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Adrenocorticotropin-Dependent Precocious Puberty of Testicular Origin in a Boy with X-Linked Adrenal Hypoplasia Congenita Due to a Novel Mutation in the DAX1 Gene

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM 42 da Disciplina de Endocrinologia e Metabologia (S.D., A.C.L., V.N.B., I.J.P.A., B.B.M.), and Departamento de Neurologia, Hospital das Clínicas (F.K.), Universidade de São Paulo, Caixa Postal 3671, Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Berenice B. Mendonca, M.D., Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Caixa Postal 3671, Sao Paulo, Brazil. E-mail: beremen{at}usp.br

Abstract

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 manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.

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