X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients

Mutations of the DAX-1 gene, which encodes a newly discovered member of the nuclear hormone receptor family, were reported to cause X-linked congenita l adrenal hypoplasia and hypogonadotrophic hypogonadism. While genetic data on DAX-1 are accumulating, information on the clinical course of the disor der are scarce. Here we present a detailed documentation of longitudinal da ta relating to three cases. We retrospectively collected clinical data on three boys (6, 14 and 14.5 ye ars old) who we examined over a period ranging between 5 and 14 years. Muta tional analysis of the DAX-1 gene was performed by means of direct sequenci ng of PCR products. The patients presented at ages between 4 and 6 weeks with salt-wasting, but there was no evidence of hypoglycaemia. All three cases were initially err oneously diagnosed with isolated aldosterone deficiency. Glucocorticoid def iciency was established by means of ACTH stimulation tests at 4 months, 3 a nd 13 years of age. One boy, whose therapy was discontinued at the age of 4 months, developed normally until adrenal crisis occurred at the age of 13 years. In all three cases, congenital hypogonadism was ruled out during inf ancy, as penis sire was normal, the testes were descended, and serum sample s contained normal testosterone levels. One boy exhibited transient hypergo nadotrophism at age 9 but showed no clinical signs of puberty or an increas e in serum testosterone. Onset of puberty and LHRH tests proved to be norma l in his case as well as in another patient studied. In two patients, genet ic analysis revealed new mutations at the C-terminus of DAX-1, these being a 1-base deletion (656delG) inherited from the mother and a de-novo 2-base insertion (728insCA) of the DAX-1 gene, respectively, both causing frame sh ift and premature stops at codons 263 and 398. One boy was affected by a ne w nonsense mutation of codon 39 (W39X) inherited from his mother. Mineralocorticoid deficiency preceded glucocorticoid deficiency which could be diagnosed through ACTH stimulation after the neonatal period. Transitor y functional recovery of the adrenal glands can occur in adrenal hypoplasia congenita (AHC). Transient hypergonadotrophism may be one of the first ind icators of defects in the gonadal axis, although normal initiation of puber ty is not rare. The definitive diagnosis was established by means of molecu lar analysis of the DAX-1 gene. There was no correlation between types of m utations and phenotypes. The diagnostic procedure in male children and adol escents presenting with adrenal crisis should include ACTH stimulation test s and mutational analysis of DAX-1 in the absence of another proven aetiolo gy.