Adrenocorticotropin-dependent precocious puberty of testicular origin in aboy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene

Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical mani festation was isosexual gonadotropin-independent precocious puberty. He pre sented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were com patible with a prepubertal pattern. Chronic GnRH agonist therapy did not re duce T levels, supporting the diagnosis of gonadotropin-independent precoci ous puberty. Testotoxicosis was ruled out after normal sequencing of exon 1 1 of the LH receptor gene. At age 3 yr he developed clinical and hormonal f eatures of severe primary adrenal insufficiency. The entire coding region o f the DAX1 gene was analyzed through direct sequencing. A nucleotide G inse rtion between nucleotides 430 and 431 in exon 1, resulting in a novel frame shift mutation and a premature stop codon at position 71 of DAX-1, was iden tified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings su ggest that chronic excessive ACTH levels resulting from adrenal insufficien cy may stimulate Leydig cells and lead to gonadotropin-independent precocio us puberty in some boys with DAX1 gene mutations.