RESUMO
Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive condition associated with exocrine pancreatic insufficiency, and is characterized by hypoplastic nasal alae, mental retardation, sensorineural hearing loss, short stature, scalp defects, dental abnormalities and abnormal hair patterns. Growth hormone deficiency, hypopituitarism, and impaired glucagon secretion response to insulin-induced hypoglycemia have been reported. Congenital heart defects have also been described in this condition. Mental retardation is typically moderate to severe in patients with JBS; however, normal intelligence can occur. In the pancreas, there is a selective defect of acinar tissue, whereas the islets of Langerhans and ducts are preserved. Diabetes has been reported in older children, suggesting the progressive nature of pancreatic disease. The molecular basis of JBS has recently been mapped to chromosome 15q15-q21 with identified mutations in the UBR1 gene. We report the case of a 7-year-old female with pancreatic insufficiency and mild phenotypic features, in whom the diagnosis of JBS was established using recently described molecular testing for the UBR1 gene.
Assuntos
Anormalidades Múltiplas/diagnóstico , Cromossomos Humanos Par 15 , Análise Mutacional de DNA , Insuficiência Pancreática Exócrina/diagnóstico , Testes Genéticos , Perda Auditiva Neurossensorial/diagnóstico , Deficiência Intelectual/diagnóstico , Ubiquitina-Proteína Ligases/genética , Anormalidades Múltiplas/genética , Criança , Insuficiência Pancreática Exócrina/genética , Feminino , Genótipo , Perda Auditiva Neurossensorial/genética , Humanos , Deficiência Intelectual/genética , Fenótipo , Índice de Gravidade de Doença , Síndrome , Tomografia Computadorizada por Raios XRESUMO
We report on two apparently unrelated girls with Johanson-Blizzard syndrome (JBS), in both children caused by a homozygous IVS26+5G>A mutation in the UBR1 gene. In both cases the parents are consanguineous and more sibs are affected. The somewhat mild phenotype (with no or slight mental retardation) in these two JBS families might be explained by residual UBR1 activity. One case has a dilated cardiomyopathy, a symptom only rarely reported in JBS, but of important clinical significance.
Assuntos
Anormalidades Múltiplas/genética , Cardiomiopatia Dilatada/genética , Deficiência Intelectual/genética , Ubiquitina-Proteína Ligases/genética , Anormalidades Múltiplas/diagnóstico , Cardiomiopatia Dilatada/diagnóstico , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Mutação , Linhagem , SíndromeRESUMO
BACKGROUND: Heterozygous gain-of-function mutations in various genes encoding proteins of the Ras-MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS. METHODS AND RESULTS: We investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene. CONCLUSION: We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gain-of-function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.