RESUMO
Mutations in the GH receptor gene have been identified as the cause of growth hormone insensitivity syndrome (GHIS), a rare autosomal recessive disorder. We studied the clinical and biochemical characteristics and the coding sequence and intron-exon boundaries of the GH receptor gene in a consanguineous family with severe short stature which consisted of two patients, their parents and five siblings. The two adolescents had heights of -4.7 and -5.5 SDS, respectively, with elevated growth hormone associated with low IGF-I, IGFBP-3 and GHBP concentrations. Molecular analysis of the GH receptor gene revealed a mutation in exon 6, present in both patients This mutation, E180 splice, has been previously described in an Ecuadorian cohort, and in one Israeli and six Brazilian patients. We determined the GH receptor haplotypes based on six polymorphic sites in intron 9. Co-segregation of the E180splice mutation with haplotype I was found in this family, compatible with a common Mediterranean ancestor, as shown for previous cases with the E180splice mutation described to date.
Assuntos
Síndrome de Laron/etnologia , Síndrome de Laron/genética , Mutação/genética , Receptores da Somatotropina/genética , População Branca/genética , Adolescente , Adulto , Estatura/genética , Criança , Chile , Éxons/genética , Feminino , Haplótipos/genética , Humanos , Masculino , Região do Mediterrâneo/etnologia , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
CONTEXT: Isolated hypospadias may result from impaired testicular function or androgen end-organ defects or, alternatively, from hormone-independent abnormalities of morphogenetic events responsible for urethral seam. OBJECTIVE: The objective was to evaluate the relative prevalence of hormone-dependent etiologies in boys with isolated hypospadias. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURES: We studied endocrine testicular capacity in 61 patients with isolated hypospadias and 28 with hypospadias associated with micropenis, cryptorchidism, or ambiguous genitalia. Serum anti-Müllerian hormone and inhibin B were used as Sertoli cell markers. A human chorionic gonadotropin test was performed to evaluate Leydig cell function. RESULTS: Testicular dysfunction was observed in 57.1% and androgen end-organ defects in 7.2% of patients with hypospadias associated with cryptorchidism, micropenis, or ambiguous genitalia. In the remaining 35.7%, the disorder was idiopathic. The presence of ambiguous genitalia predicted the existence of testicular or end-organ dysfunction with 81.8% specificity. Isolated hypospadias was associated in 14.8% of patients with testicular dysfunction and in 6.5% of cases with end-organ defects; in 78.7% of cases, the condition was idiopathic. The occurrence of isolated hypospadias ruled out the existence of testicular or end-organ disorders with 80.0% sensitivity. Altogether our data indicate that the risk for the existence of an underlying testicular or end-organ dysfunction is low in patients with isolated hypospadias (odds ratio, 0.13; 95% confidence interval, 0.05-0.36; P < 0.001). CONCLUSIONS: Boys with isolated hypospadias are more likely to have normal endocrine testicular and androgen end-organ functions, suggesting that transient disruption of morphogenetic events in early fetal life may be the predominant underlying cause.