RESUMO
The semaphorins constitute a large family of secreted and membrane-associated proteins that regulate many developmental processes, including neural circuit assembly, bone formation and angiogenesis. Recently, bi-allelic loss-of-function variants in SEMA3A (semaphorin 3A) were identified in a single patient with a particular pattern of multiple congenital anomalies (MCA). Using homozygosity mapping combined with exome sequencing, we identified a homozygous SEMA3A variant causing a premature stop codon in an 8 year old boy with the same pattern of MCA. The phenotype of these patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Motor development is delayed in both patients, and intellectual development is delayed in one patient. Our observation of a second case supports the notion that bi-allelic mutations in SEMA3A cause an autosomal recessive type of syndromic short stature.
Assuntos
Anormalidades Múltiplas/genética , Artrogripose/genética , Nanismo/genética , Semaforina-3A/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Alelos , Artrogripose/complicações , Artrogripose/diagnóstico por imagem , Artrogripose/fisiopatologia , Criança , Pré-Escolar , Nanismo/complicações , Nanismo/diagnóstico por imagem , Nanismo/fisiopatologia , Homozigoto , Humanos , Masculino , Linhagem , FenótipoRESUMO
OBJECTIVE: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal dysplasia characterized by the association of hyperkeratotic skin lesions, moderate to profound sensorineural hearing loss and vascularizing keratitis. Mutations in the GJB2 gene coding for connexin 26, a component of gap junctions in epithelial cells, have been observed in several KID patients. Variable ocular manifestations of the disease in 3 patients with molecular genetically confirmed KID syndrome are reported. DESIGN: Retrospective case series. METHODS: Clinical examination and molecular genetic analysis for mutations in the GJB2 gene were performed in 3 patients with KID syndrome ages 5, 13, and 41 years. RESULTS: Visual acuity ranged from normal to severe visual loss. The ocular signs included loss of eyebrows and lashes, thickened and keratinized lids, trichiasis, recurrent corneal epithelial defects, superficial and deep corneal stromal vascularization with scarring, keratoconjunctivitis sicca, and, in one patient, presumed limbal insufficiency. Whereas ocular surface integrity could be maintained with artificial tears in one patient, and an epithelial defect healed under conservative treatment in the second patient, multiple surgical procedures including superficial keratectomies, limbal allograft transplantation with systemic immunosuppression, amniotic membrane transplantation, lateral tarsorrhaphies, and lamellar keratoplasty could not preserve useful vision in the third patient. CONCLUSIONS: KID syndrome may affect the ocular adnexae and surface with variable severity independent of the age of the patient. Lid abnormalities, corneal surface instability, limbal stem cell deficiency with resulting corneal complications, and dry eye are the main ocular manifestations.
Assuntos
Surdez/diagnóstico , Oftalmopatias/diagnóstico , Doenças do Cabelo/diagnóstico , Eritrodermia Ictiosiforme Congênita/diagnóstico , Ceratite/diagnóstico , Adolescente , Adulto , Pré-Escolar , Conexina 26 , Conexinas/genética , Neovascularização da Córnea/diagnóstico , Substância Própria/irrigação sanguínea , Surdez/congênito , Surdez/tratamento farmacológico , Oftalmopatias/tratamento farmacológico , Oftalmopatias/genética , Pestanas/patologia , Doenças Palpebrais/diagnóstico , Feminino , Humanos , Eritrodermia Ictiosiforme Congênita/tratamento farmacológico , Ceratite/congênito , Ceratite/tratamento farmacológico , Ceratoconjuntivite Seca/diagnóstico , Masculino , Mutação , Soluções Oftálmicas/uso terapêutico , Estudos Retrospectivos , Síndrome , Acuidade VisualAssuntos
Anormalidades Múltiplas/genética , Anodontia/genética , Surdez/genética , Orelha Interna/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Tálus/anormalidades , Anormalidades Múltiplas/patologia , Pré-Escolar , Cromossomos Humanos Par 7 , Surdez/patologia , Orelha Média/anormalidades , Displasia Ectodérmica/genética , Fácies , Deformidades Congênitas do Pé/diagnóstico por imagem , Deformidades Congênitas do Pé/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Repetições de Microssatélites , Radiografia , Deleção de Sequência , SíndromeRESUMO
We report molecular and clinical findings in 13 patients with rare types of glycogen storage disease 1 (GSD1 non-a). Analysis of G6PT encoding a microsomal transporter protein has revealed mutations on both chromosomes in each case, four of which are novel. Diagnosis has been confirmed in three patients suspected of having GSD1 non-a without enzymatic studies involving liver biopsy, thus emphasising the advantage of G6PT mutation analysis for all GSD1 non-a patients.
Assuntos
Doença de Depósito de Glicogênio Tipo I/genética , Mutação , Fosfotransferases/genética , Adolescente , Antiporters , Criança , Pré-Escolar , Cromossomos Humanos Par 11 , Doença de Crohn/genética , Feminino , Transtornos do Crescimento/genética , Humanos , Lactente , Masculino , Proteínas de Transporte de Monossacarídeos , Neutropenia/genética , Transtornos Psicomotores/genéticaRESUMO
Usher syndrome is a heterogeneous autosomal recessive trait and the most common cause of hereditary deaf-blindness. Usher syndrome type I (USH1) is characterised by profound congenital sensorineural hearing loss, vestibular dysfunction, and prepubertal onset of retinitis pigmentosa. Of the at least six different loci for USH1, USH1B maps on chromosome 11q13, and the MYO7A gene has been shown to be defective in USH1B. MYO7A encodes myosin VIIA, an unconventional myosin, and it consists of 48 coding exons. In this study, MYO7A was analysed in 34 unrelated Usher type I patients by single-strand conformation polymorphism analysis and direct sequencing. We identified a total of 12 novel and unique mutations, all single base changes. In addition, we found a previously reported nonsense mutation (C31X) on nine alleles of a total of six patients from Denmark.