Weiss, Marjan M.; van Ravenswaaij-Arts, Conny M.A.; Mathijssen, Inge B.; Levesque, Sebastien; Meeks, Naomi; Rosenfeld, Jill A.; Lemke, Danielle; Hamosh, Ada; Lewis, Suzanne K.; Race, Simone; Stewart, Laura L.; Hay, Beverly; Lewis, Andrea M.; Guerreiro, Rita L.; Bras, Jose T.; Martins, Marcia P.; Derksen-Lubsen, Gerarda; Peeters, Els; Stumpel, Connie; Stegmann, Sander; Bok, Levinus A.; Santen, Gijs W.E.; Schaaf, Christian P.

    2016-01-01

    Purpose Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease, manifesting developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole gene deletions appear to cause little to no clinical phenotype. Methods Here we report a total of 18 new individuals with Schaaf-Yang syndrome from 14 families, including one family with three individuals found to be affected with a truncating variant of MAGEL2, 11 individuals clinically affected, but not tested molecularly, and a presymptomatic fetal sibling with carrying the pathogenic MAGEL2 variant. Results All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and one fetus harboring a c.1996dupC (p.Q666fs) mutation and two fetuses harboring a c.1996delC (p.Q666fs). The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to individuals with neurobehavioral disease and contractures of the small finger joints. Conclusion This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling of affected families. PMID:27195816

  14. Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome

    PubMed Central

    Wang, Li; Lin, Qiong-Fen; Wang, Hong-Yang; Guan, Jing; Lan, Lan; Xie, Lin-Yi; Yu, Lan; Yang, Ju; Zhao, Cui; Liang, Jin-Long; Zhou, Han-Lin; Yang, Huan-Ming; Xiong, Wen-Ping; Zhang, Qiu-Jing; Wang, Da-Yong; Wang, Qiu-Ju

    2017-01-01

    Background: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. Methods: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided. Results: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations. Conclusions: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated. PMID:28303854

  15. Genetic heterogeneity in benign familial neonatal convulsions: Identification of a new locus on chromosome 8q

    SciTech Connect

    Lewis, T.B.; Leach, R.J.; O'Connell, P.; Ryan, S.G. ); Ward, K. )

    1993-09-01

    The syndrome of benign familial neonatal convulsions (BFNC) is a rare autosomal dominant disorder characterized by unprovoked seizures in the first weeks of life. One locus for BFNC has been mapped to chromosome 20 in several pedigrees, but the authors have excluded linkage to chromosome 20 in one large kindred. In order to identify this novel BFNC locus, dinucleotide repeat markers distributed throughout the genome were used to screen this family. Maximum pairwise LOD scores of 4.43 were obtained with markers D8S284 and D8S256 on chromosome 8q. Multipoint analysis placed the BFNC locus in the interval spanned by D8S198-D8S274. This study establishes the presence of a new BFNC locus and confirms genetic heterogeneity of this disorder. 26 refs., 3 figs., 1 tab.

  16. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q.

    PubMed

    Yeon, H B; Lindor, N M; Seidman, J G; Seidman, C E

    2000-04-01

    Pyoderma gangrenosum, cystic acne, and aseptic arthritis are clinically distinct disorders within the broad class of inflammatory diseases. Although this triad of symptoms is rarely observed in a single patient, a three-generation kindred with autosomal-dominant transmission of these three disorders has been reported as "PAPA syndrome" (MIM 604416). We report mapping of a disease locus for familial pyoderma gangrenosum-acne-arthritis to the long arm of chromosome 15 (maximum two-point LOD score, 5.83; recombination fraction [straight theta] 0 at locus D15S206). Under the assumption of complete penetrance, haplotype analysis of recombination events defined a disease interval of 10 cM, between D15S1023 and D15S979. Successful identification of a single disease locus for this syndrome suggests that these clinically distinct disorders may share a genetic etiology. These data further indicate the role of genes outside the major histocompatibility locus in inflammatory disease.

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

    PubMed

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

    2014-03-01

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

  18. TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy.

    PubMed

    Theis, Jeanne L; Zimmermann, Michael T; Larsen, Brandon T; Rybakova, Inna N; Long, Pamela A; Evans, Jared M; Middha, Sumit; de Andrade, Mariza; Moss, Richard L; Wieben, Eric D; Michels, Virginia V; Olson, Timothy M

    2014-11-01

    Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes, yet the molecular basis for these disorders remains idiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.

  19. Estimating successive cancer risks in Lynch Syndrome families using a progressive three-state model.

    PubMed

    Choi, Yun-Hee; Briollais, Laurent; Green, Jane; Parfrey, Patrick; Kopciuk, Karen

    2014-02-20

    Lynch Syndrome (LS) families harbor mutated mismatch repair genes,which predispose them to specific types of cancer. Because individuals within LS families can experience multiple cancers over their lifetime, we developed a progressive three-state model to estimate the disease risk from a healthy (state 0) to a first cancer (state 1) and then to a second cancer (state 2). Ascertainment correction of the likelihood was made to adjust for complex sampling designs with carrier probabilities for family members with missing genotype information estimated using their family's observed genotype and phenotype information in a one-step expectation-maximization algorithm. A sandwich variance estimator was employed to overcome possible model misspecification. The main objective of this paper is to estimate the disease risk (penetrance) for age at a second cancer after someone has experienced a first cancer that is also associated with a mutated gene. Simulation study results indicate that our approach generally provides unbiased risk estimates and low root mean squared errors across different family study designs, proportions of missing genotypes, and risk heterogeneities. An application to 12 large LS families from Newfoundland demonstrates that the risk for a second cancer was substantial and that the age at a first colorectal cancer significantly impacted the age at any LS subsequent cancer. This study provides new insights for developing more effective management of mutation carriers in LS families by providing more accurate multiple cancer risk estimates.

  20. Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance.

    PubMed

    Crompton, Douglas E; Scheffer, Ingrid E; Taylor, Isabella; Cook, Mark J; McKelvie, Penelope A; Vears, Danya F; Lawrence, Kate M; McMahon, Jacinta M; Grinton, Bronwyn E; McIntosh, Anne M; Berkovic, Samuel F

    2010-11-01

    Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T₂ signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be

  1. Clinical and genetic investigation of families with type II Waardenburg syndrome

    PubMed Central

    CHEN, YONG; YANG, FUWEI; ZHENG, HEXIN; ZHOU, JIANDA; ZHU, GANGHUA; HU, PENG; WU, WEIJING

    2016-01-01

    The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia-associated transcription factor (MITF), sex-determining region Y-box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease-causing mutation in pedigree 1. However, there are novel disease-causing genes in Waardenburg syndrome type II, which require further research. PMID:26781036

  2. Mutational analysis of the androgen receptor gene in two Chinese families with complete androgen insensitivity syndrome.

    PubMed

    Wang, Song; Xu, Haikun; An, Wei; Zhu, Dechun; Li, Dejun

    2016-06-01

    Androgens are essential for normal male sex differentiation and are responsible for the normal development of male secondary sexual characteristics at puberty. The physiological effects of androgens are mediated by the androgen receptor (AR). Mutations in the AR gene are the most common cause of androgen insensitivity syndrome. The present study undertook a genetic analysis of the AR gene in two unrelated families affected by complete androgen insensitivity syndrome (CAIS) in China. In family 1, a previously reported nonsense mutation (G-to-A; p.W751X) was identified in exon 5 of the AR gene. In addition, a novel missense mutation was detected in exon 6 of the AR gene from family 2; this mutation resulted in a predicted amino acid change from phenylalanine to serine at codon 804 (T-to-C; p.F804S) in the ligand-binding domain (LBD) of AR. Computer simulation of the structural changes generated by the p.F804S substitution revealed marked conformational alterations in the hydrophobic core responsible for the stability and function of the AR-LBD. In conclusion, the present study identified two mutations from two unrelated Chinese families affected by CAIS. The novel mutation (p.F804S) may provide insights into the molecular mechanism underlying CAIS. Furthermore, it expands on the number of mutational hot spots in the international AR mutation database, which may be useful in the future for prenatal diagnosis and genetic counseling.

  3. Familial Turner syndrome with an X;Y translocation mosaicism: implications for genetic counseling.

    PubMed

    Portnoï, Marie-France; Chantot-Bastaraud, Sandra; Christin-Maitre, Sophie; Carbonne, Bruno; Beaujard, Marie-Paule; Keren, Boris; Lévy, Jonathan; Dommergues, Marc; Cabrol, Sylvie; Hyon, Capucine; Siffroi, Jean-Pierre

    2012-11-01

    Spontaneous fertility is rare among patients with Turner syndrome and is most likely in women with mosaicism for a normal 46,XX cell line. We report an unusual case of familial Turner syndrome with mosaicism for a novel X;Y translocation involving Xp and Yp. The chromosomal analysis was carried out through cytogenetics and molecular karyotyping using a SNP array platform. The mother, a Turner syndrome woman, diagnosed in midchildhood because of short stature, was found to have a 45,X/46,X,der(X)t(X;Y)(p11.4;p11.2) karyotype, with a predominant 45,X cell line. Her parents decided against prophylactic gonadectomy, generally recommended at an early age when Y chromosome has been identified, because at age 13, she had spontaneous puberty and menarche. She reached a final height of 154 cm after treatment with growth hormone. At age 24, she became spontaneously pregnant. She had a mild aortic coarctation and close follow-up cardiac evaluation, including cardiac magnetic resonance imaging, had been performed during her pregnancy, which progressed uneventfully, except for intra-uterine growth retardation. Prenatal diagnosis revealed a female karyotype, with transmission of the maternal translocation with an unexpected different mosaic:47,X,der(X)t(X;Y)x2/46,X,der(X)t(X;Y) karyotype. This complex and unusual karyotype, including a mosaic partial trisomy X and a non-mosaic Xpter-Xp11.4 monosomy, results in transmission of Turner syndrome from mother to daughter. At birth, the girl had normal physical examination except for growth retardation. This family illustrates the complexity and difficulties, in term of patient counseling and management in Turner syndrome, in determining ovarian status, fertility planning, risks associated with pregnancies, particularly when mosaicism for Y material chromosome is identified.

  4. Reduced Penetrance of PRRT2 Mutation in a Chinese Family With Infantile Convulsion and Choreoathetosis Syndrome.

    PubMed

    Zhang, L M; An, Y; Pan, G; Ding, Y F; Zhou, Y F; Yao, Y H; Wu, B L; Zhou, S Z

    2015-09-01

    Paroxysmal kinesigenic dyskinesia is a rare episodic movement disorder that can be isolated or associated with benign infantile seizures as part of choreoathetosis syndrome. Mutations in the PRRT2 gene have been recently identified as a cause of paroxysmal kinesigenic dyskinesia and infantile convulsion and choreoathetosis (ICCA). We reported a PRRT2 heterozygous mutation (c.604-607delTCAC, p.S202Hfs*25) in a 3-generation Chinese family with infantile convulsion and choreoathetosis and paroxysmal kinesigenic dyskinesia. The mutation was present in 5 family members, of which 4 were clinically affected and 1 was an obligate carrier with reduced penetrance of PRRT2. The affected carriers of this mutation presented with a similar type of infantile convulsion during early childhood and developed additional paroxysmal kinesigenic dyskinesia symptoms later in life. In addition, they all had a dramatic clinical response to oxcarbazepine/phenytoin therapy. Reduced penetrance of the PRRT2 mutation in this family could warrant genetic counseling.

  5. Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch Syndrome

    PubMed Central

    Cruz-Correa, Marcia; Diaz-Algorri, Yaritza; Pérez-Mayoral, Julyann; Suleiman-Suleiman, Wasilah; Gonzalez-Pons, Maria del Mar; Bertrán, Carlos; Casellas, Nicolás; Rodríguez, Natalia; Pardo, Sherly; Rivera, Keyla; Mosquera, Rafael; Rodriguez-Quilichini, Segundo

    2015-01-01

    Lynch Syndrome (LS) is an inherited form of colorectal cancer caused by germline mutations in the Mismatch Repair (MMR) genes. It accounts for approximately 5% of all colorectal cancers. The prevalence of Lynch Syndrome among US Hispanics is unknown. The objective of this study was to describe the germline mutations of Lynch Syndrome in Caribbean Hispanics from Puerto Rico and Dominican Republic. A total of 89 subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. A total of 35 individuals with deficient MMR system were identified: 22 had MMR mutations and 13 had tumors with absent MMR protein expression. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7 %) mutations, followed by MLH1 (25.0 %). One mutation was identified in MSH6 (8.3 %). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutation-positive individuals were found to be more likely to have a prominent family history of CRC and tumors located at the proximal colon. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC and LS associated cancers. Furthermore, insurance coverage for genetic testing was found to be limited in the study population with 65.1% of the individuals recruited were denied coverage. This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients. PMID:25782445

  6. Genetic counselling in hereditary osteo-onychodysplasia (HOOD, nail-patella syndrome) with nephropathy.

    PubMed Central

    Looij, B J; te Slaa, R L; Hogewind, B L; van de Kamp, J J

    1988-01-01

    Hereditary osteo-onychodysplasia (HOOD, nail-patella syndrome) is an autosomal dominant condition characterised by nail dysplasia, patellar hypoplasia or aplasia, and nephropathy. The risk for HOOD patients to have a child with HOOD who will develop renal failure cannot easily be deduced from published pedigrees. We have studied a large family with 30 patients with HOOD and have analysed 34 kindreds with HOOD nephropathy from published reports, comprising 213 patients. For a patient with HOOD from a family in which HOOD nephropathy occurs, the risk of having a child with HOOD nephropathy is about 1:4; the risk of having a child in whom renal failure will develop is about 1:10. PMID:3225824

  7. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis.

  8. Hereditary Melanoma: Update on Syndromes and Management - Genetics of familial atypical multiple mole melanoma syndrome

    PubMed Central

    Soura, E.; Eliades, P.; Shannon, K.; Stratigos, A.; Tsao, H.

    2015-01-01

    Malignant melanoma is considered the most lethal skin cancer if not detected and treated at its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (i.e. unilateral lineage, multi-generational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. Such patients have a high risk of developing multiple primary melanomas and internal organ malignancies especially pancreatic cancer; thus, a multidisciplinary approach is necessary in many cases. The value of dermoscopy examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. But, this must be performed with care and only by qualified individuals trained in cancer risk analysis. PMID:26892650

  9. A family with fragile X syndrome, Duchenne muscular dystrophy and ichthyosis transmitted by an asymptomatic carrier.

    PubMed

    Todorova, A; Litvinenko, I; Todorov, T; Tincheva, R; Avdjieva, D; Tincheva, S; Mitev, V

    2014-03-01

    The human X chromosome carries regions prone to genomic instability: deletions in the Xp22.31 region, involving the steroid sulfatase gene (STS) cause X-linked ichthyosis; rearrangements in the Xp21.2 region are associated with Duchenne or Becker muscular dystrophies (DMD or BMD); and the Xq27.3 unstable region, containing the (CGG)n repeat expansion in the FMR1 gene is associated with fragile X syndrome. We report on a family with two affected boys, the elder diagnosed with fragile X syndrome, the younger with DMD, and both suffering from severe ichthyosis. The family was analyzed by polymerase chain reaction, multiplex ligation-dependent probe amplification and haplotype analysis. The mother proved to be an asymptomatic carrier of all three non-contiguous mutation events, involving the STS gene, the DMD gene and a FMR1 expansion. To the best of our knowledge, this is the first description of an asymptomatic carrier of three different X-linked disorders, involving severe genetic rearrangements on both long and short arms of the X chromosomes. The boy with fragile X syndrome has inherited a triple recombinant maternal X chromosome, this way inheriting the FMR1 expansion and ichthyosis, originating most probably from different maternal Xes and excluding the DMD gene deletion. The transmission of these extremely defective maternal chromosomes to the next generation involved several recombinations.

  10. Exome Analysis of a Family with Wolff–Parkinson–White Syndrome Identifies a Novel Disease Locus

    PubMed Central

    Bowles, Neil E.; Jou, Chuanchau J.; Arrington, Cammon B.; Kennedy, Brett J.; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L.; Etheridge, Susan P.; Saarel, Elizabeth V.; Bleyl, Steven B.; Yost, H. Joseph; Yandell, Mark; Leppert, Mark F.; Tristani-Firouzi, Martin; Gruber, Peter J.

    2016-01-01

    Wolff–Parkinson–White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5’ -AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. PMID:26284702

  11. Genomic diagnosis by whole genome sequencing in a Korean family with atypical progeroid syndrome.

    PubMed

    Lee, Seungbok; Park, Sae Mi; Kim, Hyun Ji; Kim, Jin-Wou; Yu, Dong Soo; Lee, Young Bok

    2015-12-01

    Clinical genomic diagnosis is unfamiliar to many dermatologists. Limited knowledge of bioinformatics has limited the use of the next generation sequencing method in dermatological clinics. We evaluated the usefulness of whole genome sequencing as a diagnostic approach to inherited dermatological disease. Here, we present our experience with two female siblings with atypical familial generalized lipodystrophy with diabetes mellitus and dyslipidemia. Whole genome sequencing was performed to diagnose the inherited disease. We compared control genomic databases using the Exome Aggregation Consortium, and filtered false-positive calls with the segmental duplication, non-flagged single nucleotide variants and COSMIC mutation databases, and applied the prediction tools of SIFT and PolyPhen2. The two siblings who presented with generalized lipodystrophy were diagnosed with an atypical progeroid syndrome with a p.D136H mutation in the LMNA gene (NM_005572). We diagnosed a familial atypical progeroid syndrome using whole genome sequencing. In this paper, we present our experience with whole genome sequencing and demonstrate that it can provide useful information for clinical genomic diagnosis of inherited diseases with atypical clinical features, such as atypical progeroid syndrome.

  12. Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2: report of five families with a review of the literature.

    PubMed

    Leana-Cox, J; Pangkanon, S; Eanet, K R; Curtin, M S; Wulfsberg, E A

    1996-11-11

    The DiGeorge (DG), velocardiofacial (VCF), and conotruncal anomaly-face (CTAF) syndromes were originally described as distinct disorders, although overlapping phenotypes have been recognized. It is now clear that all three syndromes result from apparently similar or identical 22q11.2 deletions, suggesting that they represent phenotypic variability of a single genetic syndrome. We report on 12 individuals in five families with del(22)(q11.2) by fluorescent in situ hybridization, and define the frequency of phenotypic abnormalities in those cases and in 70 individuals from 27 del(22)(q11.2) families from the literature. Common manifestations include mental impairment (97%), abnormal face (93%), cardiac malformations (68%), thymic (64%) and parathyroid (63%) abnormalities, and cleft palate or velopharyngeal insufficiency (48%). Familial DG, VCF, and CTAF syndromes due to del(22) (q11.2) show significant inter- and intrafamilial clinical variability consistent with the hypothesis that a single gene or group of tightly linked genes is the common cause of these syndromes. Up to 25% of 22q deletions are inherited, indicating that parents of affected children warrant molecular cytogenetic evaluation. We propose use of the compound term "DiGeorge/velocardiofacial (DG/VCF) syndrome" in referring to this condition, as it calls attention to the phenotypic spectrum using historically familiar names.

  13. Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2: Report of five families with a review of the literature

    SciTech Connect

    Leana-Cox, J.; Pangkanon, Suthipong; Eanet, K.R.

    1996-11-11

    The DiGeorge (DG), velocardiofacial (VCF), and conotruncal anomaly-face (CTAF) syndromes were originally described as distinct disorders, although overlapping phenotypes have been recognized. It is now clear that all three syndromes result from apparently similar or identical 22q11.2 deletions, suggesting that they represent phenotypic variability of a single genetic syndrome. We report on 12 individuals in five families with del(22)(q11.2) by fluorescent in situ hybridization, and define the frequency of phenotypic abnormalities in those cases and in 70 individuals from 27 del(22)(q11.2) families from the literature. Common manifestations include mental impairment (97%), abnormal face (93%), cardiac malformations (681%), thymic (64%) and parathyroid (63%) abnormalities, and cleft palate or velopharyngeal insufficiency (48%). Familial DG, VCF, and CTAF syndromes due to del(22)(q11.2) show significant inter- and intrafamilial clinical variability consistent with the hypothesis that a single gene or group of tightly linked genes is the common cause of these syndromes. Up to 25% of 22q deletions are inherited, indicating that parents of affected children warrant molecular cytogenetic evaluation. We propose use of the compound term {open_quotes}DiGeorge/velocardiofacial (DGNCF) syndrome{close_quotes} in referring to this condition, as it calls attention to the phenotypic spectrum using historically familiar names. 41 refs., 2 figs., 2 tabs.

  14. Coincidence of neurofibromatosis and myotonic dystrophy in a kindred.

    PubMed Central

    Ichikawa, K; Crosley, C J; Culebras, A; Weitkamp, L

    1981-01-01

    Neurofibromatosis and myotonic dystrophy have occurred in ten members of a nonconsanguineous family with a high degree of concordance. The expression of neurofibromatosis is peripheral, and the expression of myotonic dystrophy has produced at least moderately severe disability. Neither disease has appeared to alter the phenotypic expression of the other when both have occurred simultaneously. Secretor typing supports the assumption that the myotonic dystrophy in this family is the commonly recognised secretor-linked entity. The segregation pattern of the two disorders in this family suggest the possibility of close linkage between the loci for neurofibromatosis and myotonic dystrophy. PMID:6787200

  15. Barriers to diagnosis of a rare neurological disorder in China--lived experiences of Rett syndrome families.

    PubMed

    Lim, Faye; Downs, Jenny; Li, Jianghong; Bao, Xin-Hua; Leonard, Helen

    2012-01-01

    Rett syndrome is a rare neurological disorder affecting girls and usually caused by a mutation on the MECP2 gene. It is estimated that approximately 1,000 girls are born every year in China with Rett syndrome but far fewer have received a diagnosis. Fourteen of 74 Chinese families known to the International Rett Syndrome Phenotype Database participated in this qualitative study. Telephone interviews were conducted in Mandarin to explore pathways to a diagnosis of Rett syndrome in China and associated barriers. Families consulted multiple clinical centers and eventually received a diagnosis at a centrally located hospital. Over the course of this pathway, families encountered lack of knowledge and diagnostic expertise for Rett syndrome at local levels and a heavily over-burdened hospital system. There was a paucity of information available to guide management of this rare disorder after the diagnosis had been received. Our study suggests that the frustrations experienced by families could in part be addressed by the provision of information, education, and training related to Rett syndrome for clinicians, additional resources to allow clinicians to request genetic testing for confirmation of the clinical diagnosis and for information and support services for families.

  16. Variable expressivity of pfeiffer syndrome in a family with FGFR1 p.Pro252Arg mutation.

    PubMed

    Bessenyei, Beáta; Tihanyi, Mariann; Hartwig, Marianna; Szakszon, Katalin; Oláh, Éva

    2014-12-01

    Pfeiffer syndrome is an autosomal dominant disorder classically characterized by craniosynostosis, facial dysmorphism and limb anomalies. The majority of cases are caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. A specific, rare mutation p.Pro252Arg, located between the second and third extracellular immunoglobulin-like domain of FGFR1, is associated with mild clinical signs. We report on a three-generation family with five members having a heterozygous FGFR1 p.Pro252Arg mutation. Phenotypic features within the family showed high variability from the apparently normal skull and limbs to the characteristic brachycephaly and digital anomalies. The typical features of Pfeiffer syndrome appeared only in the third generation allowing us to unveil the syndrome in several further family members in two previous generations. Variable expressivity can complicate the recognition of Pfeiffer syndrome, principally the mild type 1, requiring careful phenotyping and genetic counseling.

  17. Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith–Wiedemann syndrome as a sporadic adrenocortical tumor

    PubMed Central

    H'mida Ben-Brahim, Dorra; Hammami, Sabeur; Haddaji Mastouri, Marwa; Trabelsi, Saoussen; Chourabi, Maroua; Sassi, Sihem; Mougou, Soumaya; Gribaa, Moez; Zakhama, Abdelfattah; Guédiche, Mohamed Neji; Saad, Ali

    2014-01-01

    Beckwith–Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith–Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith–Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith–Wiedemann syndrome presentation. PMID:26937341

  18. Study of the origin of nondisjunction in a family with two cases of Down syndrome using cytogenetic and molecular polymorphisms.

    PubMed

    Stinissen, P; Van Roy, B; Van Camp, G; Backhovens, H; Partoens, P; Wehnert, A; Verniers, H; Dumon, J; Vandenberghe, A; Van Broeckhoven, C

    1990-01-01

    We analyzed the possibility of inherited predisposition to nondisjunction in a family with two cases of Down syndrome using restriction fragment length polymorphisms and cytogenetic heteromorphisms. In both patients the extra chromosome 21 was the result of a nondisjunction event at first meiotic division in the mother. Since both patients are maternally related, genetic predisposition cannot be excluded in this family.

  19. Blau syndrome of granulomatous arthritis, iritis, and skin rash: a new family and review of the literature.

    PubMed

    Manouvrier-Hanu, S; Puech, B; Piette, F; Boute-Benejean, O; Desbonnet, A; Duquesnoy, B; Farriaux, J P

    1998-03-19

    Blau syndrome (MK186580) comprises granulomatous arthritis, iritis, and skin rash, and is an autosomal-dominant trait with variable expressivity. So far it was described in 5 families. We report on a sixth family with severe progression of eye involvement and discuss the nosology with similar diseases, such as early-infantile sarcoidosis.

  20. Witkop tooth and nail syndrome: a report of three cases in a family.

    PubMed

    Memarpour, Mahtab; Shafiei, Fereshteh

    2011-01-01

    Witkop tooth and nail syndrome is a rare autosomal dominant ectodermal dysplasia manifested by hypodontia and nail dysplasia. Tooth shape may vary, and conical and narrow crowns are common. Mandibular incisors, second molars, and maxillary canines are the most frequently missing teeth. Nail dysplasia affects the fingernails and especially the toenails and is often more severe in childhood. Nails may be spoon-shaped, ridged, slow-growing, and easily broken. We examined an Eastern Mediterranean family in which three siblings (two girls, one boy) had this syndrome. The severity of finger and toenail anomalies varied. The children's mother had no Witkop-related abnormalities, but their father was reported to have dental and nail anomalies. Early intervention is recommended to manage orofacial disfigurement and avoid negative social consequences for these children.

  1. Acro-dermato-ungual-lacrimal-tooth-like syndrome: report of a family with variable expression.

    PubMed

    Bedeschi, Maria Francesca; Escande, Fabienne; Bellini, Melissa; Natacci, Federica; Cavallari, Ugo; Lalatta, Faustina

    2006-10-01

    We report the case of a young boy with fine hair, mild nail dysplasia, blocked nasolacrimal ducts, absence of central incisors, bilateral oligodactyly of feet and anal stenosis. His father showed the same spectrum of anomalies with mild expression. He had mild nail dysplasia, blocked nasolacrimal ducts, inferior dental cysts with consequent premature tooth loss, frequent dental decays consequent to enamel abnormality and cutaneous syndactyly of the second and third right toe. The acro-dermato-ungual-lacrimal-tooth syndrome was suspected and molecular analysis of the P63 gene was performed, but no mutation was found. Although P63 gene analysis was negative, we think that both cases show clinical overlap with the acro-dermato-ungual-lacrimal-tooth syndrome and confirm the wide expression of this condition, even in the same family.

  2. Molecular approach in the study of Alström syndrome: Analysis of ten Spanish families

    PubMed Central

    Piñeiro-Gallego, Teresa; Cortón, Marta; Ayuso, Carmen; Baiget, Montserrat

    2012-01-01

    Purpose To describe the clinical and genetic findings in 11 Spanish patients with confirmed (n=5) or suspected (n=6) Alström syndrome (AS). Methods Patients underwent clinical evaluation, and were screened for variations in Alström syndrome 1 gene (ALMS1) using a genotyping microarray from Asper Ophthalmics and by direct sequencing of coding exons 8, 10, and 16 of ALMS1. Furthermore, we analyzed the presence of the A229T variant of retinitis pigmentosa GTPase regulator-interacting protein 1-like gene (RPGRIP1L) with direct sequencing of coding exon 6. Results A great phenotypic variability was observed in our patients. Four mutations in ALMS1—two novel nonsense mutations in one family (p.Y1715X and p.S616X), one previously described mutation in homozygous state in another family (p.V3597Efs*4), and a likely pathogenic missense variation p.P1822L in a third family—were identified with direct sequencing. All patients were homozygous for 229A allele of RPGRIP1L, with the exception of a p.A229T heterozygous patient. Conclusions Our findings expand the spectrum of ALMS1 mutations causing Alström syndrome. The phenotypic differences between patients could be attributed to interactions with other genes inherited independently from the ALMS1 gene or with environmental factors. A clear understanding of the phenotypic spectrum in AS will be important to unravel the molecular mechanisms underlying this syndrome. PMID:22876109

  3. Family Cluster Analysis of Severe Fever with Thrombocytopenia Syndrome Virus Infection in Korea

    PubMed Central

    Yoo, Jeong Rae; Heo, Sang Taek; Park, Dahee; Kim, Hyemin; Fukuma, Aiko; Fukushi, Shuetsu; Shimojima, Masayuki; Lee, Keun Hwa

    2016-01-01

    Severe fever with thrombocytopenia syndrome (SFTS) is tick-borne viral disease that was first suspected in China in 2009. The causative virus (SFTSV) was isolated in 2009 and reported in 2011, and SFTSV expanded its geographic distribution in 2012–2013, from China to South Korea and Japan. Most SFTSV infections occur through Haemaphysalis longicornis. However, SFTSV infection can also occur between family members, and nosocomial transmission of SFTSV is also possible through close contact with a patient. In this study, we first analyzed clinical, epidemiological, and laboratory data for SFTS patients and family members of an index patient in Korea. The S segment of SFTSV was amplified from the sera of three patients, and the S segment of SFTSV and IgG specific to SFTSV were detected in the serum from one family member; although this individual had no history of exposure to H. longicornis, she frequently had close contact with the index patient. In Korea, SFTSV infection among family members does not have to be reported, and we suggest that person-to-person transmission of SFTSV among family members is possible in Korea. PMID:27928083

  4. Diagnosis of fragile X syndrome: a qualitative study of African American families.

    PubMed

    Visootsak, Jeannie; Charen, Krista; Rohr, Julia; Allen, Emily; Sherman, Stephanie

    2012-12-01

    Fragile X syndrome (FXS) is an inherited genetic condition with critical consequences to the proband and family members at all levels in the generations. Although evidence demonstrates that the rates of diagnosis for FXS are the same in all racial groups, age of diagnosis in African American children has been reported to occur later than in Caucasian children. Additionally, African American families are seriously under-represented in existing FXS research studies. As such, it is important to understand the possible disparities in the underlying factors to receiving a diagnosis in African American families with FXS. Herein, a qualitative approach was adopted to describe the overall FXS diagnosis experiences (pre-diagnosis, diagnosis, and post-diagnosis stages) of a convenience sample of 10 African American mothers. We identified three major findings among our participants: (1) FXS testing is not ordered immediately once a parent expresses concerns of developmental delays to the pediatricians, (2) the diagnosis is sometimes delivered in an insensitive manner with information often being outdated and unbalanced towards negative aspects, (3) communication issues among family members exists once the diagnosis is discovered. Although these qualitative data may not be representative of the whole group, these findings have significant implications for genetic counseling and our understanding in providing support and advocacy for African American families with FXS.

  5. Rett syndrome from a family perspective: The Swedish Rett Center survey.

    PubMed

    Larsson, Gunilla; Lindström, Britta; Engerström, Ingegerd Witt

    2005-11-01

    The aim of this study was to make a description of the early development in individuals with the diagnosis Rett syndrome using parents' information. Information received from 125 cases of Rett syndrome in Sweden in 1997 provided us with families' description of early development in gross motor function, fine motor function and communication/social interplay. Best abilities before regression were presented, 62% lost their best abilities, 22% kept them and 5% kept them with deterioration. Seventy-three percent learnt to walk, 20% stopped walking and 2% retrained walking. Concerning feeding, 69% learnt to feed themselves, 57% lost this ability, 7% retrained the ability and 5% learnt to feed after regression. Sixty-four percent were one year or younger when there was a deviation in development. Sixty answers reported the girl was late in developing functions while 35 reported sudden loss of reached abilities. Seventy-four percent developed a scoliosis and 83% reported other deformities; of these, deformities in feet were the most common. Postural control was poor since all but 15 girls/women learnt in different directions when sitting. Transitional movements were difficult to perform. In 80% of cases, the families were those who suspected early that something was wrong in the child's development. Because of this it is essential that medical staff is aware of the different ways RS develops in order to give families early appropriate support and a plan for intervention. Since there is not only loss of function in this group but also kept abilities, retrained abilities and abilities achieved after regression, more research has to be focused on management and treatment to help persons with Rett syndrome keep and develop abilities according to their individual resources.

  6. Bolivian Kindred with Combined Spinocerebellar Ataxia Type 2 and 10

    PubMed Central

    Baizabal-Carvallo, José Fidel; Xia, Guangbin; Botros, Peter; Laguna, Janeth; Ashizawa, Tetsuo; Jankovic, Joseph

    2015-01-01

    Spinocerebellar ataxias (SCA) are a group of rare hereditary neurodegenerative disorders. Rare cases of two SCA mutations in the same individual have been reported in the literature, however, family descriptions are lacking. Here we present the clinical features and genetic findings of a Bolivian family expressing both SCA2 and SCA10 mutations. The index case and his mother had both SCA2 and SCA10 mutations with a combined clinical phenotype of both disorders, including slow saccades (SCA2) and seizures (SCA10). The uncle of the index case had only a SCA10 mutation. Although the presence of two SCA mutations in the same individuals may be coincidental, the low probability of having both mutations suggests that these mutations might be particularly prevalent in Bolivian population. This is the first description of a family with two SCA mutations with affected subjects having a combined SCA2 and SCA10 phenotype. PMID:25630585

  7. Ectopic Cushing syndrome associated with thymic carcinoid tumor as the first presentation of MEN1 syndrome-report of a family with MEN1 gene mutation.

    PubMed

    Hasani-Ranjbar, Shirin; Rahmanian, Masoud; Ebrahim-Habibi, Azadeh; Soltani, Akbar; Soltanzade, Akbar; Mahrampour, Elnaz; Amoli, Mahsa M

    2014-06-01

    Multiple endocrine neoplasia type 1(MEN1) is an autosomal dominant syndrome. Although thymic carcinoid tumor is recognized as a part of MEN1 syndrome but functioning thymic carcinoid tumor as the first presentation of the MEN1 seems to be very rare. In this report, we present a 29-year-old male who developed ectopic Cushing syndrome secondary to thymic carcinoid tumor and was diagnosed as MEN1 syndrome 2 years later. Further evaluation revealed the presence of carcinoid tumor and other MEN 1 manifestations in several other member of family. Genetic evaluation showed presence of a previously reported mutation in exon 10(R527X) of MEN1 gene in these patients. This presentation showed that thymic neuroendocrine tumor could be the first manifestation of the MEN1 syndrome and it might be diagnosed as a dominant manifestation of this syndrome in a family. We suggest biochemical or genetic screening for MEN-1 syndrome for patients with thymic carcinoid.

  8. Dying at 23 with 1p36 deletion syndrome: Laura's family story.

    PubMed

    Tandy, P A

    2012-09-01

    Laura was unusual. She had always been different and at times difficult. She was born with a genetic disorder, diagnosed as 1p36 deletion syndrome when she was 21 years old. At 23 she suffered her first cardiac arrest at home and entered the hospital system for the first time apart from infancy. After initially appearing to do well, she suffered a second cardiac arrest 10 weeks after admission. This was followed by an irreversible deterioration and she died 14 weeks after admission. We her family had been with her throughout her traumatic experience. This is our story.

  9. A novel FOXL2 mutation in a Chinese family with blepharophimosis, ptosis, epicanthus inversus syndrome

    PubMed Central

    Tan, Hu; Yang, Pu; Li, Haoxian; Pan, Qian; Liang, Desheng; Wu, Lingqian

    2015-01-01

    Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disease characterized by a narrowed horizontal palpehral aperture, ptosis, epicanthus inversus and telecanthus with or without premature ovarian failure. Mutations in the forkhead transcription factor 2 (FOXL2) have been shown to be responsible for BPES. We performed direct sequencing of the FOXL2 gene for molecular investigation of a Chinese family with BPES. A novel duplication mutation (c.858_868dup), resulting in a truncated protein, was detected. PMID:27081523

  10. [Application of recombinant erythropoietin during preparation for hepatic transplantation operation from the living kindred donor].

    PubMed

    Kotenko, O G; Mazur, A P; Dykhovichnaia, N Iu; Popov, A O; Gusev, A V

    2007-07-01

    First experience of application of the blood autodonorship programme, using recombinant erythropoietin (Eprex) plus preparations containing iron during their preparation for partial hepatic resection, was analyzed. Realization of this programme had permitted to escape the performance of allogenic hemotransfusion in 71.4% of donors, in whom the right or left hepatic lobe was taken out and in 100%--the left lateral section. The erythropoietin dosage regimes in different types of hepatic resections in living kindred donors were proposed.

  11. Lennox–Gastaut syndrome: impact on the caregivers and families of patients

    PubMed Central

    Gibson, Patricia A

    2014-01-01

    Lennox–Gastaut syndrome (LGS) has a major impact on the health-related quality of life (HRQL) of the affected children as well as their caregivers. The primary caregiver in the family is generally the mother, with support from the father and siblings. The burden of care and the effects of the disease on the child necessitate adjustments in virtually all aspects of the lives of their family. These adjustments inevitably affect the physical, emotional, social, and financial health of the whole family. Numerous sources of support for families can help to ease the burden of care. Improvements in the treatment of LGS, in addition to helping the child with LGS, would likely help improve the HRQL of the family members. This pilot parent survey was designed to explore the impact of epilepsy on caregiver HRQL. Parents of children with epilepsy who had contacted the Epilepsy Information Service at the Wake Forest University School of Medicine, Winston-Salem, NC, USA, were sent questionnaires comprising open- and closed-ended questions. A total of 200 surveys were distributed, with a return rate of 48%. The results revealed that 74% of the parents believed that having a child with epilepsy brought them and their partner closer together. However, when the parents were asked to explain the manner in which epilepsy affected their families, answers included continuous stress, major financial distress, and lack of time to spend with other children. Information and resources for the families of children with LGS could help improve the HRQL of both the patients and their relatives. PMID:25336963

  12. Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy

    PubMed Central

    Kapoor, Saketh; Bindu, Parayil Sankaran; Taly, Arun B.; Sinha, Sanjib; Gayathri, Narayanappa; Rani, S. Vasantha; Chandak, Giriraj Ratan

    2012-01-01

    Purpose Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentation defects of the eye, skin, and hair. It is caused by mutations in one of the following genes: PAX3 (paired box 3), MITF (microphthalmia-associated transcription factor), EDNRB (endothelin receptor type B), EDN3 (endothelin 3), SNAI2 (snail homolog 2, Drosophila) and SOX10 (SRY-box containing gene 10). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene. The purpose of this study was to identify the genetic causes of WS and DMD in an Indian family with two patients: one affected with WS and DMD, and another one affected with only WS. Methods Blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to the eight known WS loci, microsatellite markers were selected from the candidate regions and used to genotype the family. Exon-specific intronic primers for EDN3 were used to amplify and sequence DNA samples from affected individuals to detect mutations. A mutation in DMD was identified by multiplex PCR and multiplex ligation-dependent probe amplification method using exon-specific probes. Results Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. Haplotype analysis suggested linkage of the family to the WS4B (EDN3) locus. DNA sequencing identified a novel missense mutation p.T98M in EDN3. A deletion mutation was identified in DMD. Conclusions This study reports a novel missense mutation in EDN3 and a deletion mutation in DMD in the same Indian family. The present study will be helpful in genetic diagnosis of this family and increases the mutation spectrum of EDN3. PMID:22876130

  13. Linkage of morbid obesity with polymorphic microsatellite markers on chromosome 1q31 in a three-generation Canadian kindred

    SciTech Connect

    Murray, J.D.; Bulman, D.E.; Ebers, G.C. |

    1994-09-01

    Obesity is the most common nutritional disorder affecting Western societies. An estimated 3.7 million Canadians are considered to be overweight, a condition associated with hypertension, accelerated atherosclerosis, diabetes and a host of other medical problems. We have identified a 3 generation kindred in which morbid obesity appears to segregate in an autosomal dominant manner. All individuals were examined. Mass (kg) and heights (m) were measured in order to determine a body mass index (BMI) for each individual. Those individuals with BMI of greater than or equal to 30.0 were designated as affected. In the pedigree studied 25 individuals met this criteria and 12 of these were morbidly obese (BMI greater or equal to 40.0). A search of candidate genes proved unfruitful. A linkage study was initiated. All individuals in the pedigree were genotyped for microsatellite markers which were spaced every 20 centimorgans (cM). Positive evidence of linkage was detected with markers which map to 1q31-32 (lod score of 3.6 at {theta} = 0.05). Notably, strong effects for fatness in pigs have been found on pig chromosome 4 which has synteny with human chromosome 1q21-32. We are currently attempting to refine the position of this gene using linkage analysis with other microsatellite markers from this region of the genome. In addition we are screening other families in which obesity segregates for linkage to 1q31.

  14. Correlation between genotype and phenotype in three families with Peutz-Jeghers Syndrome

    PubMed Central

    Zhang, Yanli; Ke, Yao; Zheng, Xueni; Liu, Qing; Duan, Xiaohong

    2017-01-01

    Peutz-Jeghers syndrome (PJS) is a hereditary disorder characterized by mucocutaneous pigmentations, gastrointestinal (GI) polyposis and an increased risk of certain malignancies. Little is known about the causative genes of PJS, or their association with the clinical phenotypes of PJS. The present study reports the results of clinical and genetic analysis of three Chinese families with PJS. In addition, the medical histories and clinical manifestations of these families were compared. DNA was collected from the blood samples of patients with PJS and controls. Serine/threonine kinase 11 (STK11), olfactory receptor family 4 subfamily C member 45 (OR4C45) and zonadhesin (ZAN) were amplified by polymerase chain reaction, and analyzed by sequencing and cloning. Two PJS-affected members of one family had a de novo single base deletion (NM_000455.4:c.842delC) in the STK11 gene, and their clinical presentations reflected the quantity of mutant STK11 copies in a dose-dependent manner. No pathogenic variants of OR4C45 or ZAN were found in the patients with PJS, although a new single nucleotide polymorphism (NM_003386.2:c.5768delG) of ZAN was identified. The results of the current study identified that a STK11 mutation dose-dependent genotype-phenotype relationship exists in patients with PJS. In addition, an early onset and high severity of oral pigmentations in PJS was indicative of serious GI phenotypes. These findings may aid the diagnosis and treatment of PJS.

  15. Wiskott–Aldrich syndrome: review and report of a large family

    PubMed Central

    Stiehm, E. R.; McIntosh, R. M.

    1967-01-01

    Wiskott–Aldrich syndrome is a sex-linked recessive antibody-deficiency syndrome characterized by thrombocytopenia, eczema and increased susceptibility to infection. All forms of therapy are notably unsuccessful and these patients succumb in the first decade. Three cases of this syndrome are presented from a large family in which nine male infants have succumbed with manifestations of this disease. Two of the infants died at ages 10 months and 4 years respectively. A third child is alive at age 2. Serial quantitative immune globulin studies performed in two cases demonstrated markedly elevated γA, decreased γM and normal γG; levels of γM were initially normal but fell progressively as γA levels increased. The low levels of γM are probably a factor in their low or absent isoagglutinins, poor response to injected antigens, and increased susceptibility to infection; elevated γA levels may indicate immunologic unresponsiveness and/or a compensatory mechanism for the defect in γM synthesis. In two of these patients prolonged trials (17 and 23 months) of periodic plasma infusions (15 ml/kg at 6-week intervals), accompanied by γ-globulin injections (0·1 ml/kg) were undertaken. Although no remarkable effects on the platelets or their resistance to infection was noted, we feel that some benefit might have accrued and that further trails are indicated. PMID:4166240

  16. A familial case of Blau syndrome caused by a novel NOD2 genetic mutation

    PubMed Central

    Kim, Woojoong; Park, Eujin; Ahn, Yo Han; Lee, Jiwon M.; Kang, Hee Gyung; Kim, Byung Joo; Ha, Il-Soo

    2016-01-01

    Blau syndrome (BS) is a rare autosomal dominant, inflammatory syndrome that is characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis. Mutations in the nucleotide oligomerization domain 2 (NOD2) gene are responsible for causing BS. To date, up to 30 Blau-associated genetic mutations have been identified within this gene. We report a novel NOD2 genetic mutation that causes BS. A girl, aged 8 years, and her brother, aged 10 years, developed erythematous skin rashes and uveitis. The computed tomography angiogram of the younger sister showed features of midaortic dysplastic syndrome. The brother had more prominent joint involvement than the sister. Their father (38 years) was also affected by uveitis; however, only minimal skin involvement was observed in his case. The paternal aunt (39 years) and her daughter (13 years) were previously diagnosed with sarcoidosis. Mutational analysis revealed a novel c.1439 A>G mutation in the NOD2 gene in both siblings. The novel c.1439 A>G mutation in the NOD2 gene was found in a familial case of BS. Although BS is rare, it should always be considered in patients presenting with sarcoidosis-like features at a young age. Early diagnosis of BS and prompt multisystem workup including the eyes and joints can improve the patient's outcome. PMID:28018435

  17. Aortic Disease in the Young: Genetic Aneurysm Syndromes, Connective Tissue Disorders, and Familial Aortic Aneurysms and Dissections

    PubMed Central

    Cury, Marcelo; Zeidan, Fernanda; Lobato, Armando C.

    2013-01-01

    There are many genetic syndromes associated with the aortic aneurysmal disease which include Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS), Loeys-Dietz syndrome (LDS), familial thoracic aortic aneurysms and dissections (TAAD), bicuspid aortic valve disease (BAV), and autosomal dominant polycystic kidney disease (ADPKD). In the absence of familial history and other clinical findings, the proportion of thoracic and abdominal aortic aneurysms and dissections resulting from a genetic predisposition is still unknown. In this study, we propose the review of the current genetic knowledge in the aortic disease, observing, in the results that the causative genes and molecular pathways involved in the pathophysiology of aortic aneurysm disease remain undiscovered and continue to be an area of intensive research. PMID:23401778

  18. Mutational analysis of the androgen receptor gene in two Indian families with partial androgen insensitivity syndrome.

    PubMed

    Nagaraja, M R; Rastogi, Amit; Raman, Rajiva; Gupta, Dinesh K; Singh, S K

    2009-12-01

    Mutation in the androgen receptor gene (AR) is known to cause androgen insensitivity syndrome (AIS). In an X-linked recessive manner, an AR mutation gets transmitted to the offspring through carrier mothers in 70% of cases, the other 30% arising de novo. However, reports on AR mutations amongst Indian patients with AIS are scarce in the literature. This study reports mutations in AR from two Indian families, each having a proband with partial androgen insensitivity syndrome (PAIS) phenotype. Clinical, endocrine and cytogenetic evaluation of these affected children was performed. Mutational analysis was carried out by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis followed by sequencing. The two point mutations were in exon 5: p.M742I, familial in patient 1 and p.V746M de novo in patient 2. These are hitherto unrecognized mutations in our population. Similar mutational studies are suggested in patients with AIS, in order to identify their frequency and clinical severity in our population.

  19. Recovery and outcomes after the acute respiratory distress syndrome (ARDS) in patients and their family caregivers.

    PubMed

    Herridge, Margaret S; Moss, Marc; Hough, Catherine L; Hopkins, Ramona O; Rice, Todd W; Bienvenu, O Joseph; Azoulay, Elie

    2016-05-01

    Outcomes after acute respiratory distress syndrome (ARDS) are similar to those of other survivors of critical illness and largely affect the nerve, muscle, and central nervous system but also include a constellation of varied physical devastations ranging from contractures and frozen joints to tooth loss and cosmesis. Compromised quality of life is related to a spectrum of impairment of physical, social, emotional, and neurocognitive function and to a much lesser extent discrete pulmonary disability. Intensive care unit-acquired weakness (ICUAW) is ubiquitous and includes contributions from both critical illness polyneuropathy and myopathy, and recovery from these lesions may be incomplete at 5 years after ICU discharge. Cognitive impairment in ARDS survivors ranges from 70 to 100 % at hospital discharge, 46 to 80 % at 1 year, and 20 % at 5 years, and mood disorders including depression and post-traumatic stress disorder (PTSD) are also sustained and prevalent. Robust multidisciplinary and longitudinal interventions that improve these outcomes are still uncertain and data in our literature are conflicting. Studies are needed in family members of ARDS survivors to better understand long-term outcomes of the post-ICU family syndrome and to evaluate how it affects patient recovery.

  20. Linkage disequilibrium at the Machado-Joseph disease spinal cerebellar ataxia 3 locus: Evidence for a common founder effect in French and Portuguese-Brazilian families as well as a second ancestral Portuguese-Azorean mutation

    SciTech Connect

    Stevanin, G.; Cancel, G.; Didierjean, O.

    1995-11-01

    Spinal cerebellar ataxia 3 (SCA3) is a genetic subtype of the type I autosomal dominant cerebellar ataxias (ADCA type I), a clinically and genetically heterogeneous group of neurological disorders. SCA3 was mapped in French families to chromosome 14q24.3-qter in the same region as the gene for Machado-Joseph disease (MJD), which was classified as a form of ADCA type I on the basis of similarities in the clinical presentation of individual patients. The MJD gene was recently identified in Japanese kindreds, and the mutation was characterized as an unstable CAG repeat that is expanded in affected individuals. The same mutation is observed in families of Portuguese-Azorean ancestry, as well as in French SCA3 kindreds. In other disorders caused by unstable and expanded triplet repeats, such as fragile X syndrome (FRA-X), myotonic dystrophy (MD), Huntington disease (HD), and SCA1, linkage disequilibrium (LD) between the mutation and closely linked polymorphic markers was detected, suggesting that there were only one or a few founders or predisposing haplotypes. In the present study, 29 families of different geographical origins were tested for LD between the MJD/SCA3 mutation and four flanking microsatellite markers. 27 refs., 2 tabs.

  1. Genetic analysis of Tunisian families with Usher syndrome type 1: toward improving early molecular diagnosis

    PubMed Central

    Ben-Rebeh, Imen; Bonnet, Crystel; Bouassida, Walid; Hadjamor, Imen; Ayadi, Hammadi; Ghorbel, Abdelmonem; Petit, Christine; Masmoudi, Saber

    2016-01-01

    Purpose Usher syndrome accounts for about 50% of all hereditary deaf-blindness cases. The most severe form of this syndrome, Usher syndrome type I (USH1), is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. Six USH1 genes have been identified, MYO7A, CDH23, PCDH15, USH1C, SANS, and CIB2, encoding myosin VIIA, cadherin-23, protocadherin-15, harmonin, scaffold protein containing ankyrin repeats and a sterile alpha motif (SAM) domain, and calcium- and integrin-binding member 2, respectively. Methods In the present study, we recruited four Tunisian families with a diagnosis of USH1, together with healthy unrelated controls. Affected members underwent detailed audiologic and ocular examinations. We used the North African Deafness (NADf) chip to search for known North African mutations associated with USH. Then, we selected microsatellite markers covering USH1 known loci to genotype the DNA samples. Finally, we performed DNA sequencing of three known USH1 genes: MYO7A, PCDH15, and USH1C. Results Four biallelic mutations, all single base changes, were found in the MYO7A, USH1C, and PCDH15 genes. These mutations consist of a previously reported splicing defect c.470+1G>A in MYO7A, three novel variants, including two nonsense (p.Arg3X and p.Arg134X) in USH1C and PCDH15, respectively, and one frameshift (p.Lys615Asnfs*6) in MYO7A. Conclusions We found a remarkable genetic heterogeneity in the studied families with USH1 with a variety of mutations, among which three were novel. These novel mutations will be included in the NADf mutation screening chip that will allow a higher diagnosis efficiency of this extremely genetically heterogeneous disease. Ultimately, efficient molecular diagnosis of USH in a patient’s early childhood is of utmost importance, allowing better educational and therapeutic management. PMID:27440999

  2. One germline mutation of PTCH gene in a Chinese family with non-syndromic keratocystic odontogenic tumours.

    PubMed

    Wang, X; Lu, Y; Shen, G; Chen, W

    2011-08-01

    Keratocystic odontogenic tumours (KOCTs) are common benign cystic tumours that arise sporadically or associated with nevoid basal cell carcinoma syndrome (NBCCS). PTCH mutation can be found in sporadically or NBCCS associated KOCTs. Few PTCH mutations in families with non-syndromic KOCTs have been reported. Through PCR and gene sequence analysis, the authors discovered one missense mutation c.3277G>C in exon 19 of PTCH gene in a Chinese family with non-syndromic KOCTs. This mutation causes one highly conserved glycine residue transit to arginine on the 10th transmembrane region of PTCH protein. This work revealed that the missense mutation of PTCH is the causative and dominant gene of KOCTs in this family.

  3. A large deletion/insertion-induced frameshift mutation of the androgen receptor gene in a family with a familial complete androgen insensitivity syndrome.

    PubMed

    Cong, Peikuan; Ye, Yinghui; Wang, Yue; Lu, Lingping; Yong, Jing; Yu, Ping; Joseph, Kimani Kagunda; Jin, Fan; Qi, Ming

    2012-06-01

    Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disorder with a normal 46, XY karyotype caused by abnormality of the androgen receptor (AR) gene. One Chinese family consisting of the proband and 5 other members with complete androgen insensitivity syndrome (CAIS) was investigated. Mutation analysis by DNA sequencing on all 8 exons and flanking intron regions of the AR gene revealed a unique large deletion/insertion mutation in the family. A 287 bp deletion and 77 bp insertion (c.933_1219delins77) mutation at codon 312 resulted in a frameshift which caused a premature stop (p.Phe312Aspfs*7) of polypeptide formation. The proband's mother and grandmother were heterozygous for the mutant allele. The proband's father, uncle and grandfather have the normal allele. From the pedigree constructed from mutational analysis of the family, it is revealed that the probably pathogenic mutation comes from the maternal side.

  4. A novel homozygous mutation in the solute carrier family 12 member 3 gene in a Chinese family with Gitelman syndrome

    PubMed Central

    Zhang, Y.; Zhang, F.; Chen, D.; Lü, Q.; Tang, L.; Yang, C.; Lei, M.; Tong, N.

    2016-01-01

    Loss of function of mutated solute carrier family 12 member 3 (SLC12A3) gene is the most frequent etiology for Gitelman syndrome (GS), which is mainly manifested by hypokalemia, hypomagnesemia and hypocalciuria. We report the genetic characteristics of one suspicious Chinese GS pedigree by gene sequencing. Complete sequencing analysis of the SLC12A3 gene revealed that both the proband and his elder sister had a novel homozygous SLC12A3 mutation: c.2099T>C and p.Leu700Pro. Moreover, the SLC12A3 genes of his mother and daughter encoded the same mutated heterozygote. It was noted that in this pedigree, only the proband complained about recurrent episodes of bilateral lower limb weakness over 8 years, while his elder sister, mother and daughter did not present symptoms. The inconsistent clinical features of this pedigree implied that besides diverse phenotypes possibly originated from the same genotype, gender difference may also dominate the variant GS phenotypes. Further genetic and proteomic research are needed to investigate the precise mechanisms of GS, including the study of specific ethnicities. PMID:27783806

  5. A novel frameshift mutation in the EYA1 gene in a Korean family with branchio-oto-renal syndrome.

    PubMed

    Lee, Jong Dae; Kim, Shi-Chan; Koh, Yoon Woo; Lee, Hye-Jin; Choi, Soo-Young; Kim, Un-Kyung

    2009-01-01

    Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial cleft fistulae or cysts, preauricular pits, ear malformations, hearing loss, and renal anomalies. Mutations in the human homologue of the Drosophilia eyes absent gene (EYA1) are the most common cause of BOR syndrome. In this study, we found a Korean family showing clinical features of the disease. Mutation analysis of the EYA1 gene revealed a novel one-base-pair deletion resulting in truncated protein (c.321delT; p.Ala107fs). This is the first report of BOR syndrome caused by deletion mutation of the EYA1 gene in Korea.

  6. Linkage analysis in Rett syndrome families suggests that there may be a critical region at Xq28.

    PubMed Central

    Webb, T; Clarke, A; Hanefeld, F; Pereira, J L; Rosenbloom, L; Woods, C G

    1998-01-01

    A whole X chromosome study of families in which Rett syndrome had been diagnosed in more than one member indicated that the region between Xq27 and Xqter was the most likely region to harbour a gene which may be involved in the aetiology of the disease. Further, more detailed studies of Xq28 detected weak linkage and a higher than expected sharing of maternally inherited alleles. It is suggested that there may be more than one gene involved in the aetiology of this syndrome, particularly as the very rare families in which more than one girl is affected often show variable clinical symptoms. Images PMID:9863596

  7. Molecular characterization of Blau syndrome: Genetic linkage to chromosome 16

    SciTech Connect

    Tromp, G.; Duivaniemi, H.; Christiano, A.

    1994-09-01

    The Blau syndrome is an autosomal, dominantly-inherited disease characterized by multi-organ, tissue-specific inflammation. Its clinical phenotype includes granulomatous uveitis, arthritis and skin rash. The syndrome is unique in that it is the sole human model for a variety of multi-system inflammatory diseases that afflict a significant percentage of the population. Karyotypic analysis of the large, three generation kindred whose disease originally characterized the syndrome was unremarkable. Following exclusion of a number of extracellular matrix candidates genes, a genome-wide search was undertaken of the Blau susceptibility locus. Fifty-seven members of the family were genotyped for about 200 highly polymorphic dinucleotide repeat markers. Linkage analysis was performed using the LINKAGE package of programs under a model of dominant inheritance with reduced penetrance. Five liability classes were used to specify penetrances and phenocopy rates for those affected the arthritis, uveitis, skin rash and combinations thererof. In addition, five age-dependent penetrance classes were used for unaffected individuals. The marker D16S298 gave a maximum lod score of 3.6 at {theta} = 0.05 with two-point analysis. Lod scores for flanking markers were consistent. These data provide convincing evidence that the Blau susceptibility locus is situated within the 16p12-q21 interval. Fine mapping of the candidate interval with additional families exhibiting the Blau phenotype, as well as with more polymorphic markers, is underway.

  8. Autosomal dominant congenital fibre type disproportion: a clinicopathological and imaging study of a large family.

    PubMed

    Sobrido, M J; Fernández, J M; Fontoira, E; Pérez-Sousa, C; Cabello, A; Castro, M; Teijeira, S; Alvarez, S; Mederer, S; Rivas, E; Seijo-Martínez, M; Navarro, C

    2005-07-01

    Congenital fibre type disproportion (CFTD) is considered a non-progressive or slowly progressive muscle disease with relative smallness of type 1 fibres on pathological examination. Although generally benign, CFTD has a variable natural course and severe progression has been observed in some patients. The pathogenesis of the disorder is unknown and many authors consider CFTD a syndrome with multiple aetiologies rather than a separate clinical entity. A positive family history has been reported in about 40% of cases, but the inheritance pattern is not clear. Both autosomal recessive and dominant modes of inheritance have been suggested. The present paper describes a large, multigenerational kindred that has an inherited myopathy fulfilling the histological criteria of CFTD, with autosomal dominant transmission and high penetrance. The clinical picture, remarkably similar in all affected family members, started in early infancy with mild limb muscle weakness. There was slow progression of symptoms into adulthood, with moderate to severe, mainly proximal, muscle weakness without loss of ambulation. Muscle biopsy from two affected individuals demonstrated predominance of small type 1 muscle fibres without other significant findings. Nerve conduction studies were normal and needle electromyography showed a myopathic pattern. MRI examination performed on three patients from successive generations showed involvement of proximal limb and paraspinal muscles. The clinical and pathological homogeneity in the present family, together with the lack of additional histological abnormalities after decades of disease progression in two affected individuals, supports this being a distinct myopathy with fibre type disproportion. Whether the disease in this family can be regarded as a form of the congenital myopathy known as CFTD or rather a unique condition sharing histological features with CFTD needs further investigation. This is, to our knowledge, the largest kindred with muscle

  9. Mapping of Alport syndrome to the long arm of the X chromosome.

    PubMed Central

    Atkin, C L; Hasstedt, S J; Menlove, L; Cannon, L; Kirschner, N; Schwartz, C; Nguyen, K; Skolnick, M

    1988-01-01

    Five X-chromosome DNA markers were typed on 261 members of three large kindreds with Alport syndrome (hereditary glomerulonephritis). Lod scores greater than 3.0 for linkage between the disease locus and two of the markers confirmed X-linked inheritance of the disease. A decreasing gradient in the estimated recombination fractions observed when the markers were ordered on the basis of their map locations suggested that the disease locus is on the long arm distal to all the markers typed in this study. Using three-locus analysis we rejected all but three map orders for the six loci (the disease locus and five markers). In all three the Alport syndrome locus was on the long arm of the X chromosome distal to all the markers. Two types of Alport syndrome were represented in the three kindreds. Affected males in one kindred developed deafness in addition to nephritis; deafness did not occur in members of the other two kindreds. Although larger recombination-fraction estimates were obtained for all five markers in the kindreds without deafness, the difference was significant for only one marker. Evidence of heterogeneity was not found in tests using two markers. Markers distal to the disease locus are needed to determine whether two loci are responsible for the two types of Alport syndrome. PMID:3422540

  10. Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome).

    PubMed

    Meyer, Esther; Lim, Derek; Pasha, Shanaz; Tee, Louise J; Rahman, Fatimah; Yates, John R W; Woods, C Geoffrey; Reik, Wolf; Maher, Eamonn R

    2009-03-01

    Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans.

  11. Familial atypical hemolytic uremic syndrome: a review of its genetic and clinical aspects.

    PubMed

    Bu, Fengxiao; Borsa, Nicolo; Gianluigi, Ardissino; Smith, Richard J H

    2012-01-01

    Atypical hemolytic uremic syndrome (aHUS) is a rare renal disease (two per one million in the USA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Both sporadic (80% of cases) and familial (20% of cases) forms are recognized. The study of familial aHUS has implicated genetic variation in multiple genes in the complement system in disease pathogenesis, helping to define the mechanism whereby complement dysregulation at the cell surface level leads to both sporadic and familial disease. This understanding has culminated in the use of Eculizumab as first-line therapy in disease treatment, significantly changing the care and prognosis of affected patients. However, even with this bright outlook, major challenges remain to understand the complexity of aHUS at the genetic level. It is possible that a more detailed picture of aHUS can be translated to an improved understanding of disease penetrance, which is highly variable, and response to therapy, both in the short and long terms.

  12. Psychological consequences of prenatal diagnosis in a case of familial Angelman syndrome.

    PubMed

    Turchetti, Daniela; Razzaboni, Elisabetta; Zomer, Hila; Rossi, Cesare; Ferrari, Simona; Greco, Donatella; Graziano, Claudio; Romeo, Giovanni; Seri, Marco

    2006-12-01

    Angelman Syndrome (AS), characterized by mental retardation, absence of speech, seizures and motor dysfunction, is caused by genetic defects leading to loss of expression of the maternal copy of the chromosome 15q11-13 imprinted region. Most cases are sporadic, being caused by de novo deletion of maternal chromosome 15q11-13 (75%) or by paternal uniparental disomy (3-4%). Familial cases can occur, due to mutations in the UBE3A gene or in the imprinting center. We describe the case of a pregnant woman having two nephews with AS caused by a UBE3A mutation; lack of communication within the family led the woman to be completely unaware of the risk of disease recurrence until 15 weeks of gestation. UBE3A genetic testing revealed she carried the familial mutation 892-893delCT. Prenatal diagnosis was performed on amniotic fluid and demonstrated that the fetus had inherited the mutation. The unexpected diagnosis and the subsequent termination of the pregnancy caused the woman to undergo acute psychological distress showing relevant psychopathological symptoms. Nevertheless, at 2-year follow-up, adverse consequences were minimized, and the couple was planning a new pregnancy. Factors affecting the psychological outcome of abortion and the role of psychological support in reducing the risk of long-term unfavorable consequences are discussed.

  13. Recommendations for the management of irritable bowel syndrome in family practice

    PubMed Central

    Paterson, W G; Thompson, W G; Vanner, S J; Faloon, T R; Rosser, W W; Birtwhistle, R W; Morse, J L; Touzel, T A

    1999-01-01

    To help family physicians manage patients with irritable bowel syndrome (IBS), a consensus conference was convened in June 1997 at which 5 internationally recognized experts in IBS presented position papers on selected topics previously circulated to the conference participants. Five working groups comprising family physicians, gastroenterologists and allied health care professionals from across Canada were then charged with developing recommendations for the diagnosis, patient education, psychosocial management, dietary advice and pharmacotherapy, respectively. An evidence-based approach was used where possible; otherwise, recommendations were made by consensus. The participants concluded that family physicians can make a positive diagnosis of IBS using symptom criteria. The pathophysiology is poorly understood, but motility and sensory disturbances appear to play a role. Neither psychological nor specific dietary factors cause IBS, but both can trigger symptoms. Drug therapy is not recommended for the routine treatment of IBS, but short-term trials of drug therapy may be targeted to predominant symptoms in selected patients. A step-wise, patient-centred approach to management is outlined. PMID:10439825

  14. Maternal well-being and child behavior in families with fragile X syndrome.

    PubMed

    Hauser, Claire T; Kover, Sara T; Abbeduto, Leonard

    2014-10-01

    The purpose of this study was to examine the bidirectional relationships relationship between maternal mental health status, maternal stress, family environment and behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health challenges due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, heightened child challenging behavior was related to improvements in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the results regarding maternal depression and closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research.

  15. Detecting novel genetic mutations in Chinese Usher syndrome families using next-generation sequencing technology.

    PubMed

    Qu, Ling-Hui; Jin, Xin; Xu, Hai-Wei; Li, Shi-Ying; Yin, Zheng-Qin

    2015-02-01

    Usher syndrome (USH) is the most common cause of combined blindness and deafness inherited in an autosomal recessive mode. Molecular diagnosis is of great significance in revealing the molecular pathogenesis and aiding the clinical diagnosis of this disease. However, molecular diagnosis remains a challenge due to high phenotypic and genetic heterogeneity in USH. This study explored an approach for detecting disease-causing genetic mutations in candidate genes in five index cases from unrelated USH families based on targeted next-generation sequencing (NGS) technology. Through systematic data analysis using an established bioinformatics pipeline and segregation analysis, 10 pathogenic mutations in the USH disease genes were identified in the five USH families. Six of these mutations were novel: c.4398G > A and EX38-49del in MYO7A, c.988_989delAT in USH1C, c.15104_15105delCA and c.6875_6876insG in USH2A. All novel variations segregated with the disease phenotypes in their respective families and were absent from ethnically matched control individuals. This study expanded the mutation spectrum of USH and revealed the genotype-phenotype relationships of the novel USH mutations in Chinese patients. Moreover, this study proved that targeted NGS is an accurate and effective method for detecting genetic mutations related to USH. The identification of pathogenic mutations is of great significance for elucidating the underlying pathophysiology of USH.

  16. Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease.

    PubMed

    Unal Gulsuner, Hilal; Gulsuner, Suleyman; Mercan, Fatma Nazli; Onat, Onur Emre; Walsh, Tom; Shahin, Hashem; Lee, Ming K; Dogu, Okan; Kansu, Tulay; Topaloglu, Haluk; Elibol, Bulent; Akbostanci, Cenk; King, Mary-Claire; Ozcelik, Tayfun; Tekinay, Ayse B

    2014-12-23

    Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.

  17. Characterizations of 9p21 candidate genes in familial melanoma

    SciTech Connect

    Walker, G.J.; Flores, J.F.; Glendening, J.M.

    1994-09-01

    We have previously collected and characterized 16 melanoma families for the inheritance of a familial melanoma predisposition gene on 9p21. Clear evidence for genetic linkage has been detected in 8 of these families with the 9p21 markers D9S126 and 1FNA, while linkage of the remaining families to this region is less certain. A candidate for the 9p21 familial melanoma gene, the cyclin kinase inhibitor gene p16 (also known as the multiple tumor suppressor 1 (MTS1) gene), has been recently indentified. Notably, a nonsense mutation within the p16 gene has been detected in the lymphoblastoid cell line DNA from a dysplastic nevus syndrome (DNS), or familial melanoma, patient. The p16 gene is also known to be frequently deleted or mutated in a variety of tumor cell lines (including melanoma) and resides within a region that has been defined as harboring the 9p21 melanoma predisposition locus. This region is delineated on the distal side by the marker D9S736 (which resides just distal to the p16 gene) and extends in a proximal direction to the marker D9S171. Overall, the entire distance between these two loci is estimated at 3-5Mb. Preliminary analysis of our two largest 9p21-linked melanoma kindreds (by direct sequencing of PCR products) has not yet revealed mutations within the coding region of the p16 gene. Others have reported that 8/11 unrelated 9p21-linked melanoma families do not appear to carry p16 mutations; thus the possibility exists that p16 is not a melanoma susceptibility gene per se, although it appears to play some role in melanoma tumor progression. Our melanoma kindred DNAs are currently being analyzed by SSCP using primers that amplify exons of other candidate genes from the 9p21 region implicated in familial melanoma. These novel genes reside within a distinct critical region of homozygous loss in melanoma which is located >2 Mb from the p16 gene on 9p21.

  18. Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome Maps to Chromosome 15q

    PubMed Central

    Yeon, Howard B.; Lindor, Noralane M.; Seidman, J. G.; Seidman, Christine E.

    2000-01-01

    Pyoderma gangrenosum, cystic acne, and aseptic arthritis are clinically distinct disorders within the broad class of inflammatory diseases. Although this triad of symptoms is rarely observed in a single patient, a three-generation kindred with autosomal-dominant transmission of these three disorders has been reported as “PAPA syndrome” (MIM 604416). We report mapping of a disease locus for familial pyoderma gangrenosum–acne–arthritis to the long arm of chromosome 15 (maximum two-point LOD score, 5.83; recombination fraction [θ] 0 at locus D15S206). Under the assumption of complete penetrance, haplotype analysis of recombination events defined a disease interval of 10 cM, between D15S1023 and D15S979. Successful identification of a single disease locus for this syndrome suggests that these clinically distinct disorders may share a genetic etiology. These data further indicate the role of genes outside the major histocompatibility locus in inflammatory disease. PMID:10729114

  19. A Novel Mutation in a Japanese Family with X-linked Alport Syndrome

    PubMed Central

    Abe, Yoshifusa; Iyoda, Masayuki; Nozu, Kandai; Hibino, Satoshi; Hihara, Kei; Yamaguchi, Yutaka; Yamamura, Tomohiko; Minamikawa, Shogo; Iijima, Kazumoto; Shibata, Takanori; Itabashi, Kazuo

    2016-01-01

    We herein report a novel mutation in a Japanese family with an X-linked Alport syndrome (AS) mutation in COL4A5. Patient 1 was a 2-year-old Japanese girl. She and her mother (patient 2) had a history of proteinuria and hematuria without renal dysfunction, deafness, or ocular abnormalities. Pathological findings were consistent with AS, and a genetic analysis revealed that both patients had a heterozygous mutation (c.2767G>C) in exon 32. In summary, the identification of mutations and characteristic pathological findings was useful in making a diagnosis of AS. For a close long-term follow-up, the early detection and treatment of women with X-linked AS are important. PMID:27725546

  20. Abnormal B.A.E.P. in a family with Moebius syndrome: evidence for supranuclear lesion.

    PubMed

    Stabile, M; Cavaliere, M L; Scarano, G; Fels, A; Valiani, R; Ventruto, V

    1984-05-01

    A family with Moebius syndrome is presented. Neurological lesions in the affected members are various: complete VI and VII cranial nerves palsy associated with mental retardation in the proband; left convergent strabismus and mental retardation in a brother of the proband and only mental retardation in a sister of the proband. The brainstem auditory evoked potentials (B.A.E.P.), investigated in the proband and his affected sister, are abnormal. The presence of the anomaly after the 3rd wave is consistent with a disfunction of the auditory tract at a supranuclear level. The mental deficiency and the supranuclear site of the acoustic lesion are an indication for a more general involvement of C.N.S. than cranial nerve nuclei alone. Karyotype and dermatoglyphics of the three affected subjects were normal. The authors hypothesized the same disorganogenetic factor acting very early (4th-6th week of gestational age) on the metamerization process of limb buds mesoderm and brainstem gray matter.

  1. An Amino Acid Deletion in SZT2 in a Family with Non-Syndromic Intellectual Disability

    PubMed Central

    Falcone, Michelle; Yariz, Kemal O.; Ross, David B.; Foster, Joseph; Menendez, Ibis; Tekin, Mustafa

    2013-01-01

    Autosomal recessive intellectual disability (ID) is characterized by extensive genetic heterogeneity. Recently, three mutations in SZT2 were reported in two unrelated children with unexplained infantile epileptic encephalopathy with severe ID. Here we report a European American family with three children having non-syndromic mild or moderate ID without seizures. Whole-exome sequencing of three affected siblings revealed a three base pair deletion (c.4202_4204delTTC) located in a 19 mb autozygous region on chromosome 1, leading to an amino acid deletion (p.Phe1401del) in SZT2. All three children were homozygous for the deletion and their parents were heterozygous as expected in autosomal recessive inheritance. SZT2 is highly expressed in neuronal tissues and regulates seizure threshold and neuronal excitation in mice. We conclude that the disruption of SZT2 with some residual function might lead to mild or moderate ID without seizures. PMID:24324832

  2. DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions.

    PubMed

    Schultz, Kris Ann; Yang, Jiandong; Doros, Leslie; Williams, Gretchen M; Harris, Anne; Stewart, Douglas R; Messinger, Yoav; Field, Amanda; Dehner, Louis P; Hill, D Ashley

    2014-03-01

    Germline mutations in DICER1 are associated with increased risk for a wide variety of neoplastic conditions, including pleuropulmonary blastoma (PPB), cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, botryoid embryonal rhabdomyosarcoma of the uterine cervix, ciliary body medulloepithelioma, pineoblastoma, pituitary blastoma and nodular thyroid hyperplasia or thyroid carcinoma. These tumors may be seen in isolation or in constellation with other characteristic tumor types in individuals or family members. Here we describe the medical history of a child with a heterozygous, loss of function germline DICER1 mutation and multiple tumors associated with the syndrome.. Although germline mutations in DICER1 are rare, tumors of these types will be seen by practicing pathologists and should prompt consideration of an underlying DICER1 mutation.

  3. Site-specific hereditary nonpolyposis colorectal cancer (HNPCC) which develops almost exclusively in males in a large SA kindred is linked to the hMLH1 gene on chromosome 3

    SciTech Connect

    Ramesar, R.S.; Madden, M.; Bardien, S.

    1994-09-01

    The diagnosis of HNPCC was made in 16 individuals over three generations in a large kindred from the northwestern region of South Africa, on the basis of clinical, surgical and pathological data and hospital or family records; all affecteds were males. We have excluded potential candidate genes and regions on chromosomes 1, 5, 6, 8, 9, 17 and 22 by linkage analysis. Following reports of two genes underlying HNPCC, namely hMSH2 and hMLH1, on chromsomes 2 and 3 respectively, we have shown that the disorder in the SA HNPCC family cosegregates with a specific hMLH1 gene-associated haplotype on chromosome 3. Interestingly, at least one female asymptomatic carrier of the disease-associated haplotype, who is more than 70 years of age, has been identified. Four asymptomatic males who are carriers of the disease-associated haplotype have been identified, but they are all below 40 years of age. Two notable features of the disorder in this family include the extreme sex bias and lack of non-colonic malignancies which might be expected in HNPCC. We are currently investigating the hMLH1 gene for mutations which might explain the unusual phenotype of the disease in this kindred, and looking for an explanation for the apparent sex based difference in the segregation of the disorder.

  4. Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch syndrome.

    PubMed

    Cruz-Correa, Marcia; Diaz-Algorri, Yaritza; Pérez-Mayoral, Julyann; Suleiman-Suleiman, Wasilah; Gonzalez-Pons, Maria del Mar; Bertrán, Carlos; Casellas, Nicolás; Rodríguez, Natalia; Pardo, Sherly; Rivera, Keyla; Mosquera, Rafael; Rodriguez-Quilichini, Segundo

    2015-09-01

    Lynch syndrome (LS) is an inherited form of colorectal cancer (CRC) caused by germline mutations in the mismatch repair (MMR) genes. It accounts for approximately 5% of all CRCs. The prevalence of LS among US Hispanics is unknown. The objective of this study was to describe the germline mutations of LS in Caribbean Hispanics from Puerto Rico and Dominican Republic. A total of 89 subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. A total of 35 individuals with deficient MMR system were identified: 22 had MMR mutations and 13 had tumors with absent MMR protein expression. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7%) mutations, followed by MLH1 (25.0%). One mutation was identified in MSH6 (8.3%). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutation-positive individuals were found to be more likely to have a prominent family history of CRC and tumors located at the proximal colon. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC and LS associated cancers. Furthermore, insurance coverage for genetic testing was found to be limited in the study population with 65.1% of the individuals recruited were denied coverage. This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients.

  5. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.

    PubMed

    Kremeyer, Barbara; Lopera, Francisco; Cox, James J; Momin, Aliakmal; Rugiero, Francois; Marsh, Steve; Woods, C Geoffrey; Jones, Nicholas G; Paterson, Kathryn J; Fricker, Florence R; Villegas, Andrés; Acosta, Natalia; Pineda-Trujillo, Nicolás G; Ramírez, Juan Diego; Zea, Julián; Burley, Mari-Wyn; Bedoya, Gabriel; Bennett, David L H; Wood, John N; Ruiz-Linares, Andrés

    2010-06-10

    Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12-8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans.

  6. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families.

    PubMed

    Rodriguez-Revenga, Laia; Madrigal, Irene; Pagonabarraga, Javier; Xunclà, Mar; Badenas, Celia; Kulisevsky, Jaime; Gomez, Beatriz; Milà, Montserrat

    2009-10-01

    Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that approximately 20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.

  7. Coexistence of two rare genetic disorders: Kartagener syndrome and familial Mediterranean fever.

    PubMed

    Çetin, Deniz; Genç Çetin, Beyza; Şentürk, Taşkın; Şahin Çildağ, Songül; Yılmaz Akdam, İkbal

    2015-03-01

    Primary ciliary dyskinesia (PCD) is a rare disease, predominantly inherited as an autosomal recessive, with ciliary dysfunction leading to impaired mucociliary clearance, chronic airway infection and inflammation. Situs inversus totalis occurs in ~50 % of PCD patients and it is known as Kartagener syndome. Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. FMF is caused by mutations in the MEFV gene which is located on chromosome 16p13.3. p.M680I, p.M694 V, p.M694I, p.V726A on exon 10 and p.E148Q on exon 2 are the most common mutations among FMF patients and these constitute 85 % of all. Homozygosity of R202Q polymorphism is strongly associated with FMF. We would like to present a case of Kartagener syndrome accompanied by FMF with R202Q polymorphism. Our case is the first in the literature indicating the accidental coexistence of FMF and Kartagener syndrome.

  8. A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome

    PubMed Central

    Ni, Cheng; Yan, Ming; Zhang, Jia; Cheng, Ruhong; Liang, Jianying; Deng, Dan; Wang, Zhen; Li, Ming; Yao, Zhirong

    2016-01-01

    Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks—mutilating palmoplanter and periorificial keratoderma. However, there’s a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease. PMID:26902751

  9. Atypical parkinsonism and cerebrotendinous xanthomatosis: report of a family with corticobasal syndrome and a literature review.

    PubMed

    Rubio-Agusti, Ignacio; Kojovic, Maja; Edwards, Mark J; Murphy, Elaine; Chandrashekar, Hoskote S; Lachmann, Robin H; Bhatia, Kailash P

    2012-12-01

    Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of cholesterol metabolism. It presents with systemic and neurological symptoms, rarely including parkinsonism. Presented here are a clinical description of a new family with cerebrotendinous xanthomatosis and parkinsonism and a review of 13 additional cases reported in the literature. The index case developed corticobasal syndrome, previously not reported in cerebrotendinous xanthomatosis. His brother had parkinsonism with cerebellar features and cognitive impairment. In a literature review, median age of onset of parkinsonism was found to be 40 years. Nearly all patients had other neurological symptoms: cognitive (93%), pyramidal (93%), or cerebellar (53%). All patients had walking difficulties, with falls in 27%. Systemic features were common: cataracts (93%) or tendon xanthomata (87%). Frequent MRI abnormalities included cerebellar atrophy (100%), cerebral atrophy (80%), and dentate nuclei signal changes (80%). Functional dopaminergic imaging often demonstrated presynaptic denervation. Improvement with levodopa was frequent (91%) but mild. Progressive neurological decline occurred in 92% of patients despite treatment with chenodeoxycholic acid. Cerebrotendinous xanthomatosis should be considered in the differential diagnosis of atypical parkinsonism, including corticobasal syndrome, particularly with early age of onset and in the context of a complex neurological phenotype. Tendon xanthomata, early-onset cataracts, and radiological findings of cerebellar atrophy with lesions of the dentate nuclei are useful clinical clues. Symptomatic treatment with levodopa may help, but progressive neurological decline is frequent despite treatment with chenodeoxycholic acid.

  10. Twenty-Five Years after Early Intervention: A Follow-Up of Children with Down Syndrome and Their Families.

    ERIC Educational Resources Information Center

    Hanson, Marci J.

    2003-01-01

    Children with Down syndrome and their families who participated in an early intervention program between 1974 and 1977 were interviewed 25 years later. Parents reported challenges such as medical complications, teasing or ostracism, and lack of adequate services and supports as children reached adulthood. Parents also described joys and…

  11. Psychological Well-Being of Mothers and Siblings in Families of Girls and Women with Rett Syndrome

    ERIC Educational Resources Information Center

    Cianfaglione, Rina; Hastings, Richard P.; Felce, David; Clarke, Angus; Kerr, Michael P.

    2015-01-01

    Few published studies have reported on the psychological well-being of family members of individuals with Rett syndrome (RTT). Eighty-seven mothers of girls and women with RTT completed a questionnaire survey about their daughters' behavioral phenotype, current health, and behavior problems, and their own and a sibling's well-being. Mothers…

  12. Identification of the KCNJ2 Mutation in a Korean Family with Andersen-Tawil Syndrome and Developmental Delay.

    PubMed

    Kim, Na Ri; Jang, Ja-Hyun; Jeon, Ga Won; Cho, Eun-Hae; Sin, Jong Beom

    2016-01-01

    Andersen-Tawil syndrome is a rare autosomal dominant disease characterized by the clinical triad of periodic paralysis, long QT with ventricular arrhythmias, and dysmorphic facial or skeletal features. However, the phenotypic heterogeneity and poor disease awareness of this syndrome can hinder an accurate and timely diagnosis. In this study, we describe a Korean family with Andersen-Tawil syndrome with a G215D mutation of the KCNJ2 gene revealed by diagnostic exome sequencing. Two sisters had severe growth restriction, characteristic facial anomalies, and developmental delay. The father carried the same mutation with similar characteristic facial features and short stature. This family lacked periodic paralysis. This report highlights the importance of an exome study for unusual clinical manifestations, such as preand postnatal growth restriction, developmental delay, and the lack of a critical diagnostic clue, such as periodic paralysis.

  13. Clinical and oral findings in an Afro-Brazilian family with Gorlin-Goltz syndrome: case series and literature review.

    PubMed

    da Silva Pierro, Viviane Santos; Marins, Marcello Roter; Borges de Oliveira, Renata Cabral; Cortezzi, Wladimir; Janini, Maria Elisa; Maia, Lucianne Cople

    2015-01-01

    Gorlin-Goltz syndrome (GGS) seems to be unusual in black persons. The authors present an Afro-Brazilian family case report of GGS. The main complaint of the index case was a painless swelling of the left mandible, which was diagnosed as an odontogenic keratocyst. Further classical features of the Syndrome were present in this patient. Other two family members were diagnosed as cases of GGS and one of them presented 11 clinical findings characteristic of the syndrome. From the three cases reported, two of them presented five major diagnostic criteria for the GGS, and the diagnosis was only made because of an oral complaint. This case series emphasizes the importance of carefully examining the patient and close relatives for signs of GGS, even if they belong to an ethnic group in which this diagnosis is unusual.

  14. CDH23 Mutation and Phenotype Heterogeneity: A Profile of 107 Diverse Families with Usher Syndrome and Nonsyndromic Deafness

    PubMed Central

    Astuto, L. M.; Bork, J. M.; Weston, M. D.; Askew, J. W.; Fields, R. R.; Orten, D. J.; Ohliger, S. J.; Riazuddin, S.; Morell, R. J.; Khan, S.; Riazuddin, S.; Kremer, H.; van Hauwe, P.; Moller, C. G.; Cremers, C. W. R. J.; Ayuso, C.; Heckenlively, J. R.; Rohrschneider, K.; Spandau, U.; Greenberg, J.; Ramesar, R.; Reardon, W.; Bitoun, P.; Millan, J.; Legge, R.; Friedman, T. B.; Kimberling, W. J.

    2002-01-01

    Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP–like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia. PMID:12075507

  15. Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism

    PubMed Central

    Koolen, David A; Dupont, Juliette; de Leeuw, Nicole; Vissers, Lisenka ELM; van den Heuvel, Simone PA; Bradbury, Alyson; Steer, James; de Brouwer, Arjan PM; ten Kate, Leo P; Nillesen, Willy M; de Vries, Bert BA; Parker, Michael J

    2012-01-01

    The 17q21.31 microdeletion syndrome is characterised by intellectual disability, epilepsy, distinctive facial dysmorphism, and congenital anomalies. To date, all individuals reported with this syndrome have been simplex patients, resulting from de novo deletions. Here, we report sibling recurrence of the 17q21.31 microdeletion syndrome in two independent families. In both families, the mother was confirmed to be the parent-of-origin for the 17q21.31 deletion. Fluorescence in situ hybridisation analyses in buccal mucosa cells, of the mother of family 1, identified monosomy 17q21.31 in 4/50 nuclei (8%). In mother of family 2, the deletion was identified in 2/60 (3%) metaphase and in 3/100 (3%) interphase nuclei in peripheral lymphocytes, and in 7/100 (7%) interphase nuclei in buccal cells. A common 17q21.31 inversion polymorphism predisposes to non-allelic homologous recombination and hereby to the 17q21.31 microdeletion syndrome. On the basis of the 17q21.31 inversion status of the parents, we calculated that the probability of the second deletion occurring by chance alone was 1/14 438 and 1/4812, respectively. If the inversion status of the parents of a child with the 17q21.31 microdeletion syndrome is unknown, the overall risk of a second child with the 17q21.31 microdeletion is 1/9461. We conclude that the presence of low-level maternal somatic–gonadal mosaicism is associated with the microdeletion recurrence in these families. This suggests that the recurrence risk for parents with a child with a 17q21.31 microdeletion for future pregnancies is higher than by chance alone and testing for mosaicism in the parents might be considered as a helpful tool in the genetic counselling. PMID:22293690

  16. Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down Syndrome

    PubMed Central

    Lippa, Carol F.; Rosso, Andrea L.; Stutzbach, Lauren D.; Neumann, Manuela; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2010-01-01

    Objective To assess the transactive response DNA-binding protein 43 (TDP-43) burden in familial forms of Alzheimer disease (FAD) and Down syndrome (DS) to determine whether TDP-43 inclusions are also present. Design Using standard immunohistochemical techniques, we examined brain tissue samples from 42 subjects with FAD and 14 with DS. Results We found pathological TDP-43 aggregates in 14.0% of participants (6 of 42 and 2 of 14 participants with FAD and DS, respectively). In both FAD and DS, TDP-43 immunoreactivity did not colocalize with neurofibrillary tangles. Occasionally participants with FAD or DS had TDP-43–positive neuropil threads or dots. Overall, the amygdala was most commonly affected, followed by the hippocampus, with no TDP-43 pathology in neocortical regions. A similar distribution of TDP-43 inclusions is seen in sporadic Alzheimer disease, but it differs from that seen in amyotrophic lateral sclerosis and frontotemporal dementia. Conclusions Transactive response DNA-binding protein 43 pathology occurs in FAD and DS, similar to that observed in sporadic Alzheimer disease. Thus, pathological TDP-43 may contribute the cognitive impairments in familial and sporadic forms of Alzheimer disease. PMID:20008652

  17. Apolipoprotein E polymorphism in alagille syndrome and progressive familial intrahepatic cholestasis.

    PubMed

    Socha, P; Nowicka, G; Jankowska, I; Rujner, J; Pawłowska, J; Socha, J

    2000-04-01

    The aim of the study was to assess the apolipoprotein E polymorphism (apoE) in two familial cholestatic diseases-Alagille syndrome (AS) and progressive familial intrahepatic cholestasis (PFIC)-and to estimate its association with gallstone formation, cholesterol levels, and response to UDCA treatment. We investigated 16 children with AS age 8.8 +/- 5.7 years (mean +/- SD) and 18 children with PFIC age 6.3 +/- 4.6 years. The frequency of the epsilon-2 allele in AS and PFIC was higher and the frequency of the epsilon-3 allele was lower than in controls. Gallstones were diagnosed in nine children with PFIC and different apoE phenotypes. No association between phenotype and cholesterol levels or response to UDCA therapy was observed in the patients studied. In conclusion, the allele epsilon-2 is overrepresented in AS and PFIC, similar to primary biliary cirrhosis, although this does not seem to contribute to different cholesterol levels, gallstones, and response to UDCA therapy.

  18. Maternal Well-Being and Child Behavior in Families with Fragile X Syndrome

    PubMed Central

    Hauser, Claire T.; Kover, Sara T.; Abbeduto, Leonard

    2014-01-01

    The purpose of this study was to examine the bidirectional relationshipsnetres behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health disorders due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, child challenging behavior was related to changes in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the result regarding maternal closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research. PMID:24984053

  19. Molecular study of 33 families with Fraser syndrome new data and mutation review.

    PubMed

    van Haelst, M M; Maiburg, M; Baujat, G; Jadeja, S; Monti, E; Bland, E; Pearce, K; Hennekam, R C; Scambler, P J

    2008-09-01

    Fraser syndrome (FS) is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract. FS is considered to be the human equivalent of the murine blebbing mutants: in the mouse mutations at five loci cause a phenotype that is comparable to FS in humans, and thus far mutations in two syntenic human genes, FRAS1 and FREM2, have been identified to cause FS. Here we present the molecular analysis of 48 FS patients from 18 consanguineous and 15 nonconsanguineous families. Linkage analysis in consanguineous families indicated possible linkage to FRAS1 and FREM2 in 60% of the cases. Mutation analysis identified 11 new mutations in FRAS1 and one FREM2 mutation. Manifestations of these patients and previously reported cases with an FRAS1 mutation were compared to cases without detectable FRAS1 mutations to study genotype-phenotype correlations. Although our data suggest that patients with an FRAS1 mutation have more frequently skull ossification defects and low insertion of the umbilical cord, these differences are not statistically significant. Mutations were identified in only 43% of the cases suggesting that other genes syntenic to murine genes causing blebbing may be responsible for FS as well.

  20. Cytogenetic and Clinical Assessment of a Family with Treacher Collins Syndrome

    PubMed Central

    Kumar, Manoj; Kumar, Rakesh; Tanwar, Mukesh; Ghose, Supriyo; Kaur, Jasbir; Dada, Rima

    2011-01-01

    Treacher Collins syndrome (TCS) is a rare autosomal dominant disorder characterized by craniofacial deformities. It is the most common type of mandibulofacial dysostosis (MFD). The objective of this study is to do cytogenetic analysis of a TCS family. Physical examination and all available medical records were reviewed. 50 GTG-banded metaphases were analysed to detect any structural or numerical chromosomal abnormality. Downward slanting of palpebral fissures, hypoplasia of zygomatic arch complex, and hypoplasia of mandible were present in all. Cytogenetic findings show interstitial deletion in chromosomes 5(q32-q33) and 3(q23–q25). We report four members of three generations of a family having TCS in a unique way that the deletion has been found in 3q and 5q which has not been reported. Mosaicism of deletion on 5q was detected in all affected members whereas 3q deletion was found only in one member (II.2). This finding may represent a more severe manifestation of the TCS. Thus the evaluation and counselling of the TCS patients should be undertaken with caution. PMID:21765846

  1. Molecular analysis of hereditary hyperferritinemia-cataract syndrome in a large Basque family.

    PubMed

    Pérez de Nanclares, G; Castaño, L; Martul, P; Rica, I; Vela, A; Sanjurjo, P; Aldamiz-Echevarría, K; Martínez, R; Sarrionandia, M J

    2001-03-01

    Hereditary hyperferritinemia-cataract syndrome is a genetic condition characterized by constitutively increased serum ferritin values in the absence of iron overload and by bilateral cataract. It has been demonstrated that mutations in the stem loop structure of the iron regulatory element (IRE) located in the 5'-untranslated region of the ferritin L-subunit gene (19q13.1) are responsible for the anomalous expression of this protein. Although not clearly explained, cataract formation seems secondary to the increased levels of ferritin in the lens. We analyzed a large Basque family in order to identify possible germline alterations of the iron regulatory element of the ferritin-L gene in affected individuals and first-degree relatives. All members of the family presented hyperferritinemia and cataract except a young child who had hyperferritinemia but did not present cataract. Sequence analysis permitted the identification of an A40-->G mutation in all members, including this child. This could demonstrate that cataract formation is a consequence of ferritin accumulation in the lens.

  2. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome

    SciTech Connect

    Tsigos, C.; Arai, K.; Latronico, A.C. ||

    1995-07-01

    Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, usually without mineralocorticoid deficiency. Occasionally, the disorder is associated with alacrima and achalasia of the esophagus (triple A syndrome), suggesting potential heterogeneity in its etiology. Mutations in the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in 1 other family with IGD and 2 famlies with triple A syndrome. The proband with IGD was a homozygote for an A {r_arrow}G substitution, changing tyrosine 254 to cysteine in the third extracellular loop of the receptor protein, probably interfering with ligand binding. Both of her parents were heterozygotes for this mutation, which was not detected in 100 normal alleles. No mutations were identified in the entire coding area of the ACTH receptor in the 2 families with triple A syndrome, supporting the idea of a developmental or postreceptor defect in this syndrome. 19 refs., 1 fig.

  3. Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome.

    PubMed

    Hermanns-Lê, Trinh; Reginster, Marie-Annick; Piérard-Franchimont, Claudine; Delvenne, Philippe; Piérard, Gérald E; Manicourt, Daniel

    2012-01-01

    The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH.

  4. Analysis of four families with the Stickler syndrome by linkage studies. Identification of a new premature stop codon in the COL2A1 gene in a family

    SciTech Connect

    Bonaventure, J.; Lasselin, C.; Toutain, A.

    1994-09-01

    The Stickler syndrome is an arthro-ophthalmopathy which associates progressive myopia with vitreal degeneration and retinal detachment. Cleft palate, cranio-facial abnormalities, deafness and osteoarthritis are often associated symptoms. Genetic heterogeneity of this autosomal dominant disease was consistent with its large clinical variability. Linkage studies have provided evidence for cosegregation of the disease with COL2A1, the gene coding for type II collagen, in about 50% of the families. Four additional families are reported here. Linkage analyses by using a VNTR located in the 3{prime} region of the gene were achieved. In three families, positive lod scores were obtained with a cumulative maximal value of 3.5 at a recombination fraction of 0. In one of these families, single strand conformation analysis of 25 exons disclosed a new mutation in exon 42. Codon for glutamic acid at position a1-803 was converted into a stop codon. The mutation was detected in DNA samples from all the affected members of the family but not in the unaffected. This result confirms that most of the Stickler syndromes linked to COL2A1 are due to premature stop codons. In a second family, an abnormal SSCP pattern of exon 34 was detected in all the affected individuals. The mutation is likely to correspond to a splicing defect in the acceptor site of intron 33. In one family the disease did not segregate with the COL2A1 locus. Further linkage studies with intragenic dimorphic sites in the COL10A1 gene and highly polymorphic markers close to the COL9A1 locus indicated that this disorder did not result from defects in these two genes.

  5. Tandem duplication within a Neurofibromatosis type I (NFI) gene exon in a family with features of Watson syndrome and Noonan syndrome

    SciTech Connect

    Tassabehji, M.; Strachan, T.; Colley, A.; Donnai, D.; Harris, R.; Thakker, N. ); Sharland, M )

    1993-07-01

    Type 1 neurofibromatosis (NF1), Watson syndrome (WS), and Noonan syndrome (NS) show some overlap in clinical manifestations. In addition, WS has been shown to be linked to markers flanking the NF1 locus and a deletion at the NF1 locus demonstrated in a WS patient. This suggests either that WS and NF1 are allelic or the phenotypes arise from mutations in very closely linked genes. Here the authors provide evidence for the former by demonstrating a mutation in the NF1 gene in a family with features of both WS and NS. The mutation is an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classical NF1, which show a preponderance of null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product. 31 refs., 2 figs.

  6. Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.

    PubMed Central

    Tassabehji, M; Strachan, T; Sharland, M; Colley, A; Donnai, D; Harris, R; Thakker, N

    1993-01-01

    Type 1 neurofibromatosis (NF1), Watson syndrome (WS), and Noonan syndrome (NS) show some overlap in clinical manifestations. In addition, WS has been shown to be linked to markers flanking the NF1 locus and a deletion at the NF1 locus demonstrated in a WS patient. This suggests either that WS and NF1 are allelic or that phenotypes arise from mutations in very closely linked genes. Here we provide evidence for the former by demonstrating a mutation in the NF1 gene in a family with features of both WS and NS. The mutation is an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classical NF1, which show a preponderance of null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product. Images Figure 1 Figure 2 PMID:8317503

  7. Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes.

    PubMed

    Schmiegelow, Kjeld

    2016-12-01

    Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3-5% of all childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar syndromes being treated by contemporary protocols. Recent studies clearly indicate that many of these patients stand a good chance of cure, and that they should be offered chemotherapy with the intention to cure. Some of these syndromes are characterized by reduced tolerance to radiotherapy and/or specific anticancer agents, while others are not. This review summarises our current knowledge on the risk of acute toxicities for these ALL patients and provides guidance for treatment adjustments.

  8. [The social portrait of substitute families and modes of development of medical pedagogical monitoring].

    PubMed

    Aver'ianova, N I; Khanova, N A

    2014-01-01

    The study demonstrated that in Russia the major cause of orphanage is a social life-style of biological parents of orphan children. The substitute families are more often large with number of children from 3 to 8 and quarter of them are incomplete. The mean age of substitute parent consists 47.8 ± 1.4 years. The leading motivation to take orphan child/or education in family is the availability of kindred relationship regarding child or "deserted nest syndrome". At the initial phase of establishing of substitute family the most of substitute parents/tutors face with problems of health status and behavioral deviations of foster children. The substitute parents are unsatisfied with quality of medical monitoring of foster children. They also suffer fromdeficiency of information concerning characteristics of development, health conditions and modes of rehabilitation of children. In the judgment of substitute parents/tutors placing child into family conditions effects positively on one's development and health, behavior and emotional background. In substitute families, conditions organized for children can be named as approximated to conditions of residing in biological (home) families. The system of medical psychological and pedagogical monitoring of children of this category is needed in further development.

  9. Molecular heterogeneity in two families with auditory pigmentary syndromes: the role of neuroimaging and genetic analysis in deafness.

    PubMed

    Shears, D; Conlon, H; Murakami, T; Fukai, K; Alles, R; Trembath, R; Bitner-Glindzicz, M

    2004-05-01

    We report two cases in which the probands presented with deafness and a family history of a dominantly inherited auditory pigmentary syndrome, yet the cause of deafness in each proband was not associated with the pigmentary abnormalities but was a result of mutations in SLC26A4, the gene mutated in Pendred's syndrome. The first case is a young woman with congenital sensorineural hearing loss and a family history of piebaldism. Despite showing no pigmentary abnormalities, the proband was found to harbor the same KIT mutation as her relatives affected by piebaldism, as well as two mutations in the SLC26A4 gene. In the second case, 2-year-old identical twin boys born to deaf parents presented with congenital sensorineural deafness and an extensive maternal family history of Waardenburg's syndrome type I (WSI). Their father had recessively inherited deafness associated with dilated vestibular aqueducts and a clinical diagnosis of Pendred's syndrome was made in him, which was confirmed molecularly. As the twin boys did not have features of WSI, both the mother and children were tested for mutations in SLC26A4 which showed the mother to be a carrier of a single mutation and both boys to be compound heterozygotes, illustrating pseudodominant inheritance of the condition.

  10. Popliteal pterygium syndrome: a clinical study of three families and report of linkage to the Van der Woude syndrome locus on 1q32

    PubMed Central

    Lees, M.; Winter, R.; Malcolm, S.; Saal, H.; Chitty, L.

    1999-01-01

    Popliteal pterygium syndrome (PPS) is a rare autosomal dominant disorder, thought to occur with an incidence of approximately 1 in 300 000 live births. The main clinical manifestations are popliteal webbing, cleft lip, cleft palate, lower lip pits, syndactyly, and genital and nail anomalies. This report describes the clinical features in two families with PPS and one isolated case, showing the range of anomalies found both within and between the families. PPS has some features in common with Van der Woude syndrome (VWS), also inherited as an autosomal dominant condition, with cleft lip/palate and, more distinctively, lower lip pits. Although the gene for VWS has not yet been identified, it has been localised to within 1.6 cM in the region 1q32-41. To determine whether PPS and VWS represent allelic forms of the same gene, three families were genotyped for markers flanking and within the critical region. A multipoint lod score of 2.7 was obtained, with no evidence of recombination, supporting the hypothesis that these two disorders are allelic.


Keywords: pterygium; van der Woude syndrome; cleft lip; cleft palate PMID:10593995

  11. Genetic Information-Seeking Behaviors and Knowledge among Family Members and Patients with Inherited Bone Marrow Failure Syndromes.

    PubMed

    Hamilton, Jada G; Hutson, Sadie P; Frohnmayer, Amy E; Han, Paul K J; Peters, June A; Carr, Ann G; Alter, Blanche P

    2015-10-01

    Inherited bone marrow failure syndromes (IBMFS) including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome are rare genetic disorders characterized by hematologic complications and increased risk of cancer. Patients and their families likely experience obstacles in obtaining sufficient health information given their disorders' rarity. To investigate this possibility, we examined information-seeking behaviors and levels of general and disorder-specific genetic knowledge among 315 members of 174 families with an IBMFS, and how information-seeking behaviors and socio-demographic factors may be associated with their genetic knowledge. Cross-sectional survey data indicated that participants were most likely to have ever used the Internet or healthcare providers for genetic information. On average, participants correctly answered 57 % of items assessing general genetic knowledge and 49-59 % of disorder-specific knowledge items. Greater knowledge was associated with greater education and ever experiencing genetic counseling, attending a scientific meeting, and seeking information from the Internet and scientific literature. Among families with Fanconi anemia (whose family support organization has the longest history of providing information), greater disorder-specific genetic knowledge was also associated with seeking information from support groups and other affected families. Results suggest that families with IBMFS have uncertainty regarding genetic aspects of their disorder, and highlight potential channels for delivering educational resources.

  12. A novel missense mutation of the paired box 3 gene in a Turkish family with Waardenburg syndrome type 1

    PubMed Central

    Ozturk, A.Taylan; Adibelli, Hamit; Unal, Nurettin; Tukun, Ajlan

    2013-01-01

    Purpose Screening of mutations in the paired box 3 (PAX3) gene in three generations of a Turkish family with Waardenburg syndrome type 1 (WS1). Methods WS1 was diagnosed in a 13-month-old girl according to the WS Consortium criteria. Detailed family history of the proband revealed eight affected members in three generations. Routine clinical and audiological examination and ophthalmologic evaluation were performed on eight affected and five healthy members of the study family. Dystopia canthorum was detected in all affected patients; however, a brilliant blue iris was present in five patients who also had mild retinal hypopigmentation. Genomic DNA was extracted from the peripheral blood of affected and unaffected individuals in the family as well as 50 unrelated healthy volunteers. All coding exons and adjacent intronic regions of PAX3 were sequenced directly. Results A novel missense heterozygous c.788T>G mutation was identified in eight patients. This nucleotide alteration was not found in unaffected members of the study family or in the 50 unrelated control subjects. The mutation causes V263G amino-acid substitution in the homeodomain of the PAX3 protein, which represents the 45th residue of helix 3. Conclusions We identified a novel missense c.788T>G mutation in PAX3 in a family with Waardenburg syndrome with intrafamilial phenotypic heterogeneity. PMID:23378733

  13. Chocolate consumption and prevalence of metabolic syndrome in the NHLBI Family Heart Study

    PubMed Central

    Tokede, Oluwabunmi A.; Ellison, Curtis R.; Pankow, James S.; North, Kari E.; Hunt, Steven C.; Kraja, Aldi T.; Arnett, Donna K.; Djoussé, Luc

    2014-01-01

    SUMMARY Background & aims Previous studies have suggested that cocoa products, which are rich sources of flavonoids, may lower blood pressure, serum cholesterol, fasting blood glucose and improve endothelial function. However, it is unclear whether consumption of cocoa products including chocolate influences the risk of metabolic syndrome (MetS). In a cross-sectional design, we sought to examine the association between chocolate consumption and the prevalence of MetS. Methods We studied 4098 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study aged 25–93 years. Chocolate consumption was assessed using a semi-quantitative food-frequency questionnaire. MetS was defined using the NCEP III criteria. Generalized estimating equations were used to estimate prevalence odds ratios of MetS according to frequency of chocolate intake. Results Of the 4098 participants (mean age 51.7 y) included in the analyses, 2206 (53.8%) were female. The prevalence of metabolic syndrome in our population was 30.2%. Compared with those who did not consume any chocolate, multivariate adjusted odds ratios (95% CI) for MetS were 1.26 (0.94, 1.69), 1.15 (0.85, 1.55), and 0.99 (0.66, 1.51) among women who reported chocolate consumption of 1–3 times/ month, 1–4 times/week, and 5+ times/week, respectively. Corresponding values for men were: 1.13 (0.82, 1.57), 1.02 (0.74, 1.39), and 1.21 (0.79, 1.85). Conclusion These data do not support an association between chocolate intake and the prevalence of MetS in US adult men and women. PMID:25126517

  14. ANLN truncation causes a familial fatal acute respiratory distress syndrome in Dalmatian dogs

    PubMed Central

    Syrjä, Pernilla; Arumilli, Meharji; Järvinen, Anna-Kaisa; Rajamäki, Minna

    2017-01-01

    Acute respiratory distress syndrome (ARDS) is the leading cause of death in critical care medicine. The syndrome is typified by an exaggerated inflammatory response within the lungs. ARDS has been reported in many species, including dogs. We have previously reported a fatal familial juvenile respiratory disease accompanied by occasional unilateral renal aplasia and hydrocephalus, in Dalmatian dogs. The condition with a suggested recessive mode of inheritance resembles acute exacerbation of usual interstitial pneumonia in man. We combined SNP-based homozygosity mapping of two ARDS-affected Dalmatian dogs and whole genome sequencing of one affected dog to identify a case-specific homozygous nonsense variant, c.31C>T; p.R11* in the ANLN gene. Subsequent analysis of the variant in a total cohort of 188 Dalmatians, including seven cases, indicated complete segregation of the variant with the disease and confirmed an autosomal recessive mode of inheritance. Low carrier frequency of 1.7% was observed in a population cohort. The early nonsense variant results in a nearly complete truncation of the ANLN protein and immunohistochemical analysis of the affected lung tissue demonstrated the lack of the membranous and cytoplasmic staining of ANLN protein in the metaplastic bronchial epithelium. The ANLN gene encodes an anillin actin binding protein with a suggested regulatory role in the integrity of intercellular junctions. Our study suggests that defective ANLN results in abnormal cellular organization of the bronchiolar epithelium, which in turn predisposes to acute respiratory distress. ANLN has been previously linked to a dominant focal segmental glomerulosclerosis in human without pulmonary defects. However, the lack of similar renal manifestations in the affected Dalmatians suggest a novel ANLN-related pulmonary function and disease association. PMID:28222102

  15. TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes.

    PubMed

    Andrade, Raissa Coelho; Dos Santos, Anna Claudia Evangelista; de Aguirre Neto, Joaquim Caetano; Nevado, Julián; Lapunzina, Pablo; Vargas, Fernando Regla

    2017-04-01

    Li-Fraumeni and Li-Fraumeni like syndromes (LFS/LFL) represent rare cancer-prone conditions associated mostly with sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. TP53 germline mutations are present in up to 80 % of families with classic Li-Fraumeni syndrome, and in 20-60 % of families with Li-Fraumeni like phenotypes. The frequency of LFS/LFL families with no TP53 mutations detected suggests the involvement of other genes in the syndrome. In this study, we searched for mutations in TP53 in 39 probands from families with criteria for LFS/LFL. We also searched for mutations in the gene encoding the main mediator of p53 in cell cycle arrest, CDKN1A/p21, in all patients with no mutations in TP53. Eight probands carried germline disease-causing mutations in TP53: six missense mutations and two partial gene deletions. No mutations in CDKN1A coding region were detected. TP53 partial deletions in our cohort represented 25 % (2/8) of the mutations found, a much higher frequency than usually reported, emphasizing the need to search for TP53 rearrangements in patients with LFS/LFL phenotypes. Two benign tumors were detected in two TP53 mutation carriers: an adrenocortical adenoma and a neurofibroma, which raises a question about the possible implication of TP53 mutations on the development of such lesions.

  16. Craniosynostosis, Scheuermann's disease, and intellectual disability resembling Shprintzen–Goldberg syndrome: a report on a family over 4 generations

    PubMed Central

    Al Kaissi, Ali; Marrakchi, Zahra; Nassib, Nabil M.; Hofstaetter, Jochen; Grill, Franz; Ganger, Rudolf; Kircher, Susanne Gerit

    2017-01-01

    Abstract Rationale: Craniosynostosis is a disorder characterized by premature fusion of cranial sutures with subsequent development of abnormal craniofacial contour associated with variable skeletal and extra-skeletal abnormalities. In this family syndromic type of craniosynostosis was recognized and the etiology behind diverse forms of deformities have been diagnosed. Patient concerns: The negative impact of the disorder on the child and his family is enormous. Particularly when the diagnosis is late and little can be done. Though counselling the family through discussing the whole picture of the disorder might lessens their concern. Diagnoses: Diagnosis is the corner stone of management. In this paper we aimed to sensitize pediatricians, physicians, and orthopedic surgeons concerning the necessity to recognize syndromic associations early on. Interventions: Patients with syndromic craniosynostosis are usually associated with a complexity of malformation complex. Craniofacial surgery can be of remarkable help if the diagnosis is made early. It requires a series of corrections to avoid intellectual disability and other neurological deficits. The timing of interventions is strongly correlated on the timing of diagnosis. Outcomes: The earliest the diagnoses, the much better the outcomes are. And consequently avert the psychological and the financial cost on the patient and his family. Lessons: The golden principle of medicine should prevail in all medical disciplines, which states: The more you see, the more you know and conversely the more you know is the more you see. PMID:28328806

  17. A Missense Mutation in CASK Causes FG Syndrome in an Italian Family

    PubMed Central

    Piluso, Giulio; D'Amico, Francesca; Saccone, Valentina; Bismuto, Ettore; Rotundo, Ida Luisa; Di Domenico, Marina; Aurino, Stefania; Schwartz, Charles E.; Neri, Giovanni; Nigro, Vincenzo

    2009-01-01

    First described in 1974, FG syndrome (FGS) is an X-linked multiple congenital anomaly/mental retardation (MCA/MR) disorder, characterized by high clinical variability and genetic heterogeneity. Five loci (FGS1-5) have so far been linked to this phenotype on the X chromosome, but only one gene, MED12, has been identified to date. Mutations in this gene account for a restricted number of FGS patients with a more distinctive phenotype, referred to as the Opitz-Kaveggia phenotype. We report here that a p.R28L (c.83G→T) missense mutation in CASK causes FGS phenotype in an Italian family previously mapped to Xp11.4-p11.3 (FGS4). The identified missense mutation cosegregates with the phenotype in this family and is absent in 1000 control X chromosomes of the same ethnic origin. An extensive analysis of CASK protein functions as well as structural and dynamic studies performed by molecular dynamics (MD) simulation did not reveal significant alterations induced by the p.R28L substitution. However, we observed a partial skipping of the exon 2 of CASK, presumably a consequence of improper recognition of exonic splicing enhancers (ESEs) induced by the c.83G→T transversion. CASK is a multidomain scaffold protein highly expressed in the central nervous system (CNS) with specific localization to the synapses, where it forms large signaling complexes regulating neurotransmission. We suggest that the observed phenotype is most likely a consequence of an altered CASK expression profile during embryogenesis, brain development, and differentiation. PMID:19200522

  18. Popliteal pterygium syndrome in a Swedish family--clinical findings and genetic analysis with the van der Woude syndrome locus at 1q32-q41.

    PubMed

    Wong, F K; Gustafsson, B

    2000-04-01

    The present study describes a Swedish family in which the mother and her son were affected with signs of popliteal pterygium syndrome (PPS, OMIM 119500). Both individuals had bilateral complete cleft lip and palate, oral synechiae, paramedian pits on the lower lip, toe syndactyly and a piece of triangular skin overgrowth on the great toes. The son also presented with soft tissue syndactyly of the 2nd and 3rd fingers. Although popliteal pterygium was not found, the above clinical features were diagnostic for PPS. Chromosomal abnormalities were not revealed in either case by cytogenetic analyses. A test for microdeletion in the VWS region at 1q32-q41 was performed in the family using 5 polymorphic microsatellite markers from the region. The affected son was found to be heterozygous for all 5 markers, suggesting that microdeletion at the VWS region was unlikely. The VWS locus, however, was not excluded by haplotype analysis of the family.

  19. Multivariate linkage scan for metabolic syndrome traits in families with type 2 diabetes.

    PubMed

    Edwards, Karen L; Wan, Jia Y; Hutter, Carolyn M; Fong, Pui Yee; Santorico, Stephanie A

    2011-06-01

    The purpose of this study was to evaluate evidence for linkage to interrelated quantitative features of the metabolic syndrome (MetS). Data on eight quantitative MetS traits (body weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein (HDL) cholesterol, triglycerides (TGs), and fasting glucose and insulin measurements) and a 10 cM genome scan were available for 78 white families (n = 532 subjects). These data were used to conduct multipoint, multivariate linkage analyses, including tests for coincident linkage and complete pleiotropy. The strongest evidence for linkage from the bivariate analyses was observed on chromosome 1 (1p22.2) (HDL-TG; univariate lod score equivalent (lod(eq) = 3.99)) with stronger results from the trivariate analysis at the same location (HDL-TG-Insulin; lod(eq) = 4.32). Seven additional susceptibility regions (lod(eq) scores >1.9) were observed (1p36, 1q23, 2q21.2, 8q23.3, 14q23.2, 14q32.11, and 20p11.21). The results from this study indicate that several correlated traits of the MetS are influenced by the same gene(s) that account for some of the clustering of the MetS features.

  20. Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome).

    PubMed

    Roberts, Aedan; Nancarrow, Derek; Clendenning, Mark; Buchanan, Daniel D; Jenkins, Mark A; Duggan, David; Taverna, Darin; McKeone, Diane; Walters, Rhiannon; Walsh, Michael D; Young, Bruce W; Jass, Jeremy R; Rosty, Christophe; Gattas, Michael; Pelzer, Elise; Hopper, John L; Goldblatt, Jack; George, Jill; Suthers, Graeme K; Phillips, Kerry; Parry, Susan; Woodall, Sonja; Arnold, Julie; Tucker, Kathy; Muir, Amanda; Drini, Musa; Macrae, Finlay; Newcomb, Polly; Potter, John D; Pavluk, Erika; Lindblom, Annika; Young, Joanne P

    2011-06-01

    Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.

  1. Complete androgen insensitivity syndrome associated with male gender identity or female precocious puberty in the same family.

    PubMed

    Bermúdez de la Vega, José A; Fernández-Cancio, Mónica; Bernal, Susana; Audí, Laura

    2015-01-01

    In 4 complete androgen insensitivity syndrome (CAIS) members of one family, 2 presented extreme and unusual clinical features: male gender identity disorder (case 1) and female precocious central puberty (case 2). The AR gene carried the mutation c.1752C>G, p.Phe584Leu. Gender dysphoria in CAIS may be considered as a true transgender and has been described in 3 other cases. Central precocious puberty has only been described in 1 case; Müllerian ducts in case 2 permitted menarche. Despite the common CAIS phenotype, there was a familial disparity for gender identity adequacy and timing and type of puberty.

  2. Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting.

    PubMed

    Ponti, Giovanni; Luppi, Gabriele; Martorana, Davide; Rossi, Giulio; Losi, Lorena; Bertolini, Federica; Sartori, Giuliana; Pellacani, Giovanni; Seidenari, Stefania; Boni, Elisa; Neri, Tauro Maria; Silini, Enrico; Tamburini, Elisa; Maiorana, Antonio; Conte, Pier Franco

    2010-02-01

    Gastrointestinal stromal tumors (GISTs) may be sporadic or inherited. Although KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic and inherited GISTs, a small subset of GISTs are negative for both. Besides the classical Familial GIST Syndrome, GIST can occur as part of multi-neoplastic disease. The present study was designed to analyze the synchronous and metachronous tumors developed among GIST patients assessed by our institution for GIST Syndrome setting recognition. Patients (n=141) with primary GIST (77 men and 64 women) were recruited between 1988 and 2007 and their clinical and pathological records were reviewed. Mutation analysis of KIT, PDGFRA, NF1 and MMR genes was performed on somatic and peripheral blood DNA. GISTs occurred associated with other primary malignancies in 46 of 141 (32.6%) patients. The most common neoplasms were gastrointestinal and genitourinary. A novel exon 6 germline large deletion of NF1 was identified in the NF1/GIST kindred. The development of GIST associated with other neoplasms is common and diagnosis of peculiar benign associated-neoplasms warrants the search for familial cancer susceptibility. In particular, syndromic or familial settings have to be suspected in the presence of neurofibroma or lung chordoma in C-KIT and PDGFRA negative GIST patients.

  3. A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome.

    PubMed

    Cassina, Matteo; Cerqua, Cristina; Rossi, Silvia; Salviati, Leonardo; Martini, Alessandro; Clementi, Maurizio; Trevisson, Eva

    2017-02-01

    Nager syndrome is a rare preaxial acrofacial dysostosis that is caused by heterozygous loss-of-function variants in SF3B4. This gene encodes for a protein required for the assembly of spliceosomal complexes, being a master gene for splicing regulation. The main clinical features of Nager syndrome include facial-mandibular and preaxial limb malformations, with normal cognitive functioning. Most Nager patients are sporadic, but few familial cases with a highly variable phenotype have been reported. In this work, we report a novel synonymous variant within exon 3 of the SF3B4 gene in a family with three members affected by Nager syndrome. No pathogenic variants have been detected in other 24 genes associated with syndromes characterized by mandibulo-facial anomalies. The pathogenicity of the mutation was demonstrated through a hybrid minigene assay, which confirmed an aberrant splicing with the creation of a cryptic splice site, and showed that this allele is hypomorphic. Our findings emphasize the importance to perform functional analyses to assess the possible consequences of synonymous variants and confirmed that hybrid minigenes represent an effective tool to evaluate the effects of variants on splicing, particularly when RNA is not available.

  4. Parkin disease in a Brazilian kindred: Manifesting heterozygotes and clinical follow-up over 10 years.

    PubMed

    Khan, Naheed L; Horta, Wagner; Eunson, Louise; Graham, Elizabeth; Johnson, Janel O; Chang, Shannon; Davis, Mary; Singleton, Andrew; Wood, Nicholas W; Lees, Andrew J

    2005-04-01

    We report on a large Brazilian kindred with young-onset parkinsonism due to either a homozygous or heterozygous mutation in parkin. A total of 6 members were affected: 5 were homozygous and 1 heterozygous for a deletion in exon 4. Two other heterozygotes also had extrapyramidal signs. All affected subjects showed characteristic features of parkin disease with foot dystonia and an excellent response to levodopa complicated by motor fluctuations and dyskinesia within 3 years of therapy. Careful clinical follow-up over 10 years showed the phenotype was similar in all the homozygotes with asymmetrical limb bradykinesia and early walking difficulties. Some acceleration of disability was observed in some of the cases as they entered the third decade of illness, but dementia was absent.

  5. Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred

    SciTech Connect

    Barr, C.L.; Kennedy, J.L.; Pakstis, A.J.

    1994-03-15

    Genetic linkage studies of a kindred from Sweden segregating for schizophrenia have been performed using a genetic model (autosomal dominant, f - 0.72, q - 0.02, phenocopies=0.001) as described in Kennedy et al., 1988. Analyses of the restriction fragment length polymorphism (RFLP), allele-specific oligonucleotides (ASO), and short tandem repeat (STR also called microsatellite) data for 180 polymorphisms (individual probe-enzyme, ASO, or STR systems) at 155 loci have been completed using the MLINK and LIPED programs. Linkage to schizophrenia was excluded, under the given model, at 47 loci; indeterminate lod scores occurred at 108 loci. The total exclusion region across 20 chromosomes is estimated at 330 cM; 211 cM excluded by pairwise analyses and 119 cM previously excluded by multipoint analyses. 37 refs., 2 tabs.

  6. The gene for autosomal dominant spinocerebellar ataxia (SCAI) maps centromeric to D6S89 and shows no recombination, in nine large kindreds, with a dinucleotide repeat at the AM10 locus

    SciTech Connect

    Kwiatkowski, T.J. Jr.; Zoghbi, H.Y.; Beaudet, A.L.; Banfi, S.; McCall, A.E. ); Orr, H.T.; Duvick, L.A.; Ranum, L.P.W. ); Jodice, C.; Persichetti, F.; Novelletto, A.; Terrenato, L. ); LeBorgne-DeMarquoy, F. ); Subramony, S.H. )

    1993-08-01

    Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder which is genetically linked to the short arm of chromosome 6, telomeric to the human major histocompatibility complex (HLA) and very close to D6S89. Previous multipoint linkage analysis using HLA, D6S89, and SCA1 suggested that SCA1 maps centromeric to D5S89. Data from this study using nine large kindreds indicate a maximum lod score between SCA1 and D6S89 of 67.58 at a maximum recombination fraction of .004. To localize SCA1 more precisely, the authors identified five dinucleotide polymorphisms near D6S89. Genotypic analyses at these polymorphic loci were carried out in nine multigeneration SCA1 kindreds and in the Centre d'Etude du Polymorphisme Humain reference families. A new marker, AM10GA, demonstrates no recombination with SCA1. The maximum lod score for AM10GA linkage to SCA1 is 42.14 at a recombination fraction of 0. Linkage analysis and analysis of recombination events confirm that SCA1 maps centromeric to D6S89 and establish the following order: CEN-D6S109-AM10GA/SCA1-D6S89-LR40-D6S202-TEL. 20 refs., 2 figs., 5 tabs.

  7. Familial Aggregation of Metabolic Syndrome With Different Socio-Behavioral Characteristics: The Fourth Phase of Tehran Lipid and Glucose Study

    PubMed Central

    Zarkesh, Maryam; Asghari, Golaleh; Amiri, Parisa; Hosseinzadeh, Nima; Hedayati, Mehdi; Ghanbarian, Arash; Azizi, Fereidoun

    2016-01-01

    Background Since genetic and most environmental factors shape the context of families, some studies have been initiated to investigate the role of familial relationships in metabolic syndrome (MetS). Objectives To estimate the familial aggregation of MetS and its components by identifying both case and control probands among Tehranian adults with different socio-behavioral and reproductive characteristics. Patients and Methods This case-controlled/family-based study was conducted on 1,777 families (635 case probands) who participated in the Tehran Lipid and Glucose Study (TLGS). Socio-demographic and reproductive information including levels of education, marital status, occupation status, age at menarche, number of abortions, number of children, and lifestyle habits such as smoking, physical activity and regular diet were obtained from the TLGS data bank. Metabolic syndrome was defined according to the joint interim statement (JIS) criteria. To estimate the regression co-efficient for familial aggregation and environmental factors, the generalized estimation equation method was used. Results The risk of having MetS among family members for case versus control probands was 2.19 (95% CI: 1.68 - 2.84), which, after adjusting for potential confounders including age, sex, educational level, marital status, occupation, age at menarche and energy, soft drink and starchy vegetable intake, increased to 2.31 (95% CI: 1.81 - 2.94; P < 0.05). Compared to control probands, the risk of having MetS components increased significantly from OR = 1.28 for both high waist circumference (WC) and blood pressure (BP) to OR = 1.72 for high triglycerides in cases. Familial aggregation inherited from the father was significantly observed in all MetS components, from adjusted OR = 1.63 for hyperglycemia to adjusted OR = 2.69 for high WC, except for low HDL, after controlling for potential confounders. Conclusions Considering spouses and siblings, there was a higher risk for MetS components

  8. A novel mutation in the SLC17A5 gene causing both severe and mild phenotypes of free sialic acid storage disease in one inbred Bedouin kindred.

    PubMed

    Landau, D; Cohen, D; Shalev, H; Pinsk, V; Yerushalmi, B; Zeigler, M; Birk, O S

    2004-06-01

    Four members of an extended consanguineous Bedouin family presented with different phenotypic variants of an autosomal recessive lysosomal free sialic acid storage disease. One affected individual had congenital ascites followed by rapid clinical deterioration and death, a presentation concordant with the clinical course of infantile free sialic acid storage disorder. His three first cousins had a more slowly progressive neurodegenerative disease, in line with the clinical phenotype of the milder form (Salla type) of this lysosomal disorder. Diagnosis of free sialic acid storage disease was based on clinical findings, histology, and biochemical assays of sialic acid. Molecular studies showed that all four affected individuals were homozygous for the same novel 983G > A mutation in exon 8 of the SLC17A5 gene, replacing glycine with glutamic acid at position 328 of the sialin protein. This family demonstrates the significant phenotypic variability of the disease in affected members of a single inbred kindred with precisely the same mutation, suggesting a role for modifier genes or environmental factors. It also highlights the need to consider this rare disorder in the differential diagnosis of congenital ascites and of unexplained psychomotor retardation, ataxia, and hypomyelination in infancy.

  9. Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease.

    PubMed

    Halford, S; Wadey, R; Roberts, C; Daw, S C; Whiting, J A; O'Donnell, H; Dunham, I; Bentley, D; Lindsay, E; Baldini, A

    1993-12-01

    A wide spectrum of birth defects are caused by deletions of the DiGeorge syndrome critical region (DGCR) at human chromosome 22q11. Over one hundred such deletions have now been examined and a minimally deleted region of 300kb defined. Within these sequences we have identified a gene expressed during human and murine embryogenesis. The gene, named TUPLE1, and its murine homologue, encodes a protein containing repeated motifs similar to the WD40 domains found in the beta-transducin/enhancer of split (TLE) family. The TUPLE1 product has several features typical of transcriptional control proteins and in particular has homology with the yeast Tup1 transcriptional regulator. We propose that haploinsufficiency for TUPLE1 is at least partly responsible for DiGeorge syndrome and related abnormalities.

  10. Estimated Prevalence of Heterozygous Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome.

    PubMed

    Ohmura, Hirotoshi; Fukushima, Yoshifumi; Mizuno, Atsushi; Niwa, Koichiro; Kobayashi, Yohei; Ebina, Toshiaki; Kimura, Kazuo; Ishibashi, Shun; Daida, Hiroyuki

    2017-02-07

    Heterozygous familial hypercholesterolemia (FH) represents a strong risk for development of premature coronary artery disease (CAD). However, the majority of patients with FH are undiagnosed and the prevalence likely represents an underestimate in most countries. In Japan, the possible contribution of FH to the development of CAD may be higher because of the low incidence of CAD among the general population. We estimated the prevalence of heterozygous FH by measuring Achilles tendon thickness (ATT) in patients with acute coronary syndrome (ACS).A total of 359 patients suffering from ACS were enrolled in this multicenter registration study. Heterozygous FH was defined according to the diagnostic criteria proposed by the Japan Atherosclerosis Society. After excluding 63 patients because of missing ATT data or plasma triglyceride levels that were 4.5 mmol/L or more, 296 patients were eligible for inclusion in the study. The number of patients with ATT of 9 mm or more was 53 (17.9%). They were significantly younger and had significantly higher LDL cholesterol levels than patients with an ATT less than 9 mm. The prevalence of heterozygous FH was 5.7% (1/17.5) and more prominent in younger patients who were less than 60 years old (7.8%). In patients with ATT of 9 mm or more, approximately 1 in 3.5 fulfilled the criteria for heterozygous FH.We demonstrated the usefulness of measuring ATT by radiography and the high prevalence of heterozygous FH in patients with ACS in Japan, especially in younger patients who were less than 60 years old.

  11. Management strategies in Lynch syndrome and familial adenomatous polyposis: a national healthcare survey in Japan.

    PubMed

    Yamano, Tomoki; Hamanaka, Michiko; Babaya, Akihito; Kimura, Kei; Kobayashi, Masayoshi; Fukumoto, Miki; Tsukamoto, Kiyoshi; Noda, Masafumi; Matsubara, Nagahide; Tomita, Naohiro; Sugihara, Kenichi

    2017-02-01

    Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are major sources of hereditary colorectal cancer (CRC) and are associated with other malignancies. There is some heterogeneity in management strategies in Japan. We undertook a survey of management of hereditary CRC in hospitals that are members of the Japan Society of Colorectal Cancer Research. One hundred and ninety departments responded, of which 127 were from designated cancer care hospitals (DCCHs) according to the Japanese government. There were 25 488 operations for CRC in these departments in 2015. The DCCHs performed better with regard to usage of Japan Society of Colorectal Cancer Research guidelines, referring new CRC patients for LS screening, and having in-house genetic counselors and knowledge of treatment for LS. There were 174 patients diagnosed with LS and 602 undergoing follow-up in 2011-2015, which is fewer than the number expected from CRC operations in 2015. These numbers were not affected by whether the institution was a DCCH. Universal screening for LS was carried out in 8% of the departments. In contrast, 541 patients were diagnosed with FAP and 273 received preventive proctocolectomy/colectomy in 2011-2015. The DCCH departments undertook more surgery than non-DCCH departments, although most of the management, including surgical procedures and use of non-steroidal anti-inflammatory drugs, was similar. Management of desmoid tumor in the abdominal cavity differed according to the number of patients treated. In conclusion, there was heterogeneity in management of LS but not FAP. Most patients with LS may be overlooked and universal screening for LS is not common in Japan.

  12. Genetic analysis, in silico prediction, and family segregation in long QT syndrome.

    PubMed

    Riuró, Helena; Campuzano, Oscar; Berne, Paola; Arbelo, Elena; Iglesias, Anna; Pérez-Serra, Alexandra; Coll-Vidal, Mònica; Partemi, Sara; Mademont-Soler, Irene; Picó, Ferran; Allegue, Catarina; Oliva, Antonio; Gerstenfeld, Edward; Sarquella-Brugada, Georgia; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Mont, Lluís; Brugada, Josep; Scornik, Fabiana S; Brugada, Ramon

    2015-01-01

    The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality.

  13. Genetic analysis, in silico prediction, and family segregation in long QT syndrome

    PubMed Central

    Riuró, Helena; Campuzano, Oscar; Berne, Paola; Arbelo, Elena; Iglesias, Anna; Pérez-Serra, Alexandra; Coll-Vidal, Mònica; Partemi, Sara; Mademont-Soler, Irene; Picó, Ferran; Allegue, Catarina; Oliva, Antonio; Gerstenfeld, Edward; Sarquella-Brugada, Georgia; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Mont, Lluís; Brugada, Josep; Scornik, Fabiana S; Brugada, Ramon

    2015-01-01

    The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality. PMID:24667783

  14. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

    PubMed Central

    Warner, J; Epstein, M; Sweet, A; Singh, D; Burgess, J; Stranks, S; Hill, P; Perry-Keene, D; Learoyd, D; Robinson, B; Birdsey, P; Mackenzie, E; Teh, B; Prins, J; Cardinal, J

    2004-01-01

    Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor (CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP. PMID:14985373

  15. Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum

    PubMed Central

    Maria, Maleeha; Lamers, Ideke J. C.; Schmidts, Miriam; Ajmal, Muhammad; Jaffar, Sulman; Ullah, Ehsan; Mustafa, Bilal; Ahmad, Shakeel; Nazmutdinova, Katia; Hoskins, Bethan; van Wijk, Erwin; Koster-Kamphuis, Linda; Khan, Muhammad Imran; Beales, Phil L.; Cremers, Frans P. M.; Roepman, Ronald; Azam, Maleeha; Arts, Heleen H.; Qamar, Raheel

    2016-01-01

    Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell’s signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician’s ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals. PMID:27708425

  16. Leber's congenital amaurosis associated with familial juvenile nephronophthisis and cone-shaped epiphyses of the hands (the Saldino-Mainzer syndrome).

    PubMed

    Ellis, D S; Heckenlively, J R; Martin, C L; Lachman, R S; Sakati, N A; Rimoin, D L

    1984-02-01

    Three affected children (a 13-year-old girl and her 7- and 8-year-old brothers) in a sibship of eight had findings consistent with the Saldino-Mainzer syndrome (skeletal dysplasia associated with Leber's congenital amaurosis, familial juvenile nephronophthisis, and cone-shaped epiphyses of the hands). Two also had pigmented midline nevi. Although tapetoretinal degeneration and familial juvenile nephronophthisis are associated in the inherited Senior-Loken syndrome, the rare association of these abnormalities with cone-shaped epiphyses of the hands suggested an autosomal recessive syndrome with variable expression remarkably similar to the Saldino-Mainzer syndrome, which may or may not be distinct from the Senior-Loken syndrome. The association of tapetoretinal degeneration with skeletal dysplasia may indicate asymptomatic renal or hepatic disease.

  17. Stress, Locus of Control, and Family Cohesion and Adaptability in Parents of Children with Down, Williams, Fragile X, and Prader-Willi Syndromes

    ERIC Educational Resources Information Center

    Lanfranchi, Silvia; Vianello, Renzo

    2012-01-01

    The present study analyzes differences in parental stress in families of children with Down, Williams, Fragile X, and Prader-Willi syndromes, exploring factors that influence parental stress, such as child's characteristics, parental locus of control, and family cohesion and adaptability. Differences between mothers and fathers are also…

  18. Outcome in Adult Life for People with Williams Syndrome Results from a Survey of 239 Families

    ERIC Educational Resources Information Center

    Howlin, P.; Udwin, O.

    2006-01-01

    BACKGROUND: Although there has been considerable research into the genotype and phenotype of Williams syndrome, there have been relatively few studies of long-term prognosis. As a preliminary to a more detailed investigation of adults with Williams syndrome, a parental questionnaire was distributed to members of the UK Williams Syndrome…

  19. Living with Lowe's Syndrome. A Guide for Families, Friends, and Professionals.

    ERIC Educational Resources Information Center

    Lowe's Syndrome Association, Inc., West Lafayette, IN.

    The document describes Lowe's syndrome, a hereditary condition that affects only males and is typically diagnosed during the first year of life. Effects of Lowe's syndrome on the eyes (cataracts, glaucoma, corneal degeneration, and strabismus) are discussed, as well as related problems with the central nervous system, muscles, kidneys, bones, and…

  20. Tourette Syndrome: A Collaborative Approach Focused on Empowering Students, Families and Teachers

    ERIC Educational Resources Information Center

    Christner, Beth; Dieker, Lisa A.

    2008-01-01

    Tourette syndrome (TS) is a neurobiological disorder marked by a wide range of involuntary motor and vocal movements and sounds called "tics" (American Psychiatric Association, APA, 2000). This syndrome is frequently misunderstood and difficult to diagnose (Chamberlain, 2003). Recent television shows featuring the topic of TS such as "The Oprah…

  1. A novel point mutation (R840S) in the androgen receptor in a Brazilian family with partial androgen insensitivity syndrome.

    PubMed

    Melo, K F; Latronico, A C; Costa, E M; Billerbeck, A E; Mendonca, B B; Arnhold, I J

    1999-10-01

    Mutations of the androgen receptor gene causing androgen insensitivity syndrome in 46, XY individuals, result in phenotypes ranging from complete female to ambiguous genitalia to males with minor degrees of undervirilization. We studied two Brazilian brothers with partial androgen insensitivity syndrome. They were born with perineal hypospadias, bifid scrotum, small penis and cryptorchidism, and developed gynecomastia at puberty. Genomic DNA was extracted and denaturinggradient gel electrophoresis of exon 7 of the androgen receptor gene followed by sequence analysis revealed a new mutation, a C A transversion, altering codon 840 from arginine (CGT) to serine (AGT). R840 is located in the androgen binding domain, in a "hot spot" region, important for the formation and function of the hormone receptor-complex and within the region that is involved in androgen receptor dimerization. Replacement of arginine (basic) by serine (neutral and polar) is a nonconservative substitution. Three mutations in this residue (R840C, R840G nonconservative and R840H, conservative) were previously reported in patients with partial androgen insensitivity syndrome and when expressed "in vitro" lead to a subnormal transactivation of a reporter gene. We conclude that the novel R840 mutation in the androgen receptor is the cause of partial androgen insensitivity syndrome in this Brazilian family.

  2. Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome.

    PubMed Central

    Partington, M W; Fagan, K; Soubjaki, V; Turner, G

    1997-01-01

    Three families are reported who have a translocation involving 4p16.3. Nine subjects are described with the clinical features of the Pitt-Rogers-Danks (PRD) syndrome confirming pre- and postnatal growth failure, microcephaly, severe mental retardation, seizures, and a distinctive facial appearance; a deletion of 4p16.3 was seen in all eight patients studied with fluorescence in situ hybridisation (FISH). Eleven subjects had a new syndrome with physical overgrowth, heavy facial features, and mild to moderate mental handicap; a duplication of the chromosome region 4p16.3 was found in the four subjects studied. It is suggested that the growth abnormalities in these two families may be explained by a dosage effect of the fibroblast growth factor receptor gene 3 (FGFR3), which is located at 4p16.3, that is, a single dose leads to growth failure and a triple dose to physical overgrowth. We describe the molecular mapping of the translocation breakpoint and define it to within locus D4S43. Images PMID:9321756

  3. A family with unusual Waardenburg syndrome type I (WSI), cleft lip (palate), and Hirschsprung disease is not linked to PAX 3.

    PubMed

    Pierpont, J W; St Jacques, D; Seaver, L H; Erickson, R P

    1995-03-01

    An unusual family with Waardenburg syndrome type 1 (WSI), cleft lip (palate), and Hirschsprung disease is not linked to the PAX 3 gene since there is an obligate crossover which has occurred between PAX 3 DNA markers and the disorder in this family. This family may also have anticipation of the WSI traits as the proband's grandmother is nonpenetrant, his mother has dystopia canthorum, and severe cleft lip (palate), while the proband has dystopia canthorum, severe cleft lip (palate), and Hirschsprung disease. Thus, a locus other than PAX 3 is implicated in this Waardenburg-like syndrome with Hirschsprung disease and cleft lip (palate).

  4. Identification of the forkhead transcriptional factor 2 (FOXL2) gene mutations in four Chinese families with blepharophimosis syndrome

    PubMed Central

    Zhang, Li; Wang, Liming; Han, Ruifang; Guan, Lifang; Fan, Baohong; Liu, Mingmei; Ying, Ming; Peng, Hao

    2013-01-01

    Purpose To determine the genetic origin of disease in four Chinese families with blepharophimosis syndrome. Methods Four Han Chinese families with blepharophimosis syndrome were ascertained and patients underwent complete physical and ophthalmic examinations. Blood samples were collected and genomic DNA was extracted. Sequence analysis of the forkhead transcriptional factor 2 (FOXL2) gene was performed by direct sequencing and mutations were analyzed. Results Three mutations in FOXL2 were found in four families, including c.672_701dup30 (p.Ala224_Ala234dup10), c.313C>A (p.N105H), and c.430G>T (p.R144W). The c.672_701dup30 (p.Ala224_Ala234dup10) mutation was reported previously and predicted to result in expansions of the polyalanine tract. The mutations of c.313C>A (p. N105H) and c.430G>T (p.R144W) are two novel missense mutations. Conclusions Our study further supports the view that the expansion of the polyalanine tract is the hotspot of mutations within FOXL2. The two novel missense mutations detected in this study will expand the mutation spectrum of the FOXL2 gene and contribute to the research on the molecular pathogenesis of FOXL2. PMID:24265544

  5. Novel compound heterozygous mutations in MYO7A Associated with Usher syndrome 1 in a Chinese family.

    PubMed

    Gao, Xue; Wang, Guo-Jian; Yuan, Yong-Yi; Xin, Feng; Han, Ming-Yu; Lu, Jing-Qiao; Zhao, Hui; Yu, Fei; Xu, Jin-Cao; Zhang, Mei-Guang; Dong, Jiang; Lin, Xi; Dai, Pu

    2014-01-01

    Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP), and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1). Mutations in the MYO7A gene are responsible for USH1 and account for 29-55% of USH1 cases. Here, we characterized a Chinese family (no. 7162) with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R) and a novel nonsense mutation c.462C>A (p.C154X). The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A.

  6. A novel fibrillin-1 mutation in an egyptian marfan family: A proband showing nephrotic syndrome due to focal segmental glomerulosclerosis.

    PubMed

    Al-Haggar, Mohammad; Bakr, Ashraf; Wahba, Yahya; Coucke, Paul J; El-Hussini, Fatma; Hafez, Mona; Eid, Riham; Eid, Abdel-Rahman; Sarhan, Amr; Shaltout, Ali; Hammad, Ayman; Yahia, Sohier; El-Rifaie, Ahmad; Abdel-Hadi, Dina

    2017-01-01

    Marfan syndrome (MFS), the founding member of connective tissue disorder, is an autosomal dominant disease; it is caused by a deficiency of the microfibrillar protein fibrillin-1 (FBN1) and characterized by involvement of three main systems; skeletal, ocular, and cardiovascular. More than one thousand mutations in FBN1 gene on chromosome 15 were found to cause MFS. Nephrotic syndrome (NS) had been described in very few patients with MFS being attributed to membranoproliferative glomerulonephritis secondary to infective endocarditis. Focal segmental glomerulosclerosis (FSGS) had been reported in NS in conjunction with MFS without confirming the diagnosis by mutational analysis of FBN1. We hereby present an Egyptian family with MFS documented at the molecular level; it showed a male proband with NS secondary to FSGS, unfortunately, we failed to make any causal link between FBN dysfunction and FSGS. In this context, we review the spectrum of renal involvements occurring in MFS patients.

  7. Adjustment in mothers of children with Asperger syndrome: an application of the double ABCX model of family adjustment.

    PubMed

    Pakenham, Kenneth I; Samios, Christina; Sofronoff, Kate

    2005-05-01

    The present study examined the applicability of the double ABCX model of family adjustment in explaining maternal adjustment to caring for a child diagnosed with Asperger syndrome. Forty-seven mothers completed questionnaires at a university clinic while their children were participating in an anxiety intervention. The children were aged between 10 and 12 years. Results of correlations showed that each of the model components was related to one or more domains of maternal adjustment in the direction predicted, with the exception of problem-focused coping. Hierarchical regression analyses demonstrated that, after controlling for the effects of relevant demographics, stressor severity, pile-up of demands and coping were related to adjustment. Findings indicate the utility of the double ABCX model in guiding research into parental adjustment when caring for a child with Asperger syndrome. Limitations of the study and clinical implications are discussed.

  8. A novel EFNB1 mutation (c.712delG) in a family with craniofrontonasal syndrome and diaphragmatic hernia.

    PubMed

    Hogue, Jacob; Shankar, Suma; Perry, Hazel; Patel, Reena; Vargervik, Karin; Slavotinek, Anne

    2010-10-01

    We report on the occurrence of congenital diaphragmatic hernia in a family with craniofrontonasal syndrome found to have a previously unreported mutation in EFNB1. The female proband presented with hypertelorism, telecanthus, bifid nasal tip, widow's peak, frontal bossing, and a widened metopic suture. Her father was noted to have hypertelorism, telecanthus, widow's peak, and a history of pectus carinatum. He was found to have a previously unreported mutation in exon 5 of EFNB1 predicted to cause premature protein truncation. The parents of the proband previously had a female fetus with congenital diaphragmatic hernia. The occurrence of congenital diaphragmatic hernia, phenotypic differences between males and females, and utility of molecular testing in craniofrontonasal syndrome are demonstrated.

  9. Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families.

    PubMed

    McInerney-Leo, Aideen M; Harris, Jessica E; Gattas, Michael; Peach, Elizabeth E; Sinnott, Stephen; Dudding-Byth, Tracy; Rajagopalan, Sulekha; Barnett, Christopher P; Anderson, Lisa K; Wheeler, Lawrie; Brown, Matthew A; Leo, Paul J; Wicking, Carol; Duncan, Emma L

    2016-07-01

    Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation.

  10. The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families.

    PubMed

    Pinheiro, M; Pinto, C; Peixoto, A; Veiga, I; Mesquita, B; Henrique, R; Lopes, P; Sousa, O; Fragoso, M; Dias, L M; Baptista, M; Marinho, C; Mangold, E; Vaccaro, C; Evans, D G; Farrington, S; Dunlop, M G; Teixeira, M R

    2013-09-01

    The MSH2 c.388_389del mutation has occasionally been described in Lynch families worldwide. At the Portuguese Oncology Institute in Porto, Portugal, we have identified 16 seemingly unrelated families with this germline mutation. To evaluate if this alteration is a founder or a recurrent mutation we performed haplotype analysis in the 16 Portuguese index cases and 55 relatives, as well as in four index cases and 13 relatives reported from Germany, Scotland, England, and Argentina. In the Portuguese families we observed a shared haplotype of approximately 10 Mb and all were originated from the north of Portugal. These results suggest that this alteration is a founder mutation in Portugal with a relatively recent origin. In the reported families outside Portugal with this mutation different haplotype backgrounds were observed, supporting the hypothesis that it occurred de novo on multiple occasions. We also conclude that the high proportion of families with the MSH2 c.388_389del mutation indicates that screening for this alteration as a first step may be cost-effective in the genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the north of Portugal.

  11. The incidence of deafness is non-randomly distributed among families segregating for Waardenburg syndrome type 1 (WS1).

    PubMed Central

    Morell, R; Friedman, T B; Asher, J H; Robbins, L G

    1997-01-01

    Waardenburg syndrome (WS) is caused by autosomal dominant mutations, and is characterised by pigmentary anomalies and various defects of neural crest derived tissues. It accounts for over 2% of congenital deafness. WS shows high variability in expressivity within families and differences in penetrance of clinical traits between families. While mutations in the gene PAX3 seem to be responsible for most, if not all, WS type 1, it is still not clear what accounts for the reduced penetrance of deafness. Stochastic events during development may be the factors that determine whether a person with a PAX3 mutation will be congenitally deaf or not. Alternatively, genetic background or non-random environmental factors or both may be significant. We compared the likelihoods for deafness in affected subjects from 24 families with reported PAX3 mutations, and in seven of the families originally described by Waardenburg. We found evidence that stochastic variation alone does not explain the differences in penetrances of deafness among WS families. Our analyses suggest that genetic background in combination with certain PAX3 alleles may be important factors in the aetiology of deafness in WS. Images PMID:9192262

  12. Lack of plasma membrane targeting of a G172D mutant thiamine transporter derived from Rogers syndrome family.

    PubMed Central

    Baron, Dana; Assaraf, Yehuda G.; Cohen, Nadine; Aronheim, Ami

    2002-01-01

    BACKGROUND: Rogers syndrome, also known as thiamine responsive megaloblastic anemia (TRMA), is an autosomal recessive disorder resulting in megaloblastic anemia, diabetes mellitus and sensorineural deafness. The gene associated with Rogers syndrome encodes for a plasma membrane thiamine transporter, THTR-1, a member of the solute carrier family that includes its homologue THTR-2 and the reduced folate carrier. MATERIALS AND METHODS: Using transient expression of wild-type and a missense mutant THTR-1 protein, derived from a TRMA family, in different cell lines and immunodetection analysis, we determined the expression, posttranslational modification, and subcellular localization of the wild-type and G172D mutant THTR-1. The transport activity of the transfected THTR-1 proteins was measured using a [(3) H] thiamine uptake assay. RESULTS: The mutant THTR-1 protein was undetectable in transfected cells grown at 37 degrees C but was readily expressed in transfected cells cultured at 28 degrees C, thereby allowing for further biochemical and functional analysis. In contrast to its fully glycosylated wild-type mature protein, the mutant THTR-1 protein underwent only the initial stage of N-linked glycosylation. The failure to undergo a complete glycosylation resulted in the lack of plasma membrane targeting and confinement of the mutant THTR-1 to the Golgi and endoplasmic reticulum (ER) compartment. Consistently, either treatment with tunicamycin or substitution of the THTR-1 consensus N-glycosylation acceptor asparagine 63 with glutamine, abolished its glycosylation and plasma membrane targeting. CONCLUSIONS: Taken collectively, these results suggest that the G172D mutation presumably misfolded THTR-1 protein that fails to undergo a complete glycosylation, is retained in the Golgi-ER compartment and thereby cannot be targeted to the plasma membrane. Finally, transfection studies revealed that the mutant G172D THTR-1 failed to transport thiamine. This is the first

  13. The "Dance" of Communication: Counseling Families and Children with Asperger's Syndrome

    ERIC Educational Resources Information Center

    Lozzi-Toscano, Bettina

    2004-01-01

    Counselors are trained to deal with many issues within the realm of human experience; many specialize in helping families cope with a variety of internal and external stressors. However, counselors are seldom given all the tools to handle the myriad possible difficulties families may encounter. When counselors are asked to help families cope with…

  14. Clinical features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family.

    PubMed

    Ying, Yan-Qin; Wei, Hong; Cao, Li-Zhi; Lu, Juan-Juan; Luo, Xiao-Ping

    2007-08-01

    Laron syndrome is an autosomal recessive disorder caused by defects of growth hormone receptor (GHR) gene. It is characterized by severe postnatal growth retardation and characteristic facial features as well as high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). This report described the clinical features and GHR gene mutations in 2 siblings with Laron syndrome in a Chinese family. Their heights and weights were in the normal range at birth, but the growth was retarded after birth. When they presented to the clinic, the heights of the boy (8 years old) and his sister (11 years old) were 80.0 cm (-8.2 SDS) and 96.6 cm (-6.8 SDS) respectively. They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. They had higher basal serum GH levels and lower serum levels of IGF-I, IGFBP-3 and growth hormone binding protein (GHBP) than normal controls. The peak serum GH level after colonidine and insulin stimulations in the boy was over 350 ng/mL. After one-year rhGH treatment, the boy's height increased from 80.0 cm to 83.3 cm. The gene mutation analysis revealed that two patients had same homozygous mutation of S65H (TCA -->CCA) in exon 4, which is a novel gene mutation. It was concluded that a definite diagnosis of Laron syndrome can be made based on characteristic appearance features and serum levels of GH, IGF-I, IGFBP-3 and GHBP. The S65H mutation might be the cause of Laron syndrome in the two patients.

  15. Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clincal review with six additional families

    SciTech Connect

    Schrander-Stumpel, C.; Hoeweler, C.; Jones, M.

    1995-05-22

    X-linked hydrocephalus (HSAS) (MIM{sup *}307000), MASA syndrome (MIM {sup *}303350), and complicated spastic paraplegia (SPG1) (MIM {sup *}3129000) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previous reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1. 79 refs., 6 figs., 2 tabs.

  16. A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.

    PubMed

    Cassidy, Andrew J; van Steensel, Maurice A M; Steijlen, Peter M; van Geel, Michel; van der Velden, Jaap; Morley, Susan M; Terrinoni, Alessandro; Melino, Gerry; Candi, Eleonora; McLean, W H Irwin

    2005-12-01

    Peeling skin syndrome is an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis. In the acral form, the dorsa of the hands and feet are predominantly affected. Ultrastructural analysis has revealed tissue separation at the junction between the granular cells and the stratum corneum in the outer epidermis. Genomewide linkage analysis in a consanguineous Dutch kindred mapped the gene to 15q15.2 in the interval between markers D15S1040 and D15S1016. Two homozygous missense mutations, T109M and G113C, were found in TGM5, which encodes transglutaminase 5 (TG5), in all affected persons in two unrelated families. The mutation was present on the same haplotype in both kindreds, indicating a probable ancestral mutation. TG5 is strongly expressed in the epidermal granular cells, where it cross-links a variety of structural proteins in the terminal differentiation of the epidermis to form the cornified cell envelope. An established, in vitro, biochemical cross-linking assay revealed that, although T109M is not pathogenic, G113C completely abolishes TG5 activity. Three-dimensional modeling of TG5 showed that G113C lies close to the catalytic domain, and, furthermore, that this glycine residue is conserved in all known transglutaminases, which is consistent with pathogenicity. Other families with more-widespread peeling skin phenotypes lacked TGM5 mutations. This study identifies the first causative gene in this heterogeneous group of skin disorders and demonstrates that the protein cross-linking function performed by TG5 is vital for maintaining cell-cell adhesion between the outermost layers of the epidermis.

  17. Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease

    PubMed Central

    van der Crabben, Saskia N.; Hennus, Marije P.; McGregor, Grant A.; Ritter, Deborah I.; Nagamani, Sandesh C.S.; Wells, Owen S.; Harakalova, Magdalena; Chinn, Ivan K.; Alt, Aaron; Vondrova, Lucie; Hochstenbach, Ron; van Montfrans, Joris M.; Terheggen-Lagro, Suzanne W.; van Lieshout, Stef; van Roosmalen, Markus J.; Renkens, Ivo; Duran, Karen; Nijman, Isaac J.; Kloosterman, Wigard P.; Hennekam, Eric; van Hasselt, Peter M.; Wheeler, David A.; Palecek, Jan J.; Lehmann, Alan R.; Oliver, Antony W.; Pearl, Laurence H.; Plon, Sharon E.; Murray, Johanne M.

    2016-01-01

    The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood. PMID:27427983

  18. A comparison of salivary IgA in children with Down syndrome and their family members.

    PubMed

    Balaji, Karthika; Milne, Trudy J; Drummond, Bernadette K; Cullinan, Mary P; Coates, Dawn E

    2016-07-01

    The aim of this study was to compare total IgA in the whole saliva of children with Down syndrome with levels in sibling and parent groups. IgA measurements were presented as the concentration in saliva (μg/ml) and also adjusted for salivary flow rate (SFR; μg/min). Twenty children with Down syndrome, ten siblings and twenty parents were recruited. Stimulated whole saliva was collected from the participants and SFR calculated. The measurement of salivary IgA (sIgA) was carried out using an indirect competitive Enzyme-Linked Immunosorbent Assay. The difference in the mean SFR between children with Down syndrome, parents and siblings were not statistically significant. The mean salivary concentration of IgA was higher in children with Down syndrome (95.1 μg/ml) compared with siblings (48.3 μg/ml; p=0.004). When adjusted for SFR children with Down syndrome had mean sIgA levels of 98.8 μg/min and the siblings 48.6 μg/min (p=0.008). The children with Down syndrome had sIgA levels similar to those of the parents (92.5 μg/ml; 93.2 μg/min). There was a positive correlation between age and sIgA concentration in the siblings (p=0.008) but not for children with Down syndrome (p=0.363). This suggests that under similar environmental influences, the levels of sIgA in children with Down syndrome are higher than in the siblings, from a very young age.

  19. Familial occurrence of Danish and Dutch cases of the bovine brachyspina syndrome

    PubMed Central

    Agerholm, Jørgen S; Peperkamp, Klaas

    2007-01-01

    Background The bovine brachyspina syndrome is a recently reported malformation in the Holstein breed. The aetiology of this syndrome is unknown, but its occurrence following breeding between genetically related and phenotypically normal cattle may indicate that it is an autosomal recessively inherited disorder. Three cases are reported and compared to the originally reported case. Case presentation Two Danish cases and a Dutch case are described. The calves were delivered following a slightly prolonged gestation period. Gross lesions consisted of growth retardation, significant shortening of the entire spine and long and slender limbs. Additionally, inferior brachygnatism and defects of several internal organs were recorded. The cases were diagnosed as having the brachyspina syndrome based on the presence of essential lesions. The parents of each case were genetically related and linked to the first reported case by a common ancestor. Conclusion The findings support the hypothesis that the brachyspina syndrome in Holstein cattle is inherited autosomal recessively and illustrate some of the assumed phenotypical variation of this syndrome. The brachyspina syndrome may be an emerging disease in the Holstein breed. PMID:17488494

  20. Nonimmune fetal hydrops and placentomegaly: Diagnosis of familial Wiedemann-Beckwith syndrome with trisomy 11p15 using FISH

    SciTech Connect

    Drut, R.M.; Drut, R.

    1996-03-15

    We have studied a family in which four members of the same generation were affected with Wiedemann-Beckwith syndrome (WBS). Trisomy 11p15 was demonstrated using molecular probes in interphase nuclei of formalin-fixed paraffin-embedded placenta from a stillborn fetus and in peripheral blood lymphocytes from two liveborn female relatives. Clinical examination showed nonimmune hydrops and placentomegaly in two siblings and multiple phenotypic abnormalities consistent with WBS in the two other relatives. Paternal karyotype of the stillborn infants demonstrated a reciprocal translocation (46,XY,t(10;11) (q26;p15)) explaining the origin of the extra 11p15 material. This study illustrates the advantages of FISH for interphase analysis of chromosome aberrations otherwise not detected even by conventional cytogenetic analysis and documents that nonimmune hydrops associated with placentomegaly may be presenting features in familial WBS. 24 refs., 6 figs.

  1. Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3)

    SciTech Connect

    Clarke, R.A.; Kearsley, J.H.; Singh, S.

    1995-12-01

    Klippel-Feil syndrome (KFS) is characterized by congenital vertebral fusion believed to result from faulty segmentation along the embryo`s developing axis. KFS appears to be a heterogeneous disease often associated with craniofacial malformation. Here we provide the first evidence of a familial KFS gene locus on 8q, where an inv(8)(q22.2q23.3) has been found segregating with congenital vertebral fusion. The four-generation KF2-01 family present with a dominant form of the KFS where the sequence of vertebral fusion was confined to the cervical spine (always including the C2-3 fusion and reduced expression of the C4-5 and C6-7 fusions) in association with malformation of laryngeal cartilages and mild-to-severe vocal impairment. 32 refs., 4 figs., 1 tab.

  2. Unusual (CGG)n expansion and recombination in a family with fragile X and DiGeorge syndrome.

    PubMed

    Macpherson, J N; Curtis, G; Crolla, J A; Dennis, N; Migeon, B; Grewal, P K; Hirst, M C; Davies, K E; Jacobs, P A

    1995-03-01

    In a fragile X family referred for prenatal diagnosis, the female fetus did not inherit the full fragile X mutation from her mother, but an unexpected expansion within the normal range of CGG repeats from 29 to 39 was observed in the paternal X chromosome. Also, a rare recombination between DXS548 and FRAXAC1 was recorded in the maternal meiosis. Follow up of the neonate confirmed the same DNA genotype as in the CVS, but the child died of DiGeorge syndrome after four days and was subsequently found to carry a microdeletion of chromosome 22 using probe cEO. It is suggested that in this family the deletion of chromosome 22 is likely to be a chance event but the rare recombinant and the fragile X mutation might be causally related.

  3. Miller-Dieker syndrome resulting from rearrangement of a familial chromosome 17 inversion detected by fluorescence in situ hybridisation.

    PubMed Central

    Kingston, H M; Ledbetter, D H; Tomlin, P I; Gaunt, K L

    1996-01-01

    We report a case of Miller-Dieker syndrome (MDS) owing to an unbalanced rearrangement of a familial pericentric inversion of chromosome 17 (inv(17) (p13.3q25.1)). In addition to lissencephaly and the facial features of MDS, the affected child had other congenital malformations consistent with distal 17q duplication. Initial cytogenetic analysis failed to show any abnormality and fluorescence in situ hybridisation (FISH) studies confirmed the 17p deletion in the proband and identified the chromosome 17 inversion in his mother. FISH studies were performed in other relatives and enabled first trimester prenatal diagnosis by chorionic villus sampling in a subsequent pregnancy of the proband's mother. These findings underline the value of FISH in the investigation of MDS families. Images PMID:8825053

  4. Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11.2-11.1.

    PubMed Central

    Sertié, A L; Sousa, A V; Steman, S; Pavanello, R C; Passos-Bueno, M R

    1999-01-01

    van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS. PMID:10417286

  5. Easing the Burden: Describing the Role of Social, Emotional and Spiritual Support in Research Families with Li-Fraumeni Syndrome.

    PubMed

    Peters, June A; Kenen, Regina; Bremer, Renee; Givens, Shannon; Savage, Sharon A; Mai, Phuong L

    2016-06-01

    This study presents findings of a mixed-method descriptive exploration of the role of friends and spirituality/religiosity in easing the burden of families with the rare inherited disorder, Li-Fraumeni Syndrome (LFS). LFS is caused by germline mutations in the TP53 gene and is associated with very high lifetime risk of developing one or more malignancies. During the first clinical visit we assessed several types of social support among a subset of study participants (N = 66) using an established interactive research tool called the Colored Eco-Genetic Relationship Map (CEGRM). We performed both quantitative and qualitative analyses of social relationships with LFS family members and close non-kin. Distress scores (N = 59) were mostly low normal, with some outliers. We found that reported friendships varied widely, that the friendships were often deep and enduring, and were important sources of informational, tangible, emotional and spiritual support. Confidantes tended to be best friends and/or spouses. Organized religion was important in selected families, typically from mainstream traditions. However, a number of people identified themselves as "spiritual" and reported spiritual and humanist explorations. Our results shed preliminary light on how some people in families with LFS cope in the face of tremendous medical, social and emotional challenges.

  6. VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study.

    PubMed

    Calderón, Juan Francisco; Puga, Alonso R; Guzmán, M Luisa; Astete, Carmen Paz; Arriaza, Marta; Aracena, Mariana; Aravena, Teresa; Sanz, Patricia; Repetto, Gabriela M

    2009-01-01

    Microdeletion 22q11 in humans causes velocardiofacial and DiGeorge syndromes. Most patients share a common 3Mb deletion, but the clinical manifestations are very heterogeneous. Congenital heart disease is present in 50-80% of patients and is a significant cause of morbidity and mortality. The phenotypic variability suggests the presence of modifiers. Polymorphisms in the VEGFA gene, coding for the vascular endothelial growth factor A, have been associated with non-syndromic congenital heart disease, as well as with the presence of cardiovascular anomalies in patients with microdeletion 22q11. We evaluated the association of VEGFA polymorphisms c.-2578C>A (rs699947), c.-1154G>A (rs1570360) and c.-634C>G (rs2010963) with congenital heart disease in Chilean patients with microdeletion 22q11. The study was performed using case-control and family-based association designs. We evaluated 122 patients with microdeletion 22q11 and known anatomy of the heart and great vessels, and their parents. Half the patients had congenital heart disease. We obtained no evidence of association by either method of analysis. Our results provide further evidence of the incomplete penetrance of the cardiovascular phenotype of microdeletion 22ql 1, but do not support association between VEGFA promoter polymorphisms and the presence of congenital heart disease in Chilean patients with this syndrome.

  7. Inheritance of skewed X chromosome inactivation in a large family with an X-linked recessive deafness syndrome

    SciTech Connect

    Orstavik, K.H.; Orstavik, R.E.; Eiklid, K.; Tranebjaerg, L.

    1996-07-12

    A new X-linked recessive deafness syndrome was recently reported and mapped to Xq22 (Mohr-Tranebjaeerg syndrome). In addition to deafness, the patients had visual impairment, dystonia, fractures, and mental deterioration. The female carriers did not have any significant manifestations of the syndrome. We examined X chromosome inactivation in 8 obligate and 12 possible carriers by using a polymerase chain reaction analysis of the methylation-dependent amplification of the polymorphic triplet repeat at the androgen receptor locus. Seven of 8 obligate carriers and 1 of 5 carriers by linkage analysis had an extremely skewed pattern in blood DNA not found in 30 normal females. The X inactivation pattern in fibroblast DNA from 2 of the carriers with the extremely skewed pattern was also skewed but to a lesser degree than in blood DNA. One obligate carrier had a random X inactivation pattern in both blood and fibroblast DNA. A selection mechanism for the skewed pattern is therefore not likely. The extremely skewed X inactivation in 8 females of 3 generations in this family may be caused by a single gene that influences skewing of X chromosome inactivation. 22 refs., 2 figs., 1 tab.

  8. Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome.

    PubMed

    Sirotkin, H; O'Donnell, H; DasGupta, R; Halford, S; St Jore, B; Puech, A; Parimoo, S; Morrow, B; Skoultchi, A; Weissman, S M; Scambler, P; Kucherlapati, R

    1997-04-01

    Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS) are characterized by a wide spectrum of phenotypes, including conotruncal heart defects, cleft palate, and facial dysmorphology. Hemizygosity for a portion of chromosome 22q11 has been detected in 80-85% of VCFS/DGS patients. Both syndromes are thought to be the result of a developmental field defect. Using two independent gene-isolation procedures, we isolated a new catenin family member termed ARVCF (armadillo repeat gene deleted in VCFS) from the interval deleted in VCFS. ARVCF encodes a protein of 962 amino acids that contains a coiled coil domain and 10 tandem armadillo repeats. The primary structure of the protein is most closely related to the murine catenin p120CAS, which suggests a role for ARVCF in protein-protein interactions at adherens junctions. ARVCF is expressed ubiquitously in all fetal and adult tissues examined. This gene is hemizygous in all VCFS patients with interstitial deletions. Based on the physical location and potential functions of ARVCF, we suggest that hemizygosity at this locus may play a role in the etiology of some of the phenotypes associated with VCFS.

  9. Further localization of the gene for nevoid basal cell carcinoma syndrome (NBCCS) in 15 Australasian families: Linkage and loss of heterozygosity

    SciTech Connect

    Chenevix-Trench, G.; Wicking, C.; Berkman, J.; Sharpe, H.; Hockey, A.; Haan, E.; Oley, C.; Ravine, D.; Turner, A.; Searle, J.

    1993-09-01

    Nevoid basal cell carcinoma syndrome (NBCCS; basal cell nevus syndrome or Gorlin syndrome) is a cancer-predisposition syndrome characterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene for NBCCS has been mapped to 9q23.1-q31 in North Americal and European families. In addition, loss of heterozygosity (LOH) for genetic markers in this region has been detected in sporadic BCCs, indicating that the NBCCs gene is probably a tumor-suppressor gene. In this study the authors have determined that the NBCCS gene is also linked to this region in Australasian pedigrees and that there is no significant evidence of heterogeneity. They have defined the localization of the gene by multipoint and haplotype analysis of 15 families, using four microsatellite markers. LOH at these loci was detected in 50% of sporadic BCCs, a rate that is significantly higher than that in other skin lesions used as controls. 21 refs., 3 figs., 2 tabs.

  10. Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16.

    PubMed Central

    Szepetowski, P; Rochette, J; Berquin, P; Piussan, C; Lathrop, G M; Monaco, A P

    1997-01-01

    Benign infantile familial convulsions is an autosomal dominant disorder characterized by nonfebrile seizures, with the first attack occurring at age 3-12 mo. It is one of the rare forms of epilepsy that are inherited as monogenic Mendelian traits, thus providing a powerful tool for mapping genes involved in epileptic syndromes. Paroxysmal choreoathetosis is an involuntary-movement disorder characterized by attacks that occur spontaneously or are induced by a variety of stimuli. Classification is still elusive, and the epileptic nature of this movement disorder has long been discussed and remains controversial. We have studied four families from northwestern France in which benign infantile convulsions was inherited as an autosomal dominant trait together with variably expressed paroxysmal choreoathetosis. The human genome was screened with microsatellite markers regularly spaced, and strong evidence of linkage for the disease gene was obtained in the pericentromeric region of chromosome 16, with a maximum two-point LOD score, for D16S3133, of 6.76 at a recombination fraction of 0. Critical recombinants narrowed the region of interest to a 10-cM interval around the centromere. Our study provides the first genetic evidence for a common basis of convulsive and choreoathetotic disorders and will help in the understanding and classification of paroxysmal neurological syndromes. PMID:9382100

  11. 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.

  12. A clinical case study of a Wolfram syndrome-affected family: pattern-reversal visual evoked potentials and electroretinography analysis.

    PubMed

    Langwińska-Wośko, Ewa; Broniek-Kowalik, Karina; Szulborski, Kamil

    2012-04-01

    Wolfram syndrome (WFS), or DIDMOAD, is a rare (1/100 000 to 1/770 000), progressive neurodegenerative disorder. In its early stages, it is characterized by insulin-dependent diabetes mellitus, optic atrophy and loss of sensorineural hearing-this is followed by diabetes insipidus, progressive neurological abnormalities and other endocrine abnormalities, which occur in later years. The aim of this study was to report on the clinical and electrophysiological findings from a family with the WFS1 mutation. The five family members were subjected to a complete ophthalmic examination, which included a flash full-field electroretinogram and pattern-reversal visual evoked potentials (PVEPs) performed according to ISCEV standards. Optic atrophy was confirmed in two homozygotic patients, where P100 latencies were significantly delayed-up to 146 ms in PVEP. P100 latencies were normal in the three heterozygotic patients we examined. Curve morphology abnormalities were observed in all five patients we examined. No literature describing the morphology of PVEP in Wolfram syndrome patients was found. In flash electroretinography, scotopic and photopic responses appeared in normal morphology and value. Diabetic retinopathy was not observed in the diabetes mellitus patients.

  13. Novel and recurrent mutations in the TAT gene in Tunisian families affected with Richner-Hanhart syndrome.

    PubMed

    Bouyacoub, Yosra; Zribi, Hela; Azzouz, Hatem; Nasrallah, Fehmi; Abdelaziz, Rim Ben; Kacem, Monia; Rekaya, Ben; Messaoud, Olfa; Romdhane, Lilia; Charfeddine, Cherine; Bouziri, Mustapha; Bouziri, Sonia; Tebib, Neji; Mokni, Mourad; Kaabachi, Naziha; Boubaker, Samir; Abdelhak, Sonia

    2013-10-15

    Tyrosinemia type II, also designated as oculocutaneous tyrosinemia or Richner-Hanhart syndrome (RHS), is a very rare autosomal recessive disorder. In the present study, we report clinical features and molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in two young patients, both born to consanguineous unions between first-degree cousins. These two unrelated families originated from Northern and Southern Tunisia. The clinical diagnosis was based on the observation of several complications related to Richner-Hanhart syndrome: recurrent eye redness, tearing and burning pain, photophobia, bilateral pseudodendritic keratitis, an erythematous and painful focal palmo-plantar hyperkeratosis and a mild delay of mental development. The diagnosis was confirmed by biochemical analysis. Sequencing of the TAT gene revealed the presence of a previously reported missense mutation (c.452G>A, p.Cys151Tyr) in a Tunisian family, and a novel G duplication (c.869dupG, p.Trp291Leufs 6). Early diagnosis of RHS and protein-restricted diet are crucial to reduce the risk and the severity of long-term complications of hypertyrosinemia such as intellectual disability.

  14. Marfan Syndrome

    MedlinePlus

    ... Like for Kids With Marfan Syndrome? en español Síndrome de Marfan Evan couldn't wait for school ... for Marfan syndrome runs in families, getting passed down to children from parents who have the disease. ...

  15. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon 22, Q[22]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in...

  16. Familial recurrent hypersomnia: two siblings with Kleine-Levin syndrome and menstrual-related hypersomnia.

    PubMed

    Rocamora, Rodrigo; Gil-Nagel, Antonio; Franch, Oriol; Vela-Bueno, Antonio

    2010-11-01

    Kleine-Levin syndrome and menstrual-related hypersomnia are rare idiopathic sleep disorders occurring primarily in adolescence. They are characterized by intermittent periods of excessive sleepiness, cognitive disturbances, and behavioral abnormalities. In both, the etiology remains unknown but autoinmune, hormonal, infectious, and inflammatory mechanisms have been proposed. The authors describe, for the first time, the association of Kleine-Levin syndrome and menstrual-related hypersomnia in 2 adolescent siblings who shared the human leukocyte antigen (HLA) loci DQB1*0501. The same haplotype has been associated with sleepwalking and with rapid eye movement (REM) sleep behavior disorder. This gender differences in the manifestation of a probably genetic influenced sleep disorder suggests that hormonal mechanisms could be implicated in the phenotypical expression of this sleep disorder. The male sibling with Kleine-Levin syndrome was easily controlled with carbamazepine in low doses, but his sister could be only efficaciously treated with oral contraceptives.

  17. Two cases of partial trisomy 10q syndrome due to a familial 10;20 translocation.

    PubMed

    Tüysüz, B; Hacihanefioglu, S; Silahtaroglu, A; Yilmaz, S; Deviren, A; Cenani, A

    2000-01-01

    We describe an eleven day-old boy and his first degree double cousin who both have distal trisomy 10q syndrome. Their cytogenetic analysis using GTG-banding showed an unbalanced translocation 46, XY, -20, +der(20), t(10;20)(q22.3, p11) mat and 46, XX, -20, +der(20), t(10;20)(q22.3, p11) mat. The translocation was confirmed by FISH. We have found balanced translocation t(10;20)(q22.3; p11) with cytogenetic and FISH studies in the mothers and maternal grandfather of these children. Our cases had typical craniofacial and visceral anomalies of this syndrome. However case 1 had an agenesia of corpus callosum which was not previously described and case 2 had hypertrophied cardiomyopathy and cliteromegaly which were previously described as rare anomalies for this syndrome.

  18. The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families

    PubMed Central

    Tuppen, Helen A. L.; Hogan, Vanessa E.; He, Langping; Blakely, Emma L.; Worgan, Lisa; Al-Dosary, Mazhor; Saretzki, Gabriele; Alston, Charlotte L.; Morris, Andrew A.; Clarke, Michael; Jones, Simon; Devlin, Anita M.; Mansour, Sahar; Chrzanowska-Lightowlers, Zofia M. A.; Thorburn, David R.; McFarland, Robert

    2010-01-01

    Isolated complex I deficiency is the most frequently observed oxidative phosphorylation defect in children with mitochondrial disease, leading to a diverse range of clinical presentations, including Leigh syndrome. For most patients the genetic cause of the biochemical defect remains unknown due to incomplete understanding of the complex I assembly process. Nonetheless, a plethora of pathogenic mutations have been described to date in the seven mitochondrial-encoded subunits of complex I as well as in 12 of the nuclear-encoded subunits and in six assembly factors. Whilst several mitochondrial DNA mutations are recurrent, the majority of these mutations are reported in single families. We have sequenced core structural and functional nuclear-encoded subunits of complex I in a cohort of 34 paediatric patients with isolated complex I deficiency, identifying pathogenic mutations in 6 patients. These included a novel homozygous NDUFS1 mutation in an Asian child with Leigh syndrome, a previously identified NDUFS8 mutation (c.236C>T, p.P79L) in a second Asian child with Leigh-like syndrome and six novel, compound heterozygous NDUFS2 mutations in four white Caucasian patients with Leigh or Leigh-like syndrome. Three of these children harboured an identical NDUFS2 mutation (c.875T>C, p.M292T), which was also identified in conjunction with a novel NDUFS2 splice site mutation (c.866+4A>G) in a fourth Caucasian child who presented to a different diagnostic centre, with microsatellite and single nucleotide polymorphism analyses indicating that this was due to an ancient common founder event. Our results confirm that NDUFS2 is a mutational hotspot in Caucasian children with isolated complex I deficiency and recommend the routine diagnostic investigation of this gene in patients with Leigh or Leigh-like phenotypes. PMID:20819849

  19. Hereditary Colorectal Cancer Syndromes: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the Familial Risk–Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guidelines

    PubMed Central

    Stoffel, Elena M.; Mangu, Pamela B.; Gruber, Stephen B.; Hamilton, Stanley R.; Kalady, Matthew F.; Lau, Michelle Wan Yee; Lu, Karen H.; Roach, Nancy; Limburg, Paul J.

    2015-01-01

    Purpose To provide recommendations on prevention, screening, genetics, treatment, and management for people at risk for hereditary colorectal cancer (CRC) syndromes. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The Familial Risk–Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guideline published in 2013 on behalf of the European Society for Medical Oncology (ESMO) Guidelines Working Group in Annals of Oncology was reviewed for developmental rigor by methodologists, with content and recommendations reviewed by an ASCO endorsement panel. Results The ASCO endorsement panel determined that the recommendations of the ESMO guidelines are clear, thorough, and based on the most relevant scientific evidence. The ASCO panel endorsed the ESMO guidelines and added a few qualifying statements. Recommendations Approximately 5% to 6% of patient cases of CRC are associated with germline mutations that confer an inherited predisposition for cancer. The possibility of a hereditary cancer syndrome should be assessed for every patient at the time of CRC diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management for patients with CRC and their family members. Screening for hereditary cancer syndromes in patients with CRC should include review of personal and family histories and testing of tumors for DNA mismatch repair deficiency and/or microsatellite instability. Formal genetic evaluation is recommended for individuals who meet defined criteria. PMID:25452455

  20. Broad scan linkage analysis in a large Tourette family pedigree

    SciTech Connect

    Peiffer, A.; Leppert, M.; Wetering, B.J.M. van der

    1994-09-01

    Attempts to find a gene causing Tourette syndrome (TS) using linkage analysis have been unsuccessful even though as much as 65% of the autosomal genetic map has been excluded by the pooled results from several laboratories collaborating worldwide. One reason for this failure may be the misclassification of affection status of marry-in spouses. Specifically, we have found that six unrelated spouses in our Utah TS pedigree suffer from TS, obsessive-compulsive disorder or chronic motor tics. In light of these findings we decided to conduct a complete genomic scan from this Utah kindred with polymorphic markers in three related sibships in which there was no assortative mating. A linkage study assuming autosomal dominant inheritance was done using tetranucleotide repeat markers developed at the University of Utah. We selected markers that were less than 300 bp in size and that gave a heterozygosity of over 70% upon analysis in 4 CEPH families. Results to date with 95 markers run at an interval of 30 cM (covering 61% of the genome) show no evidence of linkage. We intend to extend the coverage to 100% of the genome. Pending completion of this scan, failure to provide evidence of linkage in our TS pedigree might then be attributed to phenotypic misclassification or erroneous assumptions regarding the genetic model of transmission.

  1. Evolution of the RECQ family of helicases: A drosophila homolog, Dmblm, is similar to the human bloom syndrome gene.

    PubMed Central

    Kusano, K; Berres, M E; Engels, W R

    1999-01-01

    Several eukaryotic homologs of the Escherichia coli RecQ DNA helicase have been found. These include the human BLM gene, whose mutation results in Bloom syndrome, and the human WRN gene, whose mutation leads to Werner syndrome resembling premature aging. We cloned a Drosophila melanogaster homolog of the RECQ helicase family, Dmblm (Drosophila melanogaster Bloom), which encodes a putative 1487-amino-acid protein. Phylogenetic and dot plot analyses for the RECQ family, including 10 eukaryotic and 3 prokaryotic genes, indicate Dmblm is most closely related to the Homo sapiens BLM gene, suggesting functional similarity. Also, we found that Dmblm cDNA partially rescued the sensitivity to methyl methanesulfonate of Saccharomyces cerevisiae sgs1 mutant, demonstrating the presence of a functional similarity between Dmblm and SGS1. Our analyses identify four possible subfamilies in the RECQ family: (1) the BLM subgroup (H. sapiens Bloom, D. melanogaster Dmblm, and Caenorhabditis elegans T04A11.6); (2) the yeast RECQ subgroup (S. cerevisiae SGS1 and Schizosaccharomyces pombe rqh1/rad12); (3) the RECQL/Q1 subgroup (H. sapiens RECQL/Q1 and C. elegans K02F3.1); and (4) the WRN subgroup (H. sapiens Werner and C. elegans F18C5.2). This result may indicate that metazoans hold at least three RECQ genes, each of which may have a different function, and that multiple RECQ genes diverged with the generation of multicellular organisms. We propose that invertebrates such as nematodes and insects are useful as model systems of human genetic diseases. PMID:10049920

  2. A Williams syndrome patient with a familial t(6;7) translocation and deletion of the elastin gene

    SciTech Connect

    Pober, B.R.; Gibson, L.H.; Yang-Feng, T.L.

    1994-09-01

    Discovery of a {open_quotes}balanced{close_quotes} reciprocal translocation [46,XX,t(6;7)(q11.2;q11.23)] on routine amniocentesis prompted clinical and cytogenetic study of additional family members. The same t(6;7) translocation was found in the clincally normal father and in a sibling with Williams syndrome (WS). WS had been diagnosed previously according to clinical criteria including distinctive facial features, supravalvar aortic stenosis requiring surgical repair, dental abnormalties and developmental delay. A clinically normal female was delivered and the translocation was confirmed with a cord blood specimen. Hemizygosity for the gene, elastin, (which has been mapped to the chromosome 7 translocation breakpoint, 7q11.23, in this family) appears to be a cause of WS. We therefore investigated whether the t(6;7) in the phenotypically normal father represented more than a simple reciprocal translocation. FISH using a chromosome 7 specific library revealed no differences between the cytogenetically identical, yet phenotypically distinct, father and son. Hybridization with a cosmid MR127D4 containing elastin sequence showed that the WS patient was missing one allele from the derivative chromosome 7 whereas both his mother and father had two copies of the elastin gene. This family indicates that the de novo loss of one copy of the elastin gene produces the recognizable phenotype of Williams syndrome. Molecular characterization (with additional probes) of the extent of this de novo deletion near the translocation breakpoint is in progress. This information will be valuable for defining the WS-critical region and will lead to a better understanding of the molecular basis for WS.

  3. Fetal Alcohol Syndrome and Fetal Alcohol Effects-- Support for Teachers and Families.

    ERIC Educational Resources Information Center

    Duckworth, Susanna V.; Norton, Terry L.

    2000-01-01

    Reviews genesis of fetal alcohol syndrome and fetal alcohol effects in children. Identifies physical characteristics and behavioral indicators found and provides three checklists of observable signs for both disorders. Recommends seven steps for educators to follow in seeking assistance with these conditions. (DLH)

  4. Chromosome 14 and late-onset familial alzheimer disease (FAD)

    SciTech Connect

    Schellenberg, G.D.; Anderson, L.; Nemens, E.; Bird, T.D.; Wijsman, E.M.; Martin, G.M.; Payami, H.; Orr, H.T.; White, J.A.; Alonso, M.E.

    1993-09-01

    Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analysis were used, in 49 families with a mean age at onset [>=]60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score [>=]2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P<.02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset [>=]60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds. 37 refs., 1 fig., 6 tabs.

  5. Chromosome 14 and late-onset familial Alzheimer disease (FAD)

    PubMed Central

    Schellenberg, Gerard D.; Payami, Haydeh; Wijsman, Ellen M.; Orr, Harry T.; Goddard, Katrina A. B.; Anderson, Leojean; Nemens, Ellen; White, June A.; Alonso, M. Elisa; Ball, Melvyn J.; Kaye, Jeffrey; Morris, John C.; Chui, Helena; Sadovnick, A. Dessa; Heston, Leonard L.; Martin, George M.; Bird, Thomas D.

    1993-01-01

    Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analyses were used, in 49 families with a mean age at onset ≥60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score ≤ –2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P < .02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset ≥60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds. PMID:8352272

  6. Bernard-Soulier syndrome: common ancestry in two African American families with the GP Ib alpha Leu129Pro mutation.

    PubMed

    Antonucci, J V; Martin, E S; Hulick, P J; Joseph, A; Martin, S E

    2000-10-01

    Bernard-Soulier syndrome (BSs) is a rare bleeding disorder characterized by circulating giant platelets, thrombocytopenia, and a prolonged bleeding time. BSs usually has an autosomal recessive inheritance pattern, with a preponderance of Caucasian and Japanese ancestry when the ethnic background has been reported. Underlying this disorder of platelet function is a defect in the platelet glycoprotein (GP) Ib-IX-V complex, composed of four polypeptides, GP Ib alpha, GP Ib beta, GP IX, and GP V. Molecular characterization of individuals with BSs has identified mutations in the GP Ib alpha, GP Ib beta, and GP IX genes responsible for the expressed phenotype. In this study, we report a family of African-American descent, with autosomal recessive BSs showing a point mutation in codon 129 of the GP Ib alpha gene. This mutation, CTC:wild-type to CCC:mutant, is similar to that of another African American family where the resulting leucine to proline substitution in the 5(th) leucine-rich repeat of GP Ib alpha is responsible for the observed BSs phenotype. Comparison of the intragenic polymorphisms of GP Ib alpha, as well as microsatellite markers in a 17.5 cM region of chromosome 17p12 that contains the GP Ib alpha gene, suggests that, although socially unrelated, the Leu129Pro mutation in these two families has a common founder.

  7. Wide clinical variability in cat eye syndrome patients: four non-related patients and three patients from the same family.

    PubMed

    Belangero, S I; Pacanaro, A N X; Bellucco, F T; Christofolini, D M; Kulikowski, L D; Guilherme, R S; Bortolai, A; Dutra, A R N; Piazzon, F B; Cernach, M C; Melaragno, M I

    2012-01-01

    A small supernumerary marker chromosome (sSMC) derived from chromosome 22 is a relatively common cytogenetic finding. This sSMC typically results in tetrasomy for a chromosomal region that spans the chromosome 22p arm and the proximal 2 Mb of 22q11.21. Using classical cytogenetics, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and array techniques, 7 patients with sSMCs derived from chromosome 22 were studied: 4 non-related and 3 from the same family (mother, daughter, and son). The sSMCs in all patients were dicentric and bisatellited chromosomes with breakpoints in the chromosome 22 low-copy repeat A region, resulting in cat eye syndrome (CES) due to chromosome 22 partial tetrasomy 22pter→q11.2 including the cat eye chromosome region. Although all subjects presented the same chromosomal abnormality, they showed a wide range of phenotypic differences, even in the 3 patients from the same family. There are no previous reports of CES occurring within 3 patients in the same family. Thus, the clinical and follow-up data presented here contribute to a better delineation of the phenotypes and outcomes of CES patients and will be useful for genetic counseling.

  8. Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes

    PubMed Central

    Pengelly, Reuben J.; Arias, Liliana; Martínez, Julio; Upstill-Goddard, Rosanna; Seaby, Eleanor G.; Gibson, Jane; Ennis, Sarah; Collins, Andrew; Briceño, Ignacio

    2016-01-01

    Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting. PMID:27456059

  9. Birt-Hogg-Dubé Syndrome, a Genodermatosis Associated with Spontaneous Pneumothorax and Kidney Neoplasia, Maps to Chromosome 17p11.2

    PubMed Central

    Schmidt, Laura S.; Warren, Michelle B.; Nickerson, Michael L.; Weirich, Gregor; Matrosova, Vera; Toro, Jorge R.; Turner, Maria L.; Duray, Paul; Merino, Maria; Hewitt, Stephen; Pavlovich, Christian P.; Glenn, Gladys; Greenberg, Cheryl R.; Linehan, W. Marston; Zbar, Berton

    2001-01-01

    Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects. PMID:11533913

  10. The Shwachman-Bodian-Diamond Syndrome Protein Family Is Involved in RNA Metabolism

    SciTech Connect

    Savchenko, A; Krogan, Nevan; Cort, John R.; Evdokimova, Elena; Lew, Jocelyne M.; Yee, Adelinda; Sanchez-Pulido, Luis; Andrade, Miguel; Bochkarev, Alexey; Watson, James D.; Kennedy, Michael A.; Greenblatt, Jack; Hughes, Timothy; Arrowsmith, Cheryl H.; Rommens, Johanna M.; Edwards, Aled M.

    2005-05-13

    A combination of structural, biochemical, and genetic studies in model organisms was used to infer a cellular role for the human protein (SBDS) responsible for Shwachman-Bodian-Diamond syndrome. The crystal structure of the SBDS homologue in Archaeoglobus fulgidus, AF0491, revealed a three domain protein. The N-terminal domain, which harbors the majority of disease-linked mutations, has a novel three-dimensional fold.

  11. Lethal familial fetal akinesia sequence (FAS) with distinct neuropathological pattern: type III lissencephaly syndrome.

    PubMed

    Encha Razavi, F; Larroche, J C; Roume, J; Gonzales, M; Kondo, H C; Mulliez, N

    1996-03-01

    We report on a distinct pattern of primary central nervous system (CNS) degeneration affecting neuronal survival in the brain and spinal cord in 5 fetuses with fetal akinesia sequence (FAS). This neuropathological pattern is characteristic of a lethal entity that we propose calling type III lissencephaly syndrome. Parental consanguinity and the recurrence in sibs support a genetic cause. The mechanism of neuronal death is not yet understood; abnormal apoptosis and/or deficiency in neurotropic factors may be considered possible causes.

  12. A Novel Intronic Splice Site Tafazzin Gene Mutation Detected Prenatally in a Family with Barth Syndrome

    PubMed Central

    Bakšienė, M; Benušienė, E; Morkūnienė, A; Ambrozaitytė, L; Utkus, A; Kučinskas, V

    2016-01-01

    Abstract Barth syndrome (BTHS) is a rare X-linked disease characterized by dilated cardiomyopathy, proximal skeletal myopathy and cyclic neutropenia. It is caused by various mutations in the tafazzin (TAZ) gene located on Xq28 that results in remodeling of cardiolipin and abnormalities in mitochondria stability and energy production. Here we report on a novel c.285-1G>C splice site mutation in intron 3 of the TAZ gene that was detected prenatally. PMID:28289596

  13. [Microbial community in wound defects of patients with diabetic foot syndrome in practice of family doctor].

    PubMed

    Rosul, M B; Patskan', B M; Nemesh, I I

    2014-01-01

    Microbial content of the wound were analyzed in 49 patients with diabetic foot syndrome before and after ozone treatment. The wound defects was characterized by high level of colonization by microorganisms in associations, prevalence of the staphylococci, was estimated local wound treatment by ozone at 4000 mμ/l has positive effect onto wound healing process. This was manifested by significant decrease in density of the microbial colonization of the wounds and was accompanied by change of degenerative processes onto regeneration.

  14. Phenotypic discordance in a family with monozygotic twins and non-syndromic cleft lip and palate

    SciTech Connect

    Wyszynski, D.F. |; Lewanda, A.F. |; Beaty, T.H.

    1996-12-30

    Despite considerable research, the cause of non-syndromic cleft lip with or without cleft palate (NSCLP) is still an enigma. Case-control and cohort studies have searched for environmental factors that might influence the development of this common malformation, such as maternal cigarette smoking, periconceptional supplementation of folic acid and multivitamins, agricultural chemical use, and place of residence, among others. However, these studies are subject to numerous biases, and their results have often been contradictory and inconclusive. 41 refs., 1 fig.

  15. Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome.

    PubMed

    Wilson, Gabrielle R; Sunley, Jasmine; Smith, Katherine R; Pope, Kate; Bromhead, Catherine J; Fitzpatrick, Elizabeth; Di Rocco, Maja; van Steensel, Maurice; Coman, David J; Leventer, Richard J; Delatycki, Martin B; Amor, David J; Bahlo, Melanie; Lockhart, Paul J

    2014-06-01

    Borrone Dermato-Cardio-Skeletal (BDCS) syndrome is a severe progressive autosomal recessive disorder characterized by coarse facies, thick skin, acne conglobata, dysmorphic facies, vertebral abnormalities and mitral valve prolapse. We identified a consanguineous kindred with a child clinically diagnosed with BDCS. Linkage analysis of this family (BDCS1) identified five regions homozygous by descent with a maximum LOD score of 1.75. Linkage analysis of the family that originally defined BDCS (BDCS3) identified an overlapping linkage peak at chromosome 5q35.1. Sequence analysis identified two different homozygous mutations in BDCS1 and BDCS3, affecting the gene encoding the protein SH3 and PX domains 2B (SH3PXD2B), which localizes to 5q35.1. Western blot analysis of patient fibroblasts derived from affected individuals in both families demonstrated complete loss of SH3PXD2B. Homozygosity mapping and sequence analysis in a second published BDCS family (BDCS2) excluded SH3PXD2B. SH3PXD2B is required for the formation of functional podosomes, and loss-of-function mutations in SH3PXD2B have recently been shown to underlie 7 of 13 families with Frank-Ter Haar syndrome (FTHS). FTHS and BDCS share some overlapping clinical features; therefore, our results demonstrate that a proportion of BDCS and FTHS cases are allelic. Mutations in other gene(s) functioning in podosome formation and regulation are likely to underlie the SH3PXD2B-mutation-negative BDSC/FTHS patients.

  16. Clinical and molecular studies in two families with Fraser syndrome: a new FRAS1 gene mutation, prenatal ultrasound findings and implications for genetic counselling.

    PubMed

    Ogur, G; Zenker, M; Tosun, M; Ekici, F; Schanze, D; Ozyilmaz, B; Malatyalioglu, E

    2011-01-01

    Fraser syndrome is a rare autosomal recessive genetic disorder characterized by cryptophthalmus, variable expression of cutaneous syndactyly of fingers and toes, genital ambiguity and renal agenesis/dysgenesis. We present here molecular and clinical findings of four fetuses with FS from two families. Molecular genetic studies in the two families revealed mutations in FRAS1 gene allowing better genetic counselling and subsequent prenatal diagnosis in one of the two families. In family one, a nonsense mutation (c.3730C>T, p.R1244X) previously described in a Polish patient was found. In family two a novel nonsense mutation previously not known was detected (c.370C>T, p.R124X). PGD is planned for family 1.

  17. Heterozygous Cylindromatosis Gene Mutation c.1628_1629delCT in a Family with Brook-Spiegler Syndrome

    PubMed Central

    Aguilera, Cintia Arjona; De la Varga Martínez, Raquel; García, Lidia Ossorio; Jiménez-Gallo, David; Planelles, Cristina Albarrán; Barrios, Mario Linares

    2016-01-01

    Brooke–Spiegler Syndrome (BSS) is a rare genodermatosis characterized by the progressive formation of adnexal skin tumors in the scalp and face, mainly trichoepitheliomas, cylindromas, and spiradenomas. It has also been associated with salivary glands neoplasms. It is due to mutations in the tumor suppressor gene cylindromatosis (CYLD gene) localized on chromosome 16q12−q13. Around 93 mutations have been described. The study of CYLD gene in patients and their relatives is of vital importance to establish the molecular diagnosis and offer appropriate genetic counseling. There is a low risk of malignancy and patients require long-term follow-up. A case of BSS in a family is described. The existence of the genetic mutation at the CYLD gene c. 1628_1629delCT in three of the women affected was demonstrated. This mutation has only been described once in a previous study. PMID:27688459

  18. A novel mutation in GJA1 causing oculodentodigital syndrome and primary lymphoedema in a three generation family.

    PubMed

    Brice, G; Ostergaard, P; Jeffery, S; Gordon, K; Mortimer, P S; Mansour, S

    2013-10-01

    Oculodentodigital syndrome (ODD; OMIM 164200) is a congenital condition with phenotypic features most commonly affecting the face, eyes, dentition and digits. The condition is caused by mutations in the GJA1 gene on chromosome 6. GJA1 codes for connexin 43, a gap junction protein important in providing cell to cell communication and is expressed in lymphatic valves. We present a patient with a clinical and molecular diagnosis of ODD and lower limb lymphoedema. Sanger sequencing of family members confirmed that the missense, p.K206R, GJA1 mutation segregated with the phenotype suggestive of causality. To our knowledge this association has not been reported previously. This is therefore the second connexin gene associated with a lymphoedema phenotype after the recent publication of GJC2 (connexin 47) as a cause of four limb lymphoedema.

  19. Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population

    PubMed Central

    Mumtaz, Sara; Riaz, Hafiza Fizzah; Touseef, Mohammad; Basit, Sulman; Haque, Muhammad Faiyaz Ul; Malik, Sajid

    2015-01-01

    Grebe syndrome (OMIM-200700) is a very rare type of acromesomelic dysplasia with autosomal recessive inheritance. We studied a Pakistani family with two affected individuals having typical features of Grebe chondrodysplasia. Patients were observed with short and deformed limbs having a proximo-distal gradient of severity. Hind-limbs were more severely affected than fore-limbs. Digits on autopods were very short and nonfunctional. Index subject also had nearsightedness. However, symptoms in the craniofacial and axial skeleton were minimal. Genetic analysis revealed four base pair insertion mutation (c.1114insGAGT) in gene coding cartilage-derived morphogenetic protein-1 (CDMP1). This mutation was predicted to cause premature stop codon. The clinical presentation in this study broadens the range of phenotypes associated with CDMP1 mutation in Pakistani population. PMID:26870132

  20. Clinical and genetic aspects of Blau syndrome: a 25-year follow-up of one family and a literature review.

    PubMed

    Punzi, Leonardo; Furlan, Antonio; Podswiadek, Marta; Gava, Alessandra; Valente, Marialuisa; De Marchi, Mario; Peserico, Andrea

    2009-01-01

    Blau syndrome (BS) is a rare familial disease transmitted as an autosomal dominant trait, characterized by arthritis, uveitis, skin rash and granulomatous inflammation. Until now BS has been observed in 136 persons belonging to 28 families as well as in 4 sporadic cases. The gene responsible for BS has recently been identified in the nucleotide-binding domain (NBD) of caspase recruitment domain (CARD15/NOD2), also involved in the pathogenesis of Crohn's disease. In addition to three missense mutations (R334Q, R334W and L469F) previously identified, a new CARD 15 mutation (E383K) has recently been described in a family followed by us for the past 25 years. The characteristics of this family which, to our knowledge, is the only one affected with BS in Italy, are the object of this manuscript. Both the proband and her daughter were originally affected with a papulonodular skin eruption and then with mild arthritis of the hands and feet. The proband, but not the daughter, complained of severe chronic bilateral uveitis, followed by glaucoma and, a few years later, by cataracts. Histological examination of skin biopsies from both subjects and a joint biopsy (daughter only), showed non-caseating granulomas with multinucleated giant cells which, at electron microscopy, revealed "comma-shaped bodies" in epithelioid cells, thought to be a marker for BS. The disease is presently well controlled with low doses of prednisone for the mother and non-steroidal anti-inflammatory drugs (NSAIDs) plus low doses of prednisone, when necessary, for the daughter. As in Crohn's disease, CARD15/NOD2 mutation is believed to be responsible for the granulomatous autoinflammatory reactions probably triggered by microorganisms in BS.

  1. Disease-targeted sequencing of ion channel genes identifies de novo mutations in patients with non-familial Brugada syndrome.

    PubMed

    Juang, Jyh-Ming Jimmy; Lu, Tzu-Pin; Lai, Liang-Chuan; Ho, Chia-Chuan; Liu, Yen-Bin; Tsai, Chia-Ti; Lin, Lian-Yu; Yu, Chih-Chieh; Chen, Wen-Jone; Chiang, Fu-Tien; Yeh, Shih-Fan Sherri; Lai, Ling-Ping; Chuang, Eric Y; Lin, Jiunn-Lee

    2014-10-23

    Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20-25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants.

  2. Clinical phenotype and prevalence of hereditary nonpolyposis colorectal cancer syndrome in Chinese population

    PubMed Central

    Zhang, Yuan-Zhi; Sheng, Jian-Qiu; Li, Shi-Rong; Zhang, Hong

    2005-01-01

    AIM: To describe systematically the clinical characteristics and phenotype of HNPCC families and the prevalence of HNPCC in the general population of CRC patients in China. METHODS: HNPCC kindreds and CRC patients were from two sources. One was that we consecutively investigated kindreds and patients by ourselves. And the other was the published Chinese and foreign literature related to Chinese HNPCC syndrome. There were 142 HNPCC families fulfilling AC I and/or AC II including 57 families with detailed data, and 3874 general primary CRC patients in all. All statistical tests were two-sided. RESULTS: In AC I families, the number of Lynch syndrome I and II families were 25 (47.2%) and 28 (52.8%) respectively. There were 215 patients (82.4%) with CRC, 67 patients (25.7%) with extracolonic cancer and 50 patients (19.2%) with multiple primary cancers. In all CRC patients, multiple primary CRC were in 41 patients (19.1%), and the first-CRC was right-sided colorectal cancer in 143 patients (66.5%) and rectal cancer in 44 patients (20.5%). 8.8% and 19.2% of the first cancer were CRC and extracolonic cancers. Among those patients whose first cancer was CRC, 66.8% and 19.9% were right-sided colorectal cancer and rectal cancer, respectively. The similar results were found in AC II families. Normal distribution was only found in the distribution of the age of diagnosis of the first cancer in both AC I families (coefficient of skewness: u = 0.81, 0.20<0.40families (coefficient of skewness: u = 0.63, P>0.5>0.20; coefficient of kurtosis: u = 0.84, 0.20<0.40families diagnosed by AC I and AC II, the mean age and median age were 45.1±12.7 years and 44.0 years, 45.2±12.7 years and 44.5 years, respectively. The median

  3. Mutations in SPINT2 Cause a Syndromic Form of Congenital Sodium Diarrhea

    PubMed Central

    Heinz-Erian, Peter; Müller, Thomas; Krabichler, Birgit; Schranz, Melanie; Becker, Christian; Rüschendorf, Franz; Nürnberg, Peter; Rossier, Bernard; Vujic, Mihailo; Booth, Ian W.; Holmberg, Christer; Wijmenga, Cisca; Grigelioniene, Giedre; Kneepkens, C. M. Frank; Rosipal, Stefan; Mistrik, Martin; Kappler, Matthias; Michaud, Laurent; Dóczy, Ludwig-Christoph; Siu, Victoria Mok; Krantz, Marie; Zoller, Heinz; Utermann, Gerd; Janecke, Andreas R.

    2009-01-01

    Autosomal-recessive congenital sodium diarrhea (CSD) is characterized by perinatal onset of a persistent watery diarrhea with nonproportionally high fecal sodium excretion. Defective jejunal brush-border Na+/H+ exchange has been reported in three sporadic patients, but the molecular basis of the disease has not been elucidated. We reviewed data from a large cohort of CSD patients (n = 24) and distinguished CSD associated with choanal or anal atresia, hypertelorism, and corneal erosions—i.e., a syndromic form of CSD—occurring in ten families from an isolated form—i.e., classic CSD—presenting in seven families. Patients from both groups have a high risk of mortality due to immediate electrolyte imbalances and complications from long-term parenteral nutrition in the first years of life, but survivors can eventually adapt to partial or complete enteral nutrition. A genome-wide SNP scan was applied and identified a homozygous c.593−1G→A splicing mutation in SPINT2, encoding a Kunitz-type serine-protease inhibitor, in one extended kindred with syndromic CSD. The same mutation and four distinct, homozygous or compound heterozygous mutations (p.Y163C, c.1A→T, c.337+2T→C, c.553+2T→A) were identified in all syndromic patients. No SPINT2 mutations were found in classic-CSD patients. SPINT2 mutations were associated with loss of protein synthesis or failure to inhibit the serine protease trypsin in vitro. We delineate syndromic CSD as a distinct disease entity caused by SPINT2 loss-of-function mutations. SPINT2 mutations might lead to an excess of yet unknown serine protease activity in affected tissues. PMID:19185281

  4. 'Deletion rescue' by mitotic 11q uniparental disomy in a family with recurrence of 11q deletion Jacobsen syndrome.

    PubMed

    Johnson, J P; Haag, M; Beischel, L; McCann, C; Phillips, S; Tunby, M; Hansen, J; Schwanke, C; Reynolds, J F

    2014-04-01

    We describe a family with recurrent 11q23-qter deletion Jacobsen syndrome in two affected brothers, with unique mosaic deletion 'rescue' through development of uniparental disomy (UPD) in the mother and one of the brothers. Inheritance studies show that the deleted chromosome is of maternal origin in both boys, and microarray shows a break near the ASAM gene. Parental lymphocyte chromosomes were normal. However, the mother is homozygous in lymphocytes for all loci within the deleted region in her sons, and presumably has UPD for this region. In addition, she is mosaic for the 11q deletion seen in her sons at a level of 20-30% in skin fibroblasts. We hypothesize that one of her #11 chromosomes shows fragility, that breakage at 11q23 occurred with telomeric loss in some cells, but 'rescue' from the deletion occurred in most cells by the development of mitotic UPD. She apparently carries the 11q deletion in her germ line resulting in recurrence of the syndrome. The older son is mosaic for the 11q cell line (70-88%, remainder 46,XY), and segmental UPD11 'rescue' apparently also occurred in his cytogenetically normal cells. This is a novel phenomenon restoring disomy to an individual with a chromosomal deletion.

  5. A novel mutation in the endothelin B receptor gene in a moroccan family with shah-waardenburg syndrome.

    PubMed

    Doubaj, Yassamine; Pingault, Véronique; Elalaoui, Siham C; Ratbi, Ilham; Azouz, Mohamed; Zerhouni, Hicham; Ettayebi, Fouad; Sefiani, Abdelaziz

    2015-02-01

    Waardenburg syndrome (WS) is a neurocristopathy disorder combining sensorineural deafness and pigmentary abnormalities. The presence of additional signs defines the 4 subtypes. WS type IV, also called Shah-Waardenburg syndrome (SWS), is characterized by the association with congenital aganglionic megacolon (Hirschsprung disease). To date, 3 causative genes have been related to this congenital disorder. Mutations in the EDNRB and EDN3 genes are responsible for the autosomal recessive form of SWS, whereas SOX10 mutations are inherited in an autosomal dominant manner. We report here the case of a 3-month-old Morrocan girl with WS type IV, born to consanguineous parents. The patient had 3 cousins who died in infancy with the same symptoms. Molecular analysis by Sanger sequencing revealed the presence of a novel homozygous missense mutation c.1133A>G (p.Asn378Ser) in the EDNRB gene. The proband's parents as well as the parents of the deceased cousins are heterozygous carriers of this likely pathogenic mutation. This molecular diagnosis allows us to provide genetic counseling to the family and eventually propose prenatal diagnosis to prevent recurrence of the disease in subsequent pregnancies.

  6. [A case report of toxic shock-like syndrome associated with prevalence of streptococcal pharingitis in the family].

    PubMed

    Shimizu, Y; Sakashita, H; Takada, C; Otsuka, Y; Ooe, K; Tsumita, R

    1994-09-01

    A case of streptococcal toxic shock-like syndrome in a previously healthy, 57 year old Japanese female has been reported. Initially, she had a sore throat and low grade fever for 5 days. Because of sudden severe pain on the extremities and erythema on bilateral forearms, she was hospitalized. On admission, her conciousness was clear. Although profound hypotension, anuria and prolonged blood coagulation were observed. Antibiotics, fluid therapy and dopamine were given. Four hours after admission, she died in spite of resuscitation efforts, by sudden cardiac arrest. Streptococcus pyogenes was isolated in her blood. At the same time as when she died, three of the five people of the patient's family living with her, had pharingitis or pneumonia. From the pharynxs of the three people with pharingitis, Streptococcus pyogenes was also isolated. The serotype of all organisms was T11, and they produced exotoxintype B in vitro. This case suggests that infection of Streptococcus pyogenes is not essential for the development of toxic shock-like syndrome.

  7. A de novo deletion mutation in SOX10 in a Chinese family with Waardenburg syndrome type 4

    PubMed Central

    Wang, Xiong; Zhu, Yaowu; Shen, Na; Peng, Jing; Wang, Chunyu; Liu, Haiyi; Lu, Yanjun

    2017-01-01

    Waardenburg syndrome type 4 (WS4) or Waardenburg-Shah syndrome is a rare genetic disorder with a prevalence of <1/1,000,000 and characterized by the association of congenital sensorineural hearing loss, pigmentary abnormalities, and intestinal aganglionosis. There are three types of WS4 (WS4A–C) caused by mutations in endothelin receptor type B, endothelin 3, and SRY-box 10 (SOX10), respectively. This study investigated a genetic mutation in a Chinese family with one WS4 patient in order to improve genetic counselling. Genomic DNA was extracted, and mutation analysis of the three WS4 related genes was performed using Sanger sequencing. We detected a de novo heterozygous deletion mutation [c.1333delT (p.Ser445Glnfs*57)] in SOX10 in the patient; however, this mutation was absent in the unaffected parents and 40 ethnicity matched healthy controls. Subsequent phylogenetic analysis and three-dimensional modelling of the SOX10 protein confirmed that the c.1333delT heterozygous mutation was pathogenic, indicating that this mutation might constitute a candidate disease-causing mutation. PMID:28128317

  8. Mutational Hot Spot Potential of a Novel Base Pair Mutation of the CSPG2 Gene in a Family With Wagner Syndrome

    PubMed Central

    Ronan, Shawn M.; Tran-Viet, Khanh-Nhat; Burner, Erica L.; Metlapally, Ravikanth; Toth, Cynthia A.; Young, Terri L.

    2012-01-01

    Objective To report a 3-generation white family clinically diagnosed variably with Wagner, Stickler, and Jansen syndromes and screened for sequence variants in the COL2A1 and CSPG2 genes. Wagner syndrome is an autosomal dominant vitreoretinopathy with a predisposition to retinal detachment and cataracts. It has significant phenotypic overlap with allelic Jansen syndrome and ocular Stickler syndrome type 1. Sticker syndrome type 1 maps to chromosome 12q13.11-q13.2, with associated COL2A1 gene mutations. Wagner syndrome maps to chromosome 5q13-q14 and is associated with mutations in CSPG2 encoding versican, a proteoglycan present in human vitreous. Methods Genomic DNA samples derived from venous blood were collected from all family members. Complete sequencing of COL2A1 was performed on a proband. Primers for polymerase chain reaction and sequencing were designed to cover all exon and intronexon boundaries. Direct sequencing of CSPG2 was performed on all family member samples. Results No detectable COL2A1 mutations were noted, making the diagnosis of ocular Stickler syndrome highly unlikely for this family. A unique base pair substitution (c.9265+1G>T) in intron 8 of the CSPG2 gene cosegregating with disease status was identified. This mutation occurred in a highly conserved previously reported splice site with a similar base pair substitution(G>A). Direct sequencing of this splice site mutation in 107 unrelated external controls revealed no variants, supporting the rarity of this base pair change and its causation in Wagner syndrome. This novel base pair substitution is thought to cause the deletion of exon 8 and formation of a truncated protein product. Conclusion Mutation screening of CSPG2 in autosomal dominant vitreoretinopathy families is important for accurate diagnosis. Clinical Relevance This study underscores the importance of obtaining extensive pedigree information and comparative ophthalmologic clinical information, as the phenotypic findings may vary

  9. Familiality of Tourette Syndrome, Obsessive-Compulsive Disorder, and Attention-Deficit/Hyperactivity Disorder: Heritability Analysis in a Large Sib-Pair Sample

    ERIC Educational Resources Information Center

    Mathews, Carol A.; Grados, Marco A.

    2011-01-01

    Objective: Tourette syndrome (TS) is a neuropsychiatric disorder with a genetic component that is highly comorbid with obsessive-compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD). However, the genetic relations between these disorders have not been clearly elucidated. This study examined the familial relations among TS,…

  10. Association of the Family Environment with Behavioural and Cognitive Outcomes in Children with Chromosome 22q11.2 Deletion Syndrome

    ERIC Educational Resources Information Center

    Allen, T. M.; Hersh, J.; Schoch, K.; Curtiss, K.; Hooper, S. R.; Shashi, V.

    2014-01-01

    Background: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. Method: Guardians of children with 22q11DS…

  11. Postural Orthostatic Tachycardia Syndrome (POTS)--A novel member of the autoimmune family.

    PubMed

    Dahan, S; Tomljenovic, L; Shoenfeld, Y

    2016-04-01

    Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system in which a change from the supine position to an upright position causes an abnormally large increase in heart rate or tachycardia (30 bpm within 10 min of standing or head-up tilt). This response is accompanied by a decrease in blood flow to the brain and hence a spectrum of symptoms associated with cerebral hypoperfusion. Many of these POTS-related symptoms are also observed in chronic anxiety and panic disorders, and therefore POTS is frequently under- and misdiagnosed.

  12. Forbidden suffering: the Pollyanna syndrome of the disabled and their families.

    PubMed

    Saetersdal, B

    1997-12-01

    Has suffering become an ugly word in the normalization debate? Are the disabled and their families forced into a Pollyanna culture in order to be acknowledged and accepted in good company as the worthy disabled? This essay poses a controversial question: I would like to start a debate and ask whether normalization also has an unseen, ideological downside.

  13. The mysterious Spotted Green Pigeon and its relation to the Dodo and its kindred

    PubMed Central

    2014-01-01

    Background The closely related and extinct Dodo (Raphus cucullatus) and Rodrigues Solitaire (Pezophaps solitaria), both in the subfamily Raphinae, are members of a clade of morphologically very diverse pigeons. Genetic analyses have revealed that the Nicobar Pigeon (Caloenas nicobarica) is the closest living relative of these birds, thereby highlighting their ancestors’ remarkable migration and morphological evolution. The Spotted Green Pigeon (Caloenas maculata) was described in 1783 and showed some similarities to the Nicobar Pigeon. Soon however the taxon fell into obscurity, as it was regarded as simply an abnormal form of the Nicobar Pigeon. The relationship between both taxa has occasionally been questioned, leading some ornithologists to suggest that the two may in fact be different taxa. Today only one of the original two specimens survives and nothing is known about the origin of the taxon. Due to its potential close relationship, the Spotted Green Pigeon may hold clues to the historical migration, isolation and morphological evolution of the Dodo and its kindred. Results We use ancient DNA methodologies to investigate the phylogeny and authenticity of the Spotted Green Pigeon. A novel extraction method with the ability to retain and purify heavily fragmented DNA is used to investigate two feathers from the sole surviving specimen. Maximum Likelihood phylogenetic analyses reveal that the Spotted Green Pigeon is a unique lineage and together with the Nicobar Pigeon, is basal to the Dodo and Rodrigues Solitaire. Conclusions The distance observed for the Spotted Green Pigeon and Nicobar Pigeon is larger than that observed within other Pigeon species, indicating that the Spotted Green pigeon is a unique taxon, thereby also indicating it is a genuine addition to the list of extinct species. The phylogenetic placement of the Spotted Green Pigeon indicates that the ancestors of both Caloenas and therefore Raphinae displayed and shared the following traits

  14. A novel FGD1 mutation in a family with Aarskog–Scott syndrome and predominant features of congenital joint contractures

    PubMed Central

    Griffin, Laurie Beth; Farley, Frances A.; Antonellis, Anthony; Keegan, Catherine E.

    2016-01-01

    Mutations in FGD1 cause Aarskog–Scott syndrome (AAS), an X-linked condition characterized by abnormal facial, skeletal, and genital development due to abnormal embryonic morphogenesis and skeletal formation. Here we report a novel FGD1 mutation in a family with atypical features of AAS, specifically bilateral upper and lower limb congenital joint contractures and cardiac abnormalities. The male proband and his affected maternal uncle are hemizygous for the novel FGD1 mutation p.Arg921X. This variant is the most carboxy-terminal FGD1 mutation identified in a family with AAS and is predicted to truncate the FGD1 protein at the second to last amino acid of the carboxy-terminal pleckstrin homology (PH) domain. Our study emphasizes the importance of the 3′ peptide sequence in the structure and/or function of the FGD1 protein and further demonstrates the need to screen patients with X-linked congenital joint contractures for FGD1 mutations. PMID:27551683

  15. Clinical characterization and identification of duplication breakpoints in a Japanese family with Xq28 duplication syndrome including MECP2.

    PubMed

    Fukushi, Daisuke; Yamada, Kenichiro; Nomura, Noriko; Naiki, Misako; Kimura, Reiko; Yamada, Yasukazu; Kumagai, Toshiyuki; Yamaguchi, Kumiko; Miyake, Yoshishige; Wakamatsu, Nobuaki

    2014-04-01

    Xq28 duplication syndrome including MECP2 is a neurodevelopmental disorder characterized by axial hypotonia at infancy, severe intellectual disability, developmental delay, mild characteristic facial appearance, epilepsy, regression, and recurrent infections in males. We identified a Japanese family of Xq28 duplications, in which the patients presented with cerebellar ataxia, severe constipation, and small feet, in addition to the common clinical features. The 488-kb duplication spanned from L1CAM to EMD and contained 17 genes, two pseudo genes, and three microRNA-coding genes. FISH and nucleotide sequence analyses demonstrated that the duplication was tandem and in a forward orientation, and the duplication breakpoints were located in AluSc at the EMD side, with a 32-bp deletion, and LTR50 at the L1CAM side, with "tc" and "gc" microhomologies at the duplication breakpoints, respectively. The duplicated segment was completely segregated from the grandmother to the patients. These results suggest that the duplication was generated by fork-stalling and template-switching at the AluSc and LTR50 sites. This is the first report to determine the size and nucleotide sequences of the duplicated segments at Xq28 of three generations of a family and provides the genotype-phenotype correlation of the patients harboring the specific duplicated segment.

  16. Linkage analysis in a family with Stickler syndrome leads to the exclusion of the COL2A1 locus

    SciTech Connect

    Mottes, M.; Zolezzi, F.; Pignatti, P.F.

    1994-09-01

    Hereditary arthro-ophtalmopathy (AO) or Stickler Syndrome (MIM No. 10830) is a dominantly inherited disorder characterized by vitro-retinal degeneration and other connective tissue disturbances. Mutations in the COL2A1 gene, coding for type II collagen chains, have been described in a few patients. The wide spectrum of clinical manifestations is presumably due to genetic heterogeneity, since only about 50% of the Stickler families so far studied show cosegregation of the disease with the COL2A1 locus. We have investigated a large pedigree (19 individuals of whom 9 are affected) in which severe myopia with vitro-retinal degeneration consegregated with joint laxity, recurrent inguinal hernias, and degenerative changes of the hip and the knee. The 3{prime} end COL2A1 VNTR polymorphism was utilized for linkage analysis. In order to get the maximum informativity, we have analyzed the allelic microheterogeneity of this VNTR, due to the repeat sequence variation, by means of a single strand polymorphism. Mendelian inheritance of the different single strands was observed as expected. Discordance of segregation between the disease and the COL2A1 locus was thus established inequivocally in this family.

  17. Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome.

    PubMed

    Aziz, Abdul; Raza, Syed I; Ali, Salman; Ahmad, Wasim

    2016-01-01

    Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome.

  18. Relationship of work-family conflict, self-reported social support and job satisfaction to burnout syndrome among medical workers in southwest China: A cross-sectional study

    PubMed Central

    Yang, Shujuan; Liu, Danping; Liu, Hongbo; Zhang, Juying; Duan, Zhanqi

    2017-01-01

    Background Burnout is a psychosomatic syndrome widely observed in Chinese medical workers due to the increasing cost of medical treatment, excessive workload, and excessive prescribing behavior. No studies have evaluated the interrelationship among occupational burnout, work-family conflict, social support, and job satisfaction in medical workers. The aim of this study was to evaluate these relationships among medical workers in southwest China. Methods This cross-sectional study was conducted between March 2013 and December 2013, and was based on the fifth National Health Service Survey (NHSS). A total of 1382 medical workers were enrolled in the study. Pearson correlation analysis and general linear model univariate analysis were used to evaluate the relationship of work-family conflict, self-reported social support, and job satisfaction with burnout syndrome in medical workers. Results We observed that five dimensions of job satisfaction and self-reported social support were negatively associated with burnout syndrome, whereas three dimensions of work-family conflict showed a positive correlation. In a four-stage general linear model analysis, we found that demographic factors accounted for 5.4% of individual variance in burnout syndrome (F = 4.720, P<0.001, R2 = 0.054), and that work-family conflict, self-reported social support, and job satisfaction accounted for 2.6% (F = 5.93, P<0.001, R2 = 0.080), 5.7% (F = 9.532, P<0.001, R2 = 0.137) and 17.8% (F = 21.608, P<0.001, R2 = 0.315) of the variance, respectively. In the fourth stage of analysis, female gender and a lower technical title correlated to a higher level of burnout syndrome, and medical workers without administrative duties had more serious burnout syndrome than those with administrative duties. Conclusions In conclusion, the present study suggests that work-family conflict and self-reported social support slightly affect the level of burnout syndrome, and that job satisfaction is a much stronger

  19. Family physician-led, team-based, lifestyle intervention in patients with metabolic syndrome: results of a multicentre feasibility project

    PubMed Central

    Jeejeebhoy, Khursheed; Dhaliwal, Rupinder; Heyland, Daren K.; Leung, Roger; Day, Andrew G.; Brauer, Paula; Royall, Dawna; Tremblay, Angelo; Mutch, David M.; Pliamm, Lew; Rhéaume, Caroline; Klein, Doug

    2017-01-01

    Background: Metabolic syndrome (MetS) is a medical condition with major complications and health care costs. Previous research has shown that diet and exercise can improve and reverse this condition. The goal of this study was to test the feasibility and effectiveness of implementing the Canadian Health Advanced by Nutrition and Graded Exercise (CHANGE) program into diverse family medicine practices to improve MetS. Methods: In this longitudinal before-after study, 305 adult patients with MetS were recruited from 3 diverse family medicine team-based organizations to the CHANGE personalized diet and exercise program. Participants were followed for 12 months. Primary outcomes included feasibility and reversal of MetS. Secondary outcomes included improvement in MetS components, changes in diet quality, aerobic fitness and cardiovascular risk. Results: Participants attended 76% and 90% of the kinesiologist and dietitian visits, respectively. At 12 months, 19% of patients (95% confidence interval [CI] 14%-24%) showed reversal of MetS, VO2max increased by 16% (95% CI 13%-18%), and Healthy Eating Index and Mediterranean Diet Scores improved by 9.6% (95% CI 7.6%-11.6%) and 1.4% (1.1%-1.6%), respectively. In addition, the Prospective Cardiovascular Munster (PROCAM) 10-year risk of acute coronary event decreased by 1.4%, from a baseline of 8.6%. Interpretation: A team-based program led by the family physician that educates patients about the risks of MetS, and with a dietitian and kinesiologist, empowers them to undertake an individualized supervised program of diet modification and exercise, is feasible, improves aerobic capacity and diet quality, reverses MetS and improves MetS components at 12 months.

  20. Phenotypic variation in colorectal adenoma/cancer expression in two families. Hereditary flat adenoma syndrome.

    PubMed

    Lynch, H T; Smyrk, T C; Lanspa, S J; Lynch, P M; Watson, P; Strayhorn, P C; Bronson, E K; Lynch, J F; Priluck, I A; Appelman, H D

    1990-09-01

    Clinical, pathologic, and genetic studies on two colorectal cancer-prone families have disclosed right-sided colonic flat adenomas and colorectal cancer. Adenomatous polyp counts exceeded those found in hereditary nonpolyposis colorectal cancer (HNPCC) but were fewer than in familial adenomatous polyposis (FAP). Colon cancer occurred at a later age than in HNPCC or FAP and showed right-sided predominance. The older age of patients with colonic cancer, the right-sided predominance of colon cancer, and the paucity of rectal adenomas make FAP unlikely. Vertical transmission of polyps and colon cancer fit the pattern of autosomal dominant inheritance. A characteristic feature of this phenotype is the predominance of flat adenomas. Molecular genetic studies, with careful description of phenotype, should help clarify classification.

  1. Genetic analysis of candidate loci in non-syndromic cleft lip families from Antioquia-Colombia and Ohio.

    PubMed

    Moreno, Lina M; Arcos-Burgos, Mauricio; Marazita, Mary L; Krahn, Katherine; Maher, Brion S; Cooper, Margaret E; Valencia-Ramirez, Consuelo R; Lidral, Andrew C

    2004-03-01

    Non-syndromic cleft lip with or without cleft palate (CL/P) is a genetically complex birth defect, with a prevalence from 1/500 to 1/1,000 live births. Evidence from linkage and linkage disequilibrium studies is contradictory suggesting that heterogeneity between study populations may exist. A recent report of a genome widescan in 92 sib pairs from the United Kingdom revealed suggestive linkage to 10 loci [Prescott et al., 2000]. The purpose of this study is to replicate those results and evaluate additional candidate genes in 49 Colombian and 13 Ohio families. Genotypes were obtained for STRPs at 1p36, 2p13 (TGFA), 4p16 (MSX1), 6p23-25, 6q25-27, 8q23-24, 11p12-q13, 12q13, 14q24 (TGFB3), 16q22-24, 17q12-21 (RARA), and Xcen-q21. Linkage was performed using parametric (dominant and recessive models) and non-parametric (GenehunterNPL and SimIBD) analyses. In addition, heterogeneity was analyzed using GenehunterHLOD, and association determined by the TDT. The Colombian families showed significant SimIBD results for 11p12-q13 (P = 0.034), 12q13 (P = 0.015), 16q22-24 (0.01), and 17q12-21 (0.009), while the Ohio families showed significant SimIBD results for 1p36 (P = 0.02), TGFA (P = 0.005), 6p23 (P = 0.004), 11p12-q13 (P = 0.048) and significant NPL results for TGFA (NPL = 3.01, P = 0.009), 4p16 (MNPL = 2.07, P = 0.03) and 12q13 (SNPL = 3.55, P = 0.007). Significant association results were obtained only for the Colombian families in the regions 1p36 (P = 0.046), 6p23-25 (P = 0.020), and 12q13 (P = 0.046). In addition several families yielded LOD scores ranging from 1.09 to 1.73, for loci at 4p16, 6p23-25, 16q22-24, and 17q13. These results confirm previous reports for these loci. However, the differences between the two populations suggest that population specific locus heterogeneity exists. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.

  2. Fragile X syndrome and the (CGG)[sub n] mutation: Two families with discordant MZ twins

    SciTech Connect

    Kruyer, H.; Estivill, X.; Mila, M.; Ballesta, F.; Glover, G.; Carbonell, P. )

    1994-03-01

    The fragile X phenotype has been found, in the majority of cases, to be due to the expansion of a CGG repeat in the 5'UTR region of the FMR-1 gene, accompanied by methylation of the adjacent CpG island and inactivation of the FMR-1 gene. Although several important aspects of genetics of fragile X have been resolved, it remains to be elucidated at which stage in development the transition from the premutation to the full mutation occurs. The authors present two families in which discordance between two sets of MZ twins illustrates two important genetic points. In one family, two affected MZ brothers differed in the number of CGG repeats, demonstrating in vivo mitotic instability of this CGG repeat and suggesting that the transition to the full mutation occurred postzygotically. In the second family, two MZ sisters had the same number of repeats, but only one was mentally retarded. When the methylation status of the FMR-1 CpG island was studied, the authors found that the majority of normal chromosomes had been inactivated in the affected twin, thus leading to the expression of the fragile X phenotype. 29 refs., 3 figs., 1 tab.

  3. Genotype-phenotype relationships in fragile X syndrome: A family study

    SciTech Connect

    Loesch, D.Z.; Hay, D.A.; Huggins, R.; Gedeon, A.K.; Mulley, J.C.; Sutherland, G.R.

    1993-11-01

    Relationships between the measures of intellectual and physical status in the fragile X syndrome and the size of amplification of the fragile X-specific fragment, equivalent to the number of CCG repeats within the FMR1 locus, were studied by a maximum-likelihood scoring technique for analysis of pedigree data. This allows for estimation of random effects (genetic and environmental variance) concurrently with other (fixed) effects in a quantitative trait. FMR1 expression is usually shut down in males penetrant for the fragile X syndrome who have hypermethylated CCG amplifications of [ge] 0.6 kb. The assumption of the step versus curvilinear function representing this relationship was tested by the likelihood-ratio criterion. The maximum-likelihood parameters were based on the most appropriate model for each measure. The results were indicative of the presence of a curvilinear relationship between the amplification size and the two intellectual scores, the Peabody Picture Vocabulary Test and Block Design Test, measuring verbal and spatial abilities, respectively. Reasons for the unexpected curvilinear regression between the amplification size and intellectual scores were explained further by methylation analysis of fragile X males with amplifications of 0.6 < [delta] [le] 1.2 kb who appeared to be responsible for the curvilinearity of the relationship. Four of these showed unmethylated status of the amplified bands in lymphocytes, which were presumably transcriptionally active. Removal of the aberrant individuals led to the anticipated step function between amplification and intellectual scores. For the combined anthropometric score, as well as for several single physical measures, the step function was the most appropriate model regardless of the inclusion or omission of the aberrant individuals in the pedigree sample. 35 refs., 3 figs., 3 tabs.

  4. Prenatal Diagnosis of Walker-Warburg Syndrome Using Single Nucleotide Polymorphism Array: A Clinical Experience from Three Related Palestinian Families with Congenital Hydrocephalus.

    PubMed

    Abumansour, Iman S; Al Sulmi, Eman; Chodirker, Bernard N; Hunt, Jennifer C

    2015-10-01

    Background Congenital hydrocephalus is a common and often disabling disorder. Various syndromic forms of hydrocephalus have been reported in the Palestinian population including Walker-Warburg syndrome (WWS), Carpenter syndrome, and Meckel syndrome. Aim In this report we discuss the antenatal diagnosis of congenital hydrocephalus in three related Palestinian families. Method Single nucleotide polymorphism (SNP) array was performed prenatally for the third affected fetus. Results A diagnosis of WWS was found and molecular testing revealed a known pathogenic mutation in the POMT2 gene. An affected fetus from the other family was diagnosed and tested postnatally in light of this finding. Testing of another affected stillborn offspring was performed and revealed the same mutation. Conclusions Here, we show that the use of prenatal SNP array testing can be helpful in elucidating the etiology of congenital hydrocephalus and in guiding appropriate perinatal care. Also, testing for this specific POMT2 mutation should be considered in cases of prenatally detected hydrocephalus in Palestinian families.

  5. Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene.

    PubMed

    Cavaco, Branca M; Guerra, Laura; Bradley, Karin J; Carvalho, Davide; Harding, Brian; Oliveira, Amélia; Santos, Maria-Amparo; Sobrinho, Luís G; Thakker, Rajesh V; Leite, Valeriano

    2004-04-01

    The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors and ossifying jaw fibromas. The gene causing HPT-JT, HRPT2, is located on chromosome 1q31.2 and consists of 17 exons that encode a 531-amino acid protein, designated parafibromin. We recently identified six Roma families in Portugal with 56 members (11 affected and 45 asymptomatic), who had the HPT-JT syndrome. We postulated that they may have a common ancestor and that the HPT-JT syndrome may be due to a mutation of the HRPT2 gene. Haplotype analysis using 14 chromosome 1q24-q32 polymorphic markers showed that the 11 affected individuals shared a common haplotype defined by seven markers that spanned an approximately 12.5-cM region, flanked centromerically by D1S202 and telomerically by D1S306. DNA sequence analysis identified a 2-bp (TG or GT) frameshift deletion in exon 8, which predicts a truncated parafibromin protein, in all 11 affected individuals. This mutation was also found in 19 unaffected individuals (age range, 12-74 yr) who shared the affected haplotype, suggesting a low age-related penetrance for HPT-JT in these families. Thus, the HPT-JT syndrome in six Roma families from Portugal is due to a novel founder mutation in the HRPT2 gene.

  6. Familial dysautonomia

    MedlinePlus

    Riley-Day syndrome; FD; Hereditary sensory and autonomic neuropathy - type III (HSAN III); Autonomic crises - familial dysautonomia ... PA: Elsevier; 2016:chap 107. Sarnat HB. Autonomic neuropathies. In: Kliegman RM, Stanton BF, St. Geme JW, ...

  7. A novel compound heterozygous mutation in the GJB2 gene causing non-syndromic hearing loss in a family.

    PubMed

    Wei, Qinjun; Liu, Youguo; Wang, Shuai; Liu, Tingting; Lu, Yajie; Xing, Guangqian; Cao, Xin

    2014-02-01

    Mutations in the GJB2 gene are responsible for up to 50% of cases of non-syndromic recessive hearing loss, with c.35delG, c.167delT and c.235delC being the predominant mutations in many world populations. However, a large number of rare mutations in this gene may also contribute to hearing loss. The aim of the present study was to conduct a clinical and molecular characterization of a Chinese family with non-syndromic hearing loss. Sequence analysis of the GJB2 gene led to the identification of a novel compound heterozygous mutation c.257C>G (p.T86R)/c.605ins46 in two profoundly deaf siblings whose hearing parents were each heterozygous, either for the c.257C>G (paternal) or for the c.605ins46 (maternal) mutations. Both c.257C>G and c.605ins46 are rare GJB2 mutations that have previously been reported to segregate with autosomal recessive hearing loss exclusively in East Asian populations. To study the pathogenic effect of the compound heterozygous mutation, a three-dimensional model was constructed and Anolea mean force potential energy was predicted for a bioinformatic structural analysis. HEK293 cells were used to study the pathogenic effect of mutant connexin 26 proteins. The results suggested that the c.257C>G (p.T86R)/c.605ins46 mutations in the GJB2 gene provides a novel molecular explanation for the role of the GJB2 gene in hearing loss.

  8. Two co-existing germline mutations P53 V157D and PMS2 R20Q promote tumorigenesis in a familial cancer syndrome.

    PubMed

    Wang, Zuoyun; Sun, Yihua; Gao, Bin; Lu, Yi; Fang, Rong; Gao, Yijun; Xiao, Tian; Liu, Xin-Yuan; Pao, William; Zhao, Yun; Chen, Haiquan; Ji, Hongbin

    2014-01-01

    Germline mutations are responsible for familial cancer syndromes which account for approximately 5-10% of all types of cancers. These mutations mainly occur at tumor suppressor genes or genome stability genes, such as DNA repair genes. Here we have identified a cancer predisposition family, in which eight members were inflicted with a wide spectrum of cancer including one diagnosed with lung cancer at 22years old. Sequencing analysis of tumor samples as well as histologically normal specimens identified two germline mutations co-existing in the familial cancer syndrome, the mutation of tumor suppressor gene P53 V157D and mismatch repair gene PMS2 R20Q. We further demonstrate that P53 V157D and/or PMS2 R20Q mutant promotes lung cancer cell proliferation. These two mutants are capable of promoting colony formation in soft agar as well as tumor formation in transgenic drosophila system. Collectively, these data have uncovered the important role of co-existing germline P53 and PMS2 mutations in the familial cancer syndrome development.

  9. Perinatal and Familial Risk Factors Are Associated with Full Syndrome and Subthreshold Attention-Deficit Hyperactivity Disorder in a Korean Community Sample

    PubMed Central

    Kim, Hyo-Won; Cho, Soo-Churl; Kim, Jae-Won; Shin, Min-Sup; Kim, Yeni

    2009-01-01

    Objective The objective of this study was to examine the effect of perinatal and familial risk factors on full syndrome and subthreshold attention-deficit/hyperactivity disorder (ADHD) among Korean children and adolescents. Methods A sample of 2,673 students was randomly selected from 19 representative schools in Seoul, Korea. The parents of the students completed the Diagnostic Interview Schedule for Children-version IV (DISC-IV), as well as questionnaires on perinatal and familial risk factors. Results Maternal stress and alcohol use during pregnancy, parental marital discord, parental separation or divorce, changes in primary caregivers, and notbreastfeeding were significantly associated with full syndrome ADHD; however, maternal stress during pregnancy was the only variable that differentiated subthreshold ADHD from non-ADHD. Conclusion Our results provide evidence the perinatal and familial risk factors contribute to the development of ADHD in Korea children and adolescents, and suggest that these perinatal and familial risk factors are more closely related to full syndrome than to subthreshold ADHD. PMID:20140126

  10. Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.

    PubMed

    Steinke, Verena; Holzapfel, Stefanie; Loeffler, Markus; Holinski-Feder, Elke; Morak, Monika; Schackert, Hans K; Görgens, Heike; Pox, Christian; Royer-Pokora, Brigitte; von Knebel-Doeberitz, Magnus; Büttner, Reinhard; Propping, Peter; Engel, Christoph

    2014-07-01

    Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome.

  11. A Corticobasal Syndrome Variant of Familial Creutzfeldt-Jakob Disease with Stroke-Like Onset

    PubMed Central

    2016-01-01

    Creutzfeldt-Jakob disease (CJD) is an untreatable rare human prion disease characterized by rapidly progressive dementia along with various neurological features, including myoclonus and sometimes other movement disorders. The clinical course is typically insidious and rapid, leading to an early death. In general, the most common form is sporadic CJD; however, Slovakia is typical for a high percentage of genetic cases. We present an unusual case report of a 65-year-old man with a sudden, stroke-like onset of motor aphasia with right-sided levodopa unresponsive parkinsonism, alien hand, and other characteristic features of corticobasal syndrome (CBS), with rapid deterioration and death on the 32nd day of the disease. Various neurodegenerative disorders are manifested with CBS as a clinical phenotype, including corticobasal degeneration (CBD), progressive supranuclear palsy, Alzheimer's disease, and CJD. In our patient, mutation E200K and M129M polymorphism of the PRNP gene and typical immunohistochemical findings pointed to a diagnosis of CJD. The patient's mother died of CJD many years ago. Several CBS-CJD cases were described, but the atypical stroke-like onset of CBS-CJD, an extremely rare presentation of CJD, makes our case unique worldwide. PMID:27803826

  12. RHBDF2 Mutations Are Associated with Tylosis, a Familial Esophageal Cancer Syndrome

    PubMed Central

    Blaydon, Diana C.; Etheridge, Sarah L.; Risk, Janet M.; Hennies, Hans-Christian; Gay, Laura J.; Carroll, Rebecca; Plagnol, Vincent; McRonald, Fiona E.; Stevens, Howard P.; Spurr, Nigel K.; Bishop, D. Timothy; Ellis, Anthony; Jankowski, Janusz; Field, John K.; Leigh, Irene M.; South, Andrew P.; Kelsell, David P.

    2012-01-01

    Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective. PMID:22265016

  13. Strong Parent–Offspring Association of Metabolic Syndrome in Korean Families

    PubMed Central

    Yoo, Eun-Gyong; Park, Sang Shin; Oh, Sang Woo; Nam, Gi-Byoung; Park, Mi Jung

    2012-01-01

    OBJECTIVE To investigate the associations of metabolic syndrome (MetS) and its components between adolescents and their parents in Korea. RESEARCH DESIGN AND METHODS We analyzed data for 4,657 subjects (1,404 fathers, 1,404 mothers, 957 sons, and 892 daughters) from the Korean National Health and Nutrition Examination Surveys conducted between 1998 and 2008. RESULTS Compared with adolescents whose parents did not have MetS, the odds ratio (95% CI) for MetS in adolescents with MetS in one parent was 4.2 (2.1–8.5) and 8.7 (3.4–22.3) in those with MetS in both parents. Among obese adolescents, the prevalence of MetS was 18.2% without parental MetS, whereas 29.2% of obese adolescents with MetS in one parent and 53.9% with MetS in both parents also had MetS (P = 0.01 for trend). CONCLUSIONS The risk of MetS increased significantly in adolescents with parental MetS and was especially high in those with coexisting obesity and parental MetS. PMID:22210569

  14. Post-mortem genetic testing in a family with long-QT syndrome and hypertrophic cardiomyopathy.

    PubMed

    Kane, David A; Triedman, John

    2014-01-01

    Pediatric sudden unexplained deaths are rare and tragic events that should be evaluated with all the tools available to the medical community. The current state of genetic testing is an excellent resource that improves our ability to diagnose cardiovascular disorders that can lead to sudden cardiac arrest. Post-mortem genetic testing is not typically a covered benefit of health insurance and may not be offered to families in the setting of a negative autopsy. This unusual case includes two separate cardiovascular disorders that highlight the use of genetic testing and its role in diagnosis, screening, and risk stratification. The insurance company's decision to cover post-mortem testing demonstrated both compassion as well as an understanding of the long-term cost effectiveness.

  15. [Metabolic syndrome prevalence in Chilean children and adolescent with family history of chronic noncommunicable diseases].

    PubMed

    Burrows, Raquel; Atalah, Eduardo; Leiva, Laura; Rojas, Pamela; Maza, María Pía de la; Vásquez, Fabian; Lera, Lydia; Díaz, Erick

    2012-06-01

    Family history (FH+) of non transmisible chronic diseases (NTCD) increase MetS risk. In Chile, the MetS affects 27% of overweight children, and fasting hyperglycemia is very low prevalent (4,0%). The objective was to study the prevalence of MetS and the cardiovascular risk factors (CVRF) in overweight children with a family background of NTCD and analyze its association with the number of relatives witth NTCD and with parental history (PH). In 183 overweight children (BMI > or = p85) mean age 11,8 +/- 1,8 (86 males) with a FH+ (parental or grandparental) of NTCD, were assessed the BMI z (CDC / NCHS), waist circumference, blood arterial pressure, fasting Glucose and Insulin (RIA), triglycerides, HDL chol. The MetS and the CVRF were diagnosed using the Cook phenotype and the insulin resistance (IR) through the HOMA-IR. Chi2, ANOVA, t Student and Willcoxon test were performed. The frequency of FH+ of DM2, hypertension and dyslipidemia were 81,4%, 88,0% and 71,6 % respectively. The MeTS prevalence was 46,5 % associated to overweight magnitude an parental history of NTCD. The prevalence of hypertriglyceridemia was 54,6%, while fasting hyperglycemia affected 31,4% of the sample. There was no association between number of relatives with NTCD and CV risk profile. We conclude that in overweight children with FH+ of NTCD, the prevalence of MetS, dyslipidemia and fasting hyperglycemia are significantly higher, than those observed in the general population of obese children.

  16. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1.

    PubMed Central

    Mikami, M; Yasuda, T; Terao, A; Nakamura, M; Ueno, S; Tanabe, H; Tanaka, T; Onuma, T; Goto, Y; Kaneko, S; Sano, A

    1999-01-01

    Benign adult familial myoclonic epilepsy is an autosomal dominant idiopathic epileptic syndrome characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course. It was recently recognized in Japanese families. In this study, we report that the gene locus is assigned to the distal long arm of chromosome 8, by linkage analysis in a large Japanese kindred with a maximum two-point LOD score of 4.31 for D8S555 at recombination fraction of 0 (maximum multipoint LOD score of 5.42 for the interval between D8S555 and D8S1779). Analyses of recombinations place the locus within an 8-cM interval, between D8S1784 and D8S1694, in which three markers, D8S1830, D8S555, and D8S1779, show no recombination with the phenotypes. Although three other epilepsy-related loci on chromosome 8q have been recognized-one on chromosome 8q13-21 (familial febrile convulsion) and two others on chromosome 8q24 (KCNQ3 and childhood absence epilepsy)-the locus assigned here is distinct from these three epilepsy-related loci. This study establishes the presence of a new epilepsy-related locus on 8q23.3-q24.11. PMID:10441581

  17. Two sisters with clinical diagnosis of Wiskott-Aldrich Syndrome: Is the condition in the family autosomal recessive?

    SciTech Connect

    Kondoh, T.; Hayashi, K.; Matsumoto, T.

    1995-10-09

    We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister`s for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS. 17 refs., 6 figs., 1 tab.

  18. Single TCR-Vβ2 evaluation discloses the circulating T cell clone in Sezary syndrome: one family fits all!

    PubMed

    Scala, Enrico; Abeni, Damiano; Pomponi, Debora; Russo, Nicoletta; Russo, Giandomenico; Narducci, Maria Grazia

    2015-08-01

    Sézary Syndrome (SS/L-CTCL) is a rare but aggressive variant of cutaneous T cell lymphoma (CTCL), characterized by erythroderma, lymphadenopathy, and the presence of a circulating memory CD4(+) T cell malignant clone with a skin homing behavior, lacking CD26 and CD49d and over-expressing CD60. The availability of a panel of monoclonal antibodies recognizing distinct TCR-Vβ families, allows to typify the clone by flow cytometry in about 70 % of cases. The TCR-Vβ repertoire of 533 individuals, comprising 308 patients affected by CTCL, 50 healthy donors, and subjects affected by various non-neoplastic dermatological affections was evaluated by flow cytometry. Statistical analyses were performed using the SPSS statistical software package for Microsoft Windows (SPSS, version 21, Chicago, IL). TCR-Vβ2 levels below 5.4 % or above 39.5 %, within total CD4(+) T cells, showed the best balance between sensitivity (98.1 %) and specificity (96 %) to identify the presence of a clone in the peripheral blood of patients affected by SS. Based on this observation, a "two-step" procedure in the detection of the malignant T cell clone in CTCLs is herein suggested. TCR-Vβ2 assessment in all cases (first step). In the case of TCR-Vβ2 levels above 39.5 %, the presence of a clonal expansion of this family is suggested, deserving further confirmation by means of T cell gene rearrangement evaluation. In patients having a TCR-Vβ2 reactivity below 5.4 % (second step), the entire TCR-Vβ repertoire should be evaluated to typify the expanded clone. In conclusion, the single TCR-Vβ2 expression check, instead of the entire repertoire assessment, represents an easy and cost-effective method for the recognition of CTCL aggressive leukemic variant.

  19. Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1.

    PubMed

    Monroe, Glen R; Harakalova, Magdalena; van der Crabben, Saskia N; Majoor-Krakauer, Danielle; Bertoli-Avella, Aida M; Moll, Frans L; Oranen, Björn I; Dooijes, Dennis; Vink, Aryan; Knoers, Nine V; Maugeri, Alessandra; Pals, Gerard; Nijman, Isaac J; van Haaften, Gijs; Baas, Annette F

    2015-06-01

    Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.

  20. Identification and characterisation of an 8.7 kb deletion and a novel nonsense mutation in two Italian families with Sanfilippo syndrome type D (mucopolysaccharidosis IIID).

    PubMed

    Beesley, Clare E; Concolino, Daniela; Filocamo, Mirella; Winchester, Bryan G; Strisciuglio, Pietro

    2007-01-01

    Sanfilippo syndrome type D is an autosomal recessive lysosomal storage disease that is caused by a deficiency of N-acetylglucosamine-6-sulphatase, one of the enzymes involved in the catabolism of heparan sulphate. Only 15 patients have been described in the literature and just two mutations have been reported to date. We present the clinical, biochemical and molecular analysis of two Italian Sanfilippo D families. Novel homozygous mutations were identified in the affected patients from each family: a large intragenic deletion of 8723 bp encompassing exons 2 and 3 in family 1 and a nonsense mutation, Q272X, in family 2. The deletion is the first large intragenic deletion to be reported in any of the four Sanfilippo subtypes, including Sanfilippo type C in which the gene has recently been identified.

  1. Identification of a second HOXA2 nonsense mutation in a family with autosomal dominant non-syndromic microtia and distinctive ear morphology.

    PubMed

    Piceci, F; Morlino, S; Castori, M; Buffone, E; De Luca, A; Grammatico, P; Guida, V

    2016-08-09

    Microtia is a congenital defect affecting external ears, which appear smaller and sometimes malformed. Here we describe a five-generation family with isolated bilateral microtia segregating as an autosomal dominant trait. Similar features have been previously observed in an autosomal dominant family with non-syndromic microtia and hearing loss segregating with a HOXA2 nonsense variant. HOXA2 biallelic mutations were also described in an inbreed family with autosomal recessive microtia, hearing impairment and incomplete cleft palate. In our family, sequence analysis detected a heterozygous protein truncating nonsense variant [c.670G>T, p.(Glu224*)] segregating in all affected individuals and absent in public databases. This study confirms the role of HOXA2 gene in dominant isolated microtia and contribute to further define the dysmorphogenetic effect of this gene on ear development.

  2. A familial case of Coffin-Lowry syndrome caused by RPS6KA3 C.898C>T mutation associated with multiple abnormal brain imaging findings.

    PubMed

    Tos, T; Alp, M Y; Aksoy, A; Ceylaner, S; Hanauer, A

    2015-01-01

    Coffin-Lowry syndrome (CLS) is a rare X linked mental retardation syndrome characterised by severe psychomotor and growth retardation, distinct facial phenotype, and progressive skeletal malformations. It is caused by mutations in the RPS6KA3 gene located at Xp22.2. In this report we describe a family with CLS consists of three affected males, and two affected females, arising from c.898C>T mutation in RPS6KA3 gene. A 6 year-old, and a 3 year-old boy both had distinct clinical features of Coffin-Lowry syndrome; severe mental and motor retardation, microcephaly, prominent forehead, hypertelorism, large mouth, large ears, large soft hands, puffy tapered fingers, and pectus carinatum. In addition, they had multiple abnormal brain MRI findings. Other siblings presented with a mild and variable phenotype.

  3. Clinical and molecular characterization of seven Egyptian families with autosomal recessive robinow syndrome: Identification of four novel ROR2 gene mutations.

    PubMed

    Aglan, Mona; Amr, Khalda; Ismail, Samira; Ashour, Adel; Otaify, Ghada A; Mehrez, Mennat Allah I; Aboul-Ezz, Eman H A; El-Ruby, Mona; Mazen, Inas; Abdel-Hamid, Mohamed S; Temtamy, Samia A

    2015-12-01

    Robinow syndrome (RS) is a rare genetic disorder characterized by limb shortening, genital hypoplasia, and craniofacial/orodental abnormalities. The syndrome follows both autosomal dominant and recessive patterns of inheritance with similar phenotypic presentation and overlapping features. Autosomal recessive Robinow syndrome (ARRS) is caused by mutations in the ROR2 gene. Here, we present the clinical, radiological and molecular findings of 11 Egyptian patients from 7 unrelated consanguineous families with clinical features of ARRS. Mutation analyses of ROR2 gene identified five pathogenic mutations distributed all over the gene. The identified mutations included four novel (G326A, D166H, S677F, and R528Q) and one previously reported (Y192D). Our results extend the number of ROR2 mutations identified so far, suggest a founder effect in the Egyptian population, and emphasize the important role of genetic testing in proper counseling and patients' management.

  4. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.

    PubMed

    Masurel-Paulet, Alice; Piton, Amélie; Chancenotte, Sophie; Redin, Claire; Thauvin-Robinet, Christel; Henrenger, Yvan; Minot, Delphine; Creppy, Audrey; Ruffier-Bourdet, Marie; Thevenon, Julien; Kuentz, Paul; Lehalle, Daphné; Curie, Aurore; Blanchard, Gaelle; Ghosn, Ezzat; Bonnet, Marlene; Archimbaud-Devilliers, Mélanie; Huet, Frédéric; Perret, Odile; Philip, Nicole; Mandel, Jean-Louis; Faivre, Laurence

    2016-08-01

    Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.

  5. A novel mutation of the MITF gene in a family with Waardenburg syndrome type 2: A case report

    PubMed Central

    SHI, YUNFANG; LI, XIAOZHOU; JU, DUAN; LI, YAN; ZHANG, XIULING; ZHANG, YING

    2016-01-01

    Waardenburg syndrome (WS) is an autosomal dominant disorder with varying degrees of sensorineural hearing loss, and accumulation of pigmentation in hair, skin and iris. There are four types of WS (WS1–4) with differing characteristics. Mutations in six genes [paired box gene 3 (PAX3), microphthalmia-associated transcription factor (MITF), endothelin 3 (END3), endothelin receptor type B (EDNRB), SRY (sex determining region Y)-box 10 (SOX10) and snail homolog 2 (SNAI2)] have been identified to be associated with the various types. This case report describes the investigation of genetic mutations in three patients with WS2 from a single family. Genomic DNA was extracted, and the six WS-related genes were sequenced using next-generation sequencing technology. In addition to mutations in PAX3, EDNRB and SOX10, a novel heterozygous MITF mutation, p.Δ315Arg (c.944_946delGAA) on exon 8 was identified. This is predicted to be a candidate disease-causing mutation that may affect the structure and function of the enzyme. PMID:27073475

  6. Adaptive-filtering of trisomy 21: risk of Down syndrome depends on family size and age of previous child

    NASA Astrophysics Data System (ADS)

    Neuhäuser, Markus; Krackow, Sven

    2007-02-01

    The neonatal incidence rate of Down syndrome (DS) is well-known to accelerate strongly with maternal age. This non-linearity renders mere accumulation of defects at recombination during prolonged first meiotic prophase implausible as an explanation for DS rate increase with maternal age, but might be anticipated from chromosomal drive (CD) for trisomy 21. Alternatively, as there is selection against genetically disadvantaged embryos, the screening system that eliminates embryos with trisomy 21 might decay with maternal age. In this paper, we provide the first evidence for relaxed filtering stringency (RFS) to represent an adaptive maternal response that could explain accelerating DS rates with maternal age. Using historical data, we show that the proportion of aberrant live births decrease with increased family size in older mothers, that inter-birth intervals are longer before affected neonates than before normal ones, and that primiparae exhibit elevated levels of DS incidence at higher age. These findings are predicted by adaptive RFS but cannot be explained by the currently available alternative non-adaptive hypotheses, including CD. The identification of the relaxation control mechanism and therapeutic restoration of a stringent screen may have considerable medical implications.

  7. Whole-Exome Sequencing Identifies Homozygous GPR161 Mutation in a Family with Pituitary Stalk Interruption Syndrome

    PubMed Central

    Karaca, Ender; Buyukkaya, Ramazan; Pehlivan, Davut; Charng, Wu-Lin; Yaykasli, Kursat O.; Bayram, Yavuz; Gambin, Tomasz; Withers, Marjorie; Atik, Mehmed M.; Arslanoglu, Ilknur; Bolu, Semih; Erdin, Serkan; Buyukkaya, Ayla; Yaykasli, Emine; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.

    2015-01-01

    Context: Pituitary stalk interruption syndrome (PSIS) is a rare, congenital anomaly of the pituitary gland characterized by pituitary gland insufficiency, thin or discontinuous pituitary stalk, anterior pituitary hypoplasia, and ectopic positioning of the posterior pituitary gland (neurohypophysis). The clinical presentation of patients with PSIS varies from isolated growth hormone (GH) deficiency to combined pituitary insufficiency and accompanying extrapituitary findings. Mutations in HESX1, LHX4, OTX2, SOX3, and PROKR2 have been associated with PSIS in less than 5% of cases; thus, the underlying genetic etiology for the vast majority of cases remains to be determined. Objective: We applied whole-exome sequencing (WES) to a consanguineous family with two affected siblings who have pituitary gland insufficiency and radiographic findings of hypoplastic (thin) pituitary gland, empty sella, ectopic neurohypophysis, and interrupted pitiutary stalk—characteristic clinical diagnostic findings of PSIS. Design and Participants: WES was applied to two affected and one unaffected siblings. Results: WES of two affected and one unaffected sibling revealed a unique homozygous missense mutation in GPR161, which encodes the orphan G protein–coupled receptor 161, a protein responsible for transducing extracellular signals across the plasma membrane into the cell. Conclusion: Mutations of GPR161 may be implicated as a potential novel cause of PSIS. PMID:25322266

  8. Genetically diagnosed Birt-Hogg-Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report.

    PubMed

    Whitworth, James; Stausbøl-Grøn, Brian; Skytte, Anne-Bine

    2017-01-01

    When faced with an unusual clinical feature in a patient with a Mendelian disorder, the clinician may entertain the possibilities of either the feature representing a novel manifestation of that disorder or the co-existence of a different inherited condition. Here we describe an individual with a submandibular oncocytoma, pulmonary bullae and renal cysts as well as multiple cerebral cavernous malformations and haemangiomas. Genetic investigations revealed constitutional mutations in FLCN, associated with Birt-Hogg-Dubé syndrome (BHD) and CCM2, associated with familial cerebral cavernous malformation. Intracranial vascular pathologies (but not cerebral cavernous malformation) have recently been described in a number of individuals with BHD (Kapoor et al. in Fam Cancer 14:595-597, 10.1007/s10689-015-9807-y , 2015) but it is not yet clear whether they represent a genuine part of that conditions' phenotypic spectrum. We suggest that in such instances of potentially novel clinical features, more extensive genetic testing to consider co-existing conditions should be considered where available. The increased use of next generation sequencing applications in diagnostic settings is likely to lead more cases such as this being revealed.

  9. A Novel Missense Mutation in the CLPP Gene Causing Perrault Syndrome Type 3 in a Turkish Family

    PubMed Central

    Dursun, Fatma; Mohamoud, Hussein Sheikh Ali; Karim, Noreen; Naeem, Muhammad; Jelani, Musharraf; Kırmızıbekmez, Heves

    2016-01-01

    Perrault syndrome (PRLTS) is a heterogeneous group of clinical and genetic disorders characterized by sensory neuronal hearing loss in both sexes and premature ovarian failure or infertility in females. Neurological and hearing loss symptoms appear early in life, but female infertility cannot be detected before puberty. Spastic limbs, muscle weakness, delayed puberty and irregular menstrual cycles have also been observed in PRLTS patients. Mutations in five genes, i.e. HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. Here, we report a milder phenotype of PRLTS in a Turkish family in which two affected patients had no neurological findings. However, both were characterized by sensory neuronal hearing loss and the female sibling had secondary amenorrhea and gonadal dysgenesis. Genome-wide homozygosity mapping using 300K single-nucleotide polymorphism microarray analysis together with iScan platform (Illumina, USA) followed by candidate gene Sanger sequencing with ABI 3500 Genetic Analyzer (Life Technologies, USA) were used for molecular diagnosis. We found a novel missense alteration c.624C>G; p.Ile208Met in exon 5 of the CLPP at chromosome 19p13.3. This study expands the mutation spectrum of CLPP pathogenicity in PRLTS type 3 phenotype. PMID:27087618

  10. Insulin-resistance and metabolic syndrome are related to executive function in women in a large family-based study

    PubMed Central

    Schuur, M.; Henneman, P.; van Swieten, J. C.; Zillikens, M. C.; de Koning, I.; Janssens, A. C. J. W.; Witteman, J. C. M.; Aulchenko, Y. S.; Frants, R. R.; Oostra, B. A.; van Dijk, K. Willems

    2010-01-01

    While type 2 diabetes is well-known to be associated with poorer cognitive performance, few studies have reported on the association of metabolic syndrome (MetS) and contributing factors, such as insulin-resistance (HOMA-IR), low adiponectin-, and high C-reactive protein (CRP)- levels. We studied whether these factors are related to cognitive function and which of the MetS components are independently associated. The study was embedded in an ongoing family-based cohort study in a Dutch population. All participants underwent physical examinations, biomedical measurements, and neuropsychological testing. Linear regression models were used to determine the association between MetS, HOMA-IR, adiponectin levels, CRP, and cognitive test scores. Cross-sectional analyses were performed in 1,898 subjects (mean age 48 years, 43% men). People with MetS had significantly higher HOMA-IR scores, lower adiponectin levels, and higher CRP levels. MetS and high HOMA-IR were associated with poorer executive function in women (P = 0.03 and P = 0.009). MetS and HOMA-IR are associated with poorer executive function in women. PMID:20585974

  11. Dopa responsive dystonia with Turner's syndrome: clinical, genetic, and neuropsychological studies in a family with a new mutation in the GTP-cyclohydrolase I gene

    PubMed Central

    Nitschke, M; Steinberger, D; Heberlein, I; Otto, V; Muller, U; Vieregge, P

    1998-01-01

    A 26 year old woman with dopa responsive dystonia and cytogenetically confirmed Turner's syndrome had bilateral globus pallidus hypointensity on brain MRI. Among the living members of a five generation pedigree the patient's mother and the mother's sister also had dopa responsive dystonia; a maternal grandfather had senile parkinsonism, his niece isolated postural tremor. No other family member had Turner's syndrome. A new missense mutation in exon I of the gene of GTP-cyclohydrolase I was found in the three family members with dopa responsive dystonia. With levodopa substitution the patients with dopa responsive dystonia improved clinically as well as in quantitative tests on hand tapping, verbal and performance IQ, concept formation, and set shifting abilities.

 PMID:9647318

  12. Familial occurrence of an association of multiple intestinal atresia and choanal atresia: a new syndrome?

    PubMed

    Ferrarini, Alessandra; Osterheld, Maria-Chiara; Vial, Yvan; de Viragh, Pierre A; Cotting, Jacques; Martinet, Danielle; Beckmann, Jacques S; Fellmann, Florence

    2009-12-01

    We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

  13. Encyclopaedia of tumour-associated familial disorders. Part I: from AIMAH to CHIME syndrome

    PubMed Central

    Sijmons, Rolf H

    2008-01-01

    Cancer is associated with a wide range of hereditary disorders. Recognizing these disorders in cancer patients may be of great importance for the medical management of both patients and their relatives. Conversely, recognizing the fact that cancer may develop as a complication of a particular hereditary disorder which has already been diagnosed may be important for the same reason. The Familial Cancer Database (FaCD) is a web-based application which has been developed at our department with the intention to assist clinicians and genetic counsellors in making a genetic differential diagnosis in cancer patients, as well as in becoming aware of the tumour spectrum associated with hereditary disorders that have already been diagnosed in their patients. This encyclopaedia is published in parts and discusses the disorders included in the FaCD database in alphabetical order. It lists names, synonyms, OMIM number, mode of inheritance, associated genes, phenotype, clinical discussion and references. The purpose of presenting this encyclopaedia in paper format is simply that we hope that you as clinicians and researchers find it helpful to browse through it and familiarize yourself even better with the scope of genetic disorders that have been associated with increased tumour risk. PMID:19706204

  14. Study of a Brazilian family presenting non-syndromic hearing loss with mitochondrial inheritance.

    PubMed

    Pupo, Altair Cadrobbi; Pirana, Sulene; Spinelli, Mauro; Lezirovitz, Karina; Mingroni Netto, Regina C; Macedo, Lisandra S

    2008-01-01

    We hereby report on the audiological and genetic findings in individuals from a Brazilian family, with the following mitochondrial mutation A1555G in the 12SrRNA gene (MT-RNR-1). Nine individuals underwent speech, audiologic (tonal audiometry and logoaudiometry) and genetic evaluations. Eight individuals among the A1555G carriers were affected by hearing impairment and one person had normal hearing thresholds till the end of the present study. The audiologic evaluation results indicated normal hearing thresholds all the way to bilateral profound hearing loss with post-lingual onset and variable configuration. Two affected siblings presented progressive hearing loss. It was impossible to precise the time of hearing loss onset; however, the impairment was present in both children and adults. The genetic study revealed the A1555G mitochondrial mutation in the 12SrRNA gene. Given the prevalence of mitochondrial mutations as a cause of hearing loss, it is fundamental to perform the etiopathologic diagnosis in order to postpone the onset or avoid hearing impairment progression. This kind of hearing impairment represents a challenge to the professionals since there are no physical traits that indicate genetic transmission.

  15. Novel homozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes.

    PubMed

    Al-Owain, M; Wakil, S; Shareef, F; Al-Fatani, A; Hamadah, E; Haider, M; Al-Hindi, H; Awaji, A; Khalifa, O; Baz, B; Ramadhan, R; Meyer, B

    2011-07-01

    Desmoplakin is an important cytoskeletal linker for the function of the desmosomes. Linking desmoplakin to certain types of cardiocutaneous syndromes has been a hot topic recently. Skin fragility-woolly hair syndrome is a rare autosomal recessive disorder involving the desmosomes and is caused by mutation in the desmoplakin gene (DSP). We report five members from a large family with skin fragility-woolly hair syndrome. The index is a 14-year-old girl with palmoplantar keratoderma, woolly hair, variable alopecia, dystrophic nails, and excessive blistering to trivial mechanical trauma. No cardiac symptoms were reported. Although formal cardiac examination was not feasible, the echocardiographic evaluation of the other two affected younger siblings was normal. Homozygosity mapping and linkage analysis revealed a high LOD score region in the short arm of chromosome 6 that harbors the DSP. Full sequencing of the DSP showed a novel homozygous c.7097 G>A (p.R2366H) mutation in all affected members, and the parents were heterozygous. This is the report of the third case/family of the skin fragility-woolly hair syndrome in the literature. We also present a clinical and molecular review of various desmoplakin-related phenotypes, with emphasis on onset of cardiomyopathy. The complexity of the desmoplakin and its variable presentations warrant introducing the term 'desmoplakinopathies' to describe all the phenotypes related to defects in the desmoplakin.

  16. Familial Investigations of Childhood Cancer Predisposition

    ClinicalTrials.gov

    2017-04-12

    Acute Leukemia; Adenomatous Polyposis; Adrenocortical Carcinoma; AML; BAP1 Tumor Predisposition Syndrome; Carney Complex; Choroid Plexus Carcinoma; Constitutional Mismatch Repair Deficiency Syndrome; Diamond-Blackfan Anemia; DICER1 Syndrome; Dyskeratosis Congenita; Emberger Syndrome; Familial Acute Myeloid Leukaemia; Familial Adenomatous Polyposis; Fanconi Anemia; Familial Cancer; Familial Wilms Tumor; Familial Neuroblastoma; GIST; Hereditary Breast and Ovarian Cancer; Hereditary Paraganglioma-Pheochromocytoma Syndrome; Hodgkin Lymphoma; Juvenile Polyposis; Li-Fraumeni Syndrome; Lynch Syndrome; MDS; Melanoma Syndrome; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Neuroblastoma; Neurofibromatosis Type 1; Neurofibromatosis Type II; Nevoid Basal Cell Carcinoma Syndrome; Non Hodgkin Lymphoma; Noonan Syndrome and Other Rasopathy; Overgrowth Syndromes; Pancreatic Cancer; Peutz-Jeghers Syndrome; Pheochromocytoma/Paraganglioma; PTEN Hamartoma Tumor Syndrome; Retinoblastoma; Rhabdoid Tumor Predisposition Syndrome; Rhabdomyosarcoma; Rothmund-Thomson Syndrome; Tuberous Sclerosis; Von Hippel-Lindau Disease

  17. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16

    SciTech Connect

    Tromp, G.; Kuivaniemi, H.; Ala-Kokko, L.

    1996-11-01

    Blau syndrome (MIM 186580), first described in a large, three-generation kindred, is an autosomal, dominantly inherited disease characterized by multiorgan, tissue-specific inflammation. Its clinical phenotype includes granulomatous arthritis, skin rash, and uveitis and probably represents a subtype of a group of clinical entities referred to as {open_quotes}familial granulomatosis.{close_quotes} It is the sole human model with recognizably Mendelian inheritance for a variety of multisystem inflammatory diseases affecting a significant percentage of the population. A genomewide search for the Blau susceptibility locus was undertaken after karyotypic analysis revealed no abnormalities. Sixty-two of the 74-member pedigree were genotyped with dinucleotide-repeat markers. Linkage analysis was performed under dominant model of inheritance with reduced penetrance. The marker D16S298 gave a maximum LOD score of 3.75 at {theta} = .04, with two-point analysis. LOD scores for flanking markers were consistent and placed the Blau susceptibility locus within the 16p12-q21 interval. 46 refs., 3 figs., 3 tabs.

  18. A Korean family with KBG syndrome identified by ANKRD11 mutation, and phenotypic comparison of ANKRD11 mutation and 16q24.3 microdeletion.

    PubMed

    Kim, Hyo Jeong; Cho, Eunhae; Park, Jong Bum; Im, Woo Young; Kim, Hyon J

    2015-02-01

    KBG syndrome is a rare disease characterized by intellectual disability, typical craniofacial dysmorphism, macrodontia of the upper central incisors, short stature, and skeletal anomalies. Recently, ANKRD11 was identified as a gene that is responsible for the disease. In addition, microdeletion of 16q24.3, including ANKRD11, has been reported to result in the KBG syndrome phenotype. Herein, we discuss a Korean family with KBG syndrome, as identified by ANKRD11 gene mutation. The patients included a nine-month-old boy and his 21-month-old sister who failed to thrive and have delayed development. Chromosomal microarray was performed to identify the underlying genetic cause, but the results showed no abnormalities. However, the mother of the children was found to have features similar to her children. Therefore, we strongly suspected an autosomal-dominant inherited disease and performed whole exome sequencing. A mutation of ANKRD11 gene was found in all patients, and the frameshift variant c.2395-2398delAAAG was confirmed. Clinical manifestations of the patients were consistent with KBG syndrome. We reviewed all reported cases with confirmed ANKRD11 mutation or 16q24.3 microdeletion including ANKRD11. As a result, we conclude that severe short stature, intellectual disability, and macrodontia are the main characteristics in KBG syndrome related to ANKRD11 mutation.

  19. Eye Gaze Technology as a Form of Augmentative and Alternative Communication for Individuals with Rett Syndrome: Experiences of Families in The Netherlands.

    PubMed

    Townend, Gillian S; Marschik, Peter B; Smeets, Eric; van de Berg, Raymond; van den Berg, Mariёlle; Curfs, Leopold M G

    This paper provides a brief report on families' experiences of eye gaze technology as one form of augmentative and alternative communication (AAC) for individuals with Rett syndrome (RTT), and the advice, training and support they receive in relation to this. An online survey exploring communication and AAC was circulated to 190 Dutch families; of the 67 questionnaires that were returned, 63 had answered questions relating to eye gaze technology. These 63 were analysed according to parameters including: experiences during trial periods and longer-term use; expert knowledge, advice and support; funding; communicative progress; and family satisfaction. 20 respondents were using or had previous experience of using an eye gaze system at the time of the survey, 28 of those with no prior experience wanted to try a system in the future. Following a trial period, 11 systems had been funded through health insurance for long-term use and two families had decided a system was not appropriate for them. Levels of support during trials and following long-term provision varied. Despite frustrations with the technology, satisfaction with the systems was higher than satisfaction with the support. The majority of families reported progress in their child's skills with longer term use. These findings suggest that although eye gaze technologies offer potential to individuals with RTT and their families, greater input from suppliers and knowledgeable AAC professionals is essential for individuals and families to benefit maximally. Higher levels of training and support should be part of the 'package' when an eye gaze system is provided.

  20. 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 on 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.

  1. Mutation analysis of the RET gene in individuals with sporadic and familial pheochromocytoma

    SciTech Connect

    Iyengar, S.; Sirugo, G.; Bale, A.E.

    1994-09-01

    Pheochromocytoma is common to many familial cancer syndromes including multiple endocrine neoplasia type 2A (MEN2A), von Hippel-Lindau (VHL) and neurofibromatosis (NF). Although sporadic cases of pheochromocytoma have been examined for mutations in exons 10, 11 and 16 of the RET gene, only one case with a mutation in exon 16 has been reported thus far. We are performing systematic examination of exons of the RET gene, which has previously been associated with mutation in both MEN2 A and B, to determine the role RET may play in the etiology of pheochromocytoma. Seventeen cases of sporadic pheochromocytoma and 3 cases of sporadic medullary thyroid carcinoma were obtained from the pathology archives. Histopathology of all specimens was confirmed to be either pheochromocytoma or medullary thyroid carcinoma before DNA was extracted from 0.5{mu} thin sections of paraffin-embedded tissue. DNA from familial pheochromocytoma patients was also available for analysis. All sporadic and familial cases were amplified for exons 2, 6 and 16 of the RET gene. Single strand conformational polymorphism (SSCP) analysis was performed for exons 2 and 6. On finding a variation in the SSCP pattern in the pheochromocytoma kindred we sequenced all the samples for exon 2. A single base pair variation was found, which did not segregate with pheochromocytoma in the family. No variant SSCP patterns have been observed with the exon 6 PCR products thus far. Exon 16 PCR products were subjected to DNA restriction analysis with Fok I. This enzyme detects a single base pair change associated with MEN2 B. With the exception of one sample with sporadic medullary thyroid carcinoma, all samples showed the normal pattern on DNA restriction analysis. Thus we can exclude exons 2 and 6 of the RET gene in the pathogenesis of pheochromocytoma. SSCP analyses with other exons in the RET gene are underway.

  2. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) associated with hypogammaglobulinemia and elevated serum tumor necrosis factor-alpha levels.

    PubMed

    Edrees, Amr F; Kaplan, David L; Abdou, Nabih I

    2002-10-01

    Pyogenic aseptic arthritis, pyoderma gangrenosum, and cystic acne (PAPA) syndrome is an unusual triad that was recently mapped to a chromosome 15q mutation. We describe a patient from this kindred in whom hypogammaglobulinemia and elevated tumor necrosis factor-alpha serum levels were detected. The patient responded well to intravenous gammaglobulin and intra-articular corticosteroid therapy. Immune abnormalities can be found in PAPA syndrome and could be the consequence of the chromosomal abnormalities affecting candidate genes on this chromosome with subsequent abnormalities in cytokine or chemokine secretion. Rheumatologists should be alert for this syndrome. Correction of the immune abnormalities may be effective in controlling the disease manifestations.

  3. Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family

    PubMed Central

    Syx, Delfien; Symoens, Sofie; Steyaert, Wouter; De Paepe, Anne; Coucke, Paul J.; Malfait, Fransiska

    2015-01-01

    Joint hypermobility is a common, mostly benign, finding in the general population. In a subset of individuals, however, it causes a range of clinical problems, mainly affecting the musculoskeletal system. Joint hypermobility often appears as a familial trait and is shared by several heritable connective tissue disorders, including the hypermobility subtype of the Ehlers-Danlos syndrome (EDS-HT) or benign joint hypermobility syndrome (BJHS). These hereditary conditions provide unique models for the study of the genetic basis of joint hypermobility. Nevertheless, these studies are largely hampered by the great variability in clinical presentation and the often vague mode of inheritance in many families. Here, we performed a genome-wide linkage scan in a unique three-generation family with an autosomal dominant EDS-HT phenotype and identified a linkage interval on chromosome 8p22-8p21.1, with a maximum two-point LOD score of 4.73. Subsequent whole exome sequencing revealed the presence of a unique missense variant in the LZTS1 gene, located within the candidate region. Subsequent analysis of 230 EDS-HT/BJHS patients resulted in the identification of three additional rare variants. This is the first reported genome-wide linkage analysis in an EDS-HT family, thereby providing an opportunity to identify a new disease gene for this condition. PMID:26504261

  4. Birth of a child with Down syndrome in a family transmitting an unusual chromosome 22 arising from a translocation between chromosomes 21 and an inverted chromosome 22

    SciTech Connect

    Aviv, H.A.; Desposito, F.; Lieber, C.

    1994-09-01

    Chromosomal analysis of a child with Down syndrome resulted in the identification of a family with an unusual translocation and in the definition of the translocation breakpoints. Studies were performed on the child, his siblings, mother, mother`s sister, and grandmother. All of the family members were carriers of the translocation. We performed G-banding, silver stain, C-banding, and hybridization with the following FISH probes (Oncor): {alpha}-satellite 13/21; {beta}-satellite, coatasome 21 and 22, and the probes for chromosome 22 at 22q11 (DiGeorge region) and 22q13.3 (control region). Using the banding techniques and probes, we characterized the karyotype as: 45,XX,-21,-22,+der(22),t(21;22)(22qter{r_arrow}22q11.2::22p13{r_arrow}22q11.2::21q11.2{r_arrow}21qter). The effect of deletion of 21q11.2 and the break of chromosome 22 in the DiGeorge region in this family is not clear. However, the presence of the translocation increases the risk of family members of conceiving children with Down syndrome.

  5. Lung Cysts, Spontaneous Pneumothorax, and Genetic Associations in 89 Families with Birt-Hogg-Dubé Syndrome

    PubMed Central

    Toro, Jorge R.; Pautler, Stephen E.; Stewart, Laveta; Glenn, Gladys M.; Weinreich, Michael; Toure, Ousmane; Wei, Ming-Hui; Schmidt, Laura S.; Davis, Lewis; Zbar, Berton; Choyke, Peter; Steinberg, Seth M.; Nguyen, Dao M.; Linehan, W. Marston

    2007-01-01

    Rationale: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal, dominantly inherited genodermatosis that predisposes to fibrofolliculomas, kidney neoplasms, lung cysts, and spontaneous pneumothorax. Objectives: We evaluated 198 patients from 89 families with BHDS to characterize the risk factors for pneumothorax and genotype–pulmonary associations. Methods: Helical computed tomography scans of the chest were used to screen for pulmonary abnormalities. BHD mutation data were used for genotype–pulmonary associations. We examined the relationship of pneumothorax with categorical parameters (sex, smoking history, and lung cysts) and continuous parameters (number of cysts, lung cyst volume, and largest cyst diameter and volume). Logistic regression analyses were used to identify the risk factors associated with pneumothorax. Measurements and Main Results: Twenty-four percent (48/198) of patients with BHDS had a history of pneumothorax. The presence of lung cysts was significantly associated with pneumothorax (p = 0.006). Total lung cyst volume, largest cyst diameter and volume, and every parameter related to the number of lung cysts were significantly associated (p < 0.0001) with pneumothorax. A logistic regression analysis showed that only the total number of cysts in the right parenchymal lower lobe and the total number of cysts located on the pleural surface in the right middle lobe were needed to classify a patient as to whether or not he or she was likely to have a pneumothorax. Exon location of the BHD mutation was associated with the numbers of cysts (p = 0.0002). Conclusions: This study indicates that patients with BHDS have a significant association between lung cysts and spontaneous pneumothorax. PMID:17322109

  6. Wolcott-Rallison Syndrome Is the Most Common Genetic Cause of Permanent Neonatal Diabetes in Consanguineous Families

    PubMed Central

    Rubio-Cabezas, Oscar; Patch, Ann-Marie; Minton, Jayne A. L.; Flanagan, Sarah E.; Edghill, Emma L.; Hussain, Khalid; Balafrej, Amina; Deeb, Asma; Buchanan, Charles R.; Jefferson, Ian G.; Mutair, Angham; Hattersley, Andrew T.; Ellard, Sian

    2009-01-01

    Context and Objective: Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes. Research Design and Methods: The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6). Results: Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group. Conclusions: WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent. PMID:19837917

  7. Comparison of Carotid Intima-Media Thickness in Pediatric Patients with Metabolic Syndrome, Heterozygous Familial Hyperlipidemia and Normals

    PubMed Central

    Vijayasarathi, Arvind; Goldberg, Stanley J.

    2014-01-01

    Background. Our goal was to compare the carotid intimal-medial thickness (CIMT) of untreated pediatric patients with metabolic syndrome (MS), heterozygous familial hyperlipidemia (heFH), and MS+heFH against one another and against a control group consisting of healthy, normal body habitus children. Methods. Our population consisted of untreated pediatric patients (ages 5–20 yrs) who had CIMT measured in a standardized manner. Results. Our population included 57 with MS, 23 with heFH, and 10 with MS+heFH. The control group consisted of 84 children of the same age range. Mean CIMT for the MS group was 469.8 μm (SD = 67), 443.8 μm (SD = 61) for the heFH group, 478.3 μm (SD = 70) for the MS+heFH group, and 423.2 μm (SD = 45) for the normal control group. Significance differences between groups occurred for heFH versus MS (P = 0.022), heFH versus control (P = 0.038), MS versus control (P = 9.0E − 10), and MS+heFH versus control (P = 0.003). Analysis showed significant negative correlation between HDL and CIMT (r = −0.32, P = 0.03) but not for LDL, triglycerides, BP, waist circumference, or BMI. Conclusion. For pediatric patients, the thickest CIMT occurred for patients with MS alone or for those with MS+heFH. This indicates that MS, rather than just elevated LDL, accounts for more rapid thickening of CIMT in this population. PMID:24955251

  8. A Novel Mutation of LAMB2 in a Multi-Generational Mennonite Family Reveals a New Phenotypic Variant of Pierson Syndrome

    PubMed Central

    Mohney, Brian G.; Pulido, Jose S.; Lindor, Noralane M.; Hogan, Marie C.; Consugar, Mark B.; Peters, Justin; Pankratz, V. Shane; Nasr, Samih H.; Smith, Stephen J.; Gloor, James; Kubly, Vickie; Spencer, Dorothy; Nielson, Rebecca; Puffenberger, Erik G.; Strauss, Kevin A.; Morton, D. Holmes; Eldahdah, Lama; Harris, Peter C.

    2011-01-01

    Purpose To describe a novel laminin beta-2 (LAMB2) mutation associated with nephritic syndrome and severe retinal disease without microcoria in a large, multi-generational family with Pierson syndrome. Design Retrospective chart review and prospective family examination. Participants An extended consanguineous family of 52 members. Methods The eyes, urine, and serum DNA were evaluated in all family members after discovering 2 patients, both less than 10 years of age, with bilateral retinal detachments and concurrent renal dysfunction. Linkage analysis was performed in the 9 living affected individuals, 7 using the Illumina Human Hap370 Duo Bead Array and 2 using GeneChip 10K mapping arrays. Main Outcome Measures The prevalence and severity of ocular and kidney involvement and genetic findings. Results Eleven affected family members were identified (9 living), all manifesting chronic kidney disease and bilateral chrioretinal pigmentary changes, with or without retinal detachments, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. The causative gene was localized to a 9Mb region on chromosome 3. Comprehensive gene sequencing revealed a novel LAMB2 variant (c. 440A>G; His147R) that was homozygous in the 9 living, affected family members, observed at a frequency of 2.1% in the Old Order Mennonite population, and absent in 91 non-Mennonite controls. The mutation is located in a highly conserved site in the N-terminal domain VI of LAMB2. Conclusions This study describes a novel mutation of LAMB2 and further expands the spectrum of eye and renal manifestations associated with defects in the laminin beta-2 chain. PMID:21236492

  9. Linkage of the Wiskott-Aldrich syndrome with polymorphic DNA sequences from the human X chromosome

    SciTech Connect

    Peacocke, M.; Siminovitch, K.A.

    1987-05-01

    The Wiskott-Aldrich syndrome (WAS) is one of several human immunodeficiency diseases inherited as an X-linked trait. The location of WAS on the X chromosome is unknown. The authors have studied 10 kindreds segregating for WAS for linkage with cloned, polymorphic DNA markers and have demonstrated significant linkage between WAS and two loci, DXS14 and DXS7, that map to the proximal short arm of the X chromosome. Maximal logarithm of odds (lod scores) for WAS-DXS14 and WAS-DWS7 were 4.29 (at 0 = 0.03) and 4.12 (at 0 = 0.00), respectively. Linkage data between WAS and six markers loci indicate the order of the loci to be (DXYS1-DXS1)-WAS-DXS14-DXS7-(DXS84-OTC). These results suggest that the WAS locus lies within the pericentric region of the X chromosome and provide an initial step toward identifying the WAS gene and improving the genetic counselling WAS families.

  10. Identification of a novel collagen type IV alpha-4 (COL4A4) mutation in a Chinese family with autosomal dominant Alport syndrome using exome sequencing

    PubMed Central

    Deng, Sheng; Xu, Hongbo; Yuan, Jinzhong; Xiao, Jingjing; Yuan, Lamei; Deng, Xiong; Guan, Liping; Zhu, Anding; Rong, Pengfei; Zhang, Jianguo; Deng, Hao

    2016-01-01

    Background & objectives: Alport syndrome (AS) is an inherited disorder characterized by glomerulonephritis and end-stage renal disease (ESRD). The aim of this study was to identify the gene responsible for the glomerulopathy in a Chinese family with autosomal dominant AS using exome sequencing. Methods: A 4-generation, 30-member Chinese Han family was enrolled in this study. Exome sequencing was conducted in the proband of the family, and then direct sequencing was performed in family members of the pedigree and 100 normal controls. Results: A novel frameshift mutation, c.3213delA (p.Gly1072Glufs*69), in the collagen type IV alpha-4 gene (COL4A4) was found to be the genetic cause. Neither sensorineural hearing loss nor ocular abnormalities were present in the patients of this family. Other clinical features, such as age of onset, age of ESRD occurring and disease severity, varied among the patients of this family. Interpretation & conclusions: A novel frameshift mutation, c.3213delA (p.Gly1072Glufs*69) in the COL4A4 gene, was identified in the Chinese pedigree with autosomal dominant AS. Our findings may provide new insights into the cause and diagnosis of AS and also have implications for genetic counselling. PMID:27934798

  11. Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33-q27.3.

    PubMed

    John, Peter; Ali, Ghazanfar; Chishti, Muhammad S; Naqvi, Syed Muhammad S; Leal, Suzanne M; Ahmad, Wasim

    2006-01-01

    Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33-q27.3. A maximum two-point LOD score of 3.05 (theta = 0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33-q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.

  12. Autosomal dominant syndrome of camptodactyly, clinodactyly, syndactyly, and bifid toes.

    PubMed

    Malik, Sajid; Afzal, Muhammad; Gul, Sumera; Wahab, Abdul; Ahmad, Mahmud

    2010-09-01

    We report on a 25-year follow-up of a Pakistani kindred with a unique combination of camptodactyly and clinodactyly of 5th fingers, mesoaxial camptodactyly of toes, and ulnar deviation of 3rd fingers. The less common anomalies in the affected subjects include syndactyly involving all digits, and bifid toes. This condition is grossly bilateral, symmetrical, and affects upper and lower limbs of the 26 affected subjects in the kindred. The comparable number of affected male and female subjects (chi(2) = 0.154, P < 0.1), disease allele transmission by mother and father, and the malformation segregation in four consecutive generations are strongly suggestive of autosomal dominant inheritance. Differential diagnosis considered syndactyly types II, III, and V. Only type II syndactyly manifests noticeable phenotypic overlap with the clinical presentation in this family; however, the typical type II syndactyly changes are absent. To the best of our knowledge, this autosomal dominant limb phenotype has not been reported previously.

  13. Screening of DFNB3 in Iranian families with autosomal recessive non-syndromic hearing loss reveals a novel pathogenic mutation in the MyTh4 domain of the MYO15A gene in a linked family

    PubMed Central

    Reiisi, Somayeh; Tabatabaiefar, Mohammad Amin; Sanati, Mohammad Hosein; Chaleshtori, Morteza Hashemzadeh

    2016-01-01

    Objective(s): Non-syndromic sensorineural hearing loss (NSHL) is a common disorder affecting approximately 1 in