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.
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.
Domenice
S
S
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM 42 da Disciplina de Endocrinologia e Metabologia, Universidade de São Paulo, Caixa Postal 3671, Sao Paulo, Brazil.
Latronico
A C
AC
Brito
V N
VN
Arnhold
I J
IJ
Kok
F
F
Mendonca
B B
BB
D000307:Adrenal Gland Diseases / Q000151:congenital* / Q000235:genetics* / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000502:physiology*; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor; D004247:DNA / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics*; D006728:Hormones / Q000097:blood; D006801:Humans; D008297:Male; D009154:Mutation; D011629:Puberty, Precocious / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000473:pathology / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics*
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D006728:Hormones; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D000324:Adrenocorticotropic Hormone; D004247:DNA