Identification and Functional Analysis of Six Mutations in Patients With X-Linked Adrenal Hypoplasia Congenita.

CONTEXT

() mutations cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) in affected male patients. Affected individuals typically present with early-onset adrenal insufficiency and develop HH during puberty. Rare cases can present with late-onset adrenal insufficiency or other unusual phenotypes.

OBJECTIVES

We sought to identify and functionally characterize mutations in seven Thai male subjects in six families with X-linked AHC.

PATIENTS AND METHODS

Six patients had classic phenotypes with early-onset adrenal failure. One patient presented with late-onset Addison disease at 17 years. In the early-onset group, one patient had GnRH-independent sexual precocity at 3 years of age, and another patient had growth hormone deficiency. The gene was sequenced from all patients, and the transcriptional activities of the identified mutations were assessed using luciferase assays.

RESULTS

mutations were identified in all patients, including three novel mutations [c.363delG (p.Gly122Valfs142), c.1062delC (p.Ala355Profs17), and c.1156C>T (p.Leu386Phe)] and three known mutations [c.1148_1149delGG (p.Gly383Aspfs5), c.501_502insG (p.Ala170Argfs15), and c.805_807delGTC (p.Val269del)]. Functional studies showed that the mutants had lower levels of repressor activity on the gene promoter compared with the wild-type DAX-1 protein.

CONCLUSIONS

This study describes unusual phenotypes and three novel mutations, extending the phenotypic and mutational spectra of mutations.