A novel mutation in the NR0B1 (DAX1) gene in a large family with two boys affected by congenital adrenal hypoplasia.

OBJECTIVE X-linked Adrenal Hypoplasia Congenita (AHC) is a rare disorder caused by mutations in NR0B1 (DAX1) gene. DESIGN We present two boys (cousins) with AHC who came to our attention at the age of 10 days and 15 days, respectively, in a life-threatening state. Laboratory studies in their neonatal periods showed hyponatremia and hyperkalemia. Primary adrenal insufficiency was confirmed, with severely low serum cortisol levels and high plasma ACTH levels. Hydrocortisone therapy with additional saline and glucose infusions were started immediately. Two exons of the NR0B1 (DAX1) gene were amplified using PCR and directly sequenced. RESULTS Molecular analysis of the NR0B1 (DAX1) gene revealed a novel mutation, c.315G>A (p.W105X) in exon 1, resulting in the formation of a premature stop codon. Further studies showed that mothers, the maternal grandmother and two of six maternal great aunts were heterozygotes for the mutation. However, the mutation was absent in the maternal great-grandmother. CONCLUSIONS We show that NR0B1 (DAX1) gene analysis is of great importance for the confirmation of the clinical diagnosis of AHC and highlights the role of genetic counseling for families of AHC patients. The absence of a somatic mutation in the great-grandmother suggests gonadal mosaicism as the mechanism for transmission of the NR0B1 (DAX1) mutation in this family.