RESUMO
OBJECTIVES: To determine the genetic basis of disordered steroidogenesis in Kuwaiti siblings. STUDY DESIGN: Two siblings (46,XX and 46,XY) had normal female external genitalia and severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Abdominal ultrasonography showed normal size adrenal glands, suggesting cholesterol side chain cleavage enzyme (P450scc) deficiency. The CYP11A1 gene encoding P450scc and the STAR gene encoding the steroidogenic acute regulatory protein (StAR) were directly sequenced from leukocyte DNA. RESULTS: All exons and intron/exon boundaries of the CYP11A1 gene were normal; the STAR gene was homozygous for a novel 14-base deletion/frameshift in exon 4 (g.4643_4656del), so that no functional protein could be produced. Both parents and an unaffected sibling were heterozygous; zygosity was confirmed with a BsmF1 restriction fragment length polymorphism. CONCLUSIONS: Unlike most patients with StAR deficiency, our patients did not have the massive adrenal hyperplasia typical of congenital lipoid adrenal hyperplasia. The distinction between StAR and P450scc deficiency may require gene sequencing.
Assuntos
Insuficiência Adrenal/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/deficiência , Fosfoproteínas/deficiência , Insuficiência Adrenal/diagnóstico , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , DNA/metabolismo , Éxons , Saúde da Família , Feminino , Glucocorticoides/deficiência , Homozigoto , Humanos , Recém-Nascido , Íntrons , Kuweit , Leucócitos/metabolismo , Mineralocorticoides/deficiência , Modelos Genéticos , Mutação , Linhagem , Polimorfismo de Fragmento de RestriçãoRESUMO
The patient is a 24-year-old woman who first came for consultation at age 10 years. Based on clinical phenotype and thin-layer chromatography of urinary oligosaccharides, peripheral leukocytes were sent for beta-galactosidase assay. This testing showed a deficiency in enzyme activity, and gene mutation analysis identified a previously reported mutation p.H281Y (875C > T) and a novel mutation p.W273R (817T > C). Unlike previously reported patients, mutant enzymes in this patient's cultured skin fibroblasts did not respond to treatment with a chaperone compound, N-octyl-4-epi-beta-valienamine.