Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene

J Clin Endocrinol Metab. 1998 Aug;83(8):2666-74. doi: 10.1210/jcem.83.8.5027.


X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with glycerol kinase deficiency (GKD) and Duchenne's muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne's muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates' persisting fetocortex. Aldosterone deficiency usually preceded cortisol deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional truncated DAX-1 protein. Two brothers with primary adrenal insufficiency and a medical history that strongly suggested AHC had no mutation in the DAX-1 gene. Thus, additional, as yet unknown genes must play a part in normal adrenal cortical development.

MeSH terms

  • Adrenal Insufficiency / diagnosis*
  • Adrenal Insufficiency / genetics*
  • Adrenocorticotropic Hormone
  • Aging
  • Aldosterone / blood
  • Aldosterone / deficiency
  • Amino Acid Sequence
  • Base Sequence
  • DAX-1 Orphan Nuclear Receptor
  • DNA Mutational Analysis
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Genetic Linkage
  • Glycerol Kinase / deficiency
  • Humans
  • Hydrocortisone / blood
  • Hydrocortisone / deficiency
  • Infant
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Muscular Dystrophies / complications
  • Muscular Dystrophies / genetics
  • Point Mutation*
  • Polymerase Chain Reaction
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / genetics*
  • Repressor Proteins*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • X Chromosome


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