X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism: report on new mutation of the DAX-1 gene in two siblings.

OBJECTIVE: Adrenal hypoplasia congenita (AHC) is a hereditary disorder that leads to adrenal insufficiency and hypogonadotropic hypogonadism (HHG) in childhood. The gene responsible for the X-linked form, DAX-1 (dosage-sensitive sex-reversal, AHC, on the X-chromosome, gene 1)/NR0B1, encodes for an unusual member of the nuclear receptor superfamily. Deletions and point mutations in the DAX-1 gene have been described in more than 70 AHC families. Inter- and intra-familial variability in the clinical presentation of AHC has been observed. Here we present the clinical and genetic data of two brothers affected by AHC. SUBJECTS AND METHODS: Clinical heterogeneity was observed in the two brothers: the first presented with adrenal insufficiency in early infancy, while the second required no substitution therapy until 4 yr of age. Interestingly, mineralcorticoid hormone deficiency preceded cortisol deficiency in both brothers. HHG was observed at pubertal age in both patients and required substitution therapy with gonadal steroids.
RESULTS: Sequence analysis revealed a novel mutation in the DAX-1 gene in the two brothers and in their carrier mother. The mutation, a three nucleotide deletion, results in the loss of leucine 278 (del278L). A missense mutation affecting the same leucine (L278P) was previously shown to cause marked reduction of repressor function with respect to the wild type protein in transcription assays.
CONCLUSIONS: Missense mutations or amino acid loss in the DAX-1 gene are very rare. Their identification and genotype-phenotype correlation are important for the characterization of protein function and for patient management.