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

J Clin Endocrinol Metab. 2001 Sep;86(9):4068-71. doi: 10.1210/jcem.86.9.7816.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Diseases / congenital*
  • Adrenal Gland Diseases / genetics*
  • Adrenal Gland Diseases / physiopathology
  • Adrenocorticotropic Hormone / physiology*
  • Child, Preschool
  • DAX-1 Orphan Nuclear Receptor
  • DNA / analysis
  • DNA / genetics
  • DNA-Binding Proteins / genetics*
  • Genetic Linkage / genetics*
  • Hormones / blood
  • Humans
  • Male
  • Mutation
  • Puberty, Precocious / etiology
  • Puberty, Precocious / pathology
  • Puberty, Precocious / physiopathology*
  • Receptors, Retinoic Acid / genetics*
  • Repressor Proteins*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Testis / pathology
  • Testis / physiopathology*
  • Transcription Factors / genetics*

Substances

  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Hormones
  • NR0B1 protein, human
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Transcription Factors
  • Adrenocorticotropic Hormone
  • DNA