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

Abstract

Introduction: X-linked Adrenal Hypoplasia Congenita (AHC, OMIM#300200) is a rare disorder that can be inherited in an X-linked or autosomal recessive pattern. Primary adrenocortical failure due to the lack of permanent adult cortical zone of the adrenals occurs in X-linked AHC and is caused by mutations in DAX1 (NR0B1) gene (OMIM*300473) located on the short arm of the X-chromosome (Xp21.3) and encoding for a nuclear hormone receptor. Patients and methods: Here we present two boys with AHC aged 7 years 10 months and 1 year 3 months, respectively, who came to our attention at the age of 15 days and 10 days, respectively in a life-threatening state. Laboratory studies showed hyponatremia (124mEq/l and 112mEq/l) and hyperkaliemia (6, 06mEq/l and 7, 8mEq/l), respectively. All laboratory results are shown in the Table 1. Primary adrenal insufficiency was confirmed with a severely low serum cortisol levels and high plasma ACTH levels. The hydrocortisone therapy with saline and glucose infusions were started immediately. Two exons of the DAX1 gene were amplified using PCR and subsequently directly sequenced. Results and conclusions: Molecular analysis of the DAX1 gene coding region and the adjacent splicing sites revealed a novel mutation c.315G>A (W105X) in exon 1 that resulted in a premature stop codon generation and destroying the ligand binding domain of DAX1 protein. Similar, but not identical c.314G>A (W105X) mutation was only found in one patient described by Choi et al (Horm Res Paediatr, 2005) . c.315G>A mutation was also present in both heterozygous healthy mothers, maternal grandmother and her two out of six sisters, while was absent in the maternal grandgrandmother indicating the existence of gonadal mosaicism. We conclude the novel DAX1 mutation in this family and show that this analysis is important for the confirmation of the diagnosis and highlight the critical role of genetic counseling in families with AHC patients.