Unusual phenotype of congenital adrenal hyperplasia (CAH) with a novel mutation of the CYP21A2 gene

J Pediatr Endocrinol Metab. 2016 Jul 1;29(7):867-71. doi: 10.1515/jpem-2015-0457.

Abstract

Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.

Publication types

  • Case Reports

MeSH terms

  • Adrenal Hyperplasia, Congenital / blood
  • Adrenal Hyperplasia, Congenital / drug therapy
  • Adrenal Hyperplasia, Congenital / genetics*
  • Adrenal Hyperplasia, Congenital / physiopathology
  • Amino Acid Substitution
  • Child
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors
  • Heterozygote
  • Humans
  • Introns
  • Leuprolide / therapeutic use
  • Male
  • Mutation*
  • Puberty, Precocious / etiology
  • Puberty, Precocious / prevention & control
  • Steroid 21-Hydroxylase / genetics*
  • Testosterone / antagonists & inhibitors
  • Testosterone / blood
  • Treatment Outcome

Substances

  • Gonadotropin-Releasing Hormone
  • Testosterone
  • CYP21A2 protein, human
  • Steroid 21-Hydroxylase
  • Leuprolide

Supplementary concepts

  • Congenital adrenal hyperplasia due to 21 hydroxylase deficiency