NOVEL DAX-1 (NR0B1) MUTATION IN A THAI BOY WITH X-LINKED ADRENAL HYPOPLASIA CONGENITA (AHC): A FIRST REPORT

Abstract

Background:Adrenal hypoplasia congenita (AHC) is a rare inherited disorder of adrenal development resulting in hypoplasia of adrenal gland and inability to produce glucocorticoids, mineralocorticoids and sex steroids. X-linked AHC is the most common form and is caused by mutation of the DAX1 gene. Here we report a case of 4-year-old Thai boy with X-linked AHC, the first case of genetically confirmed novel DAX1 mutation in Thailand. Patient and Method:A 4-year-old Thai boy presented with fever and vomiting for 3 days. He was the fifth child of unrelated parents. The past medical history was unremarkable except his skin had been progressively more pigmented since early infancy. Physical examination revealed normal genital development and addisonian hyperpigmentation which prominent at skin crease, gum and knuckles. Laboratory investigations showed hyponatremia, hyperkalemia, and hypochloremia. Hormonal evaluation revealed low baseline cortisol level which is not rising after 250 mg ACTH stimulation test. ACTH level and plasma renin activity were elevated. A diagnosis of X-linked AHC was established. Glucocorticoid and mineralocorticoid replacement therapy were initiated. Molecular analysis by direct DNA sequencing of the DAX1 gene was performed in the patient and family members. Result:Mutation analysis revealed a novel hemizygous GG deletion (c.1148_1149delGG) resulting in a premature termination codon at the position 387 (p.Gly383Aspfs*5). This frameshift mutation was predicted to encode a truncated DAX1 protein missing a portion of ligand binding domain. The mutation identified in our proband was inherited from his carrier mother. Conclusion:We report a case of classical X-linked AHC with established a novel frameshift mutation in the DAX1 gene. Genetic analysisis important not only for diagnostic confirmation in the index case but also for carrier detection in his mother which provided a proper management and appropriate genetic counseling for this famity.