Multiplex ligation-dependent probe amplification analysis of the NR0B1(DAX1) locus enables explanation of phenotypic differences in patients with X-linked congenital adrenal hypoplasia

Horm Res Paediatr. 2012;77(2):100-7. doi: 10.1159/000336344. Epub 2012 Mar 23.


Background/aim: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadic hypogonadism. It is caused by deletions or point mutations of the NR0B1 gene, on Xp21. AHC can be associated with glycerol kinase deficiency, Duchenne muscular dystrophy and mental retardation (MR), as part of a contiguous gene deletion syndrome. A synthetic probe set for multiplex ligation-dependent probe amplification analysis was developed to confirm and characterize NR0B1 deletions in patients with AHC and to correlate their genotypes with their divergent phenotypes.

Results: In 2 patients, isolated AHC was confirmed, while a patient at risk for metabolic crisis was revealed as the deletion extends to the GK gene. A deletion extending to IL1RAPL1 was confirmed in both patients showing MR. Thus, a good genotype-phenotype correlation was confirmed.

Conclusions: Multiplex ligation-dependent probe amplification analysis is a valuable tool to detect NR0B1 and contiguous gene deletions in patients with AHC. It is especially helpful for IL1RAPL1 deletion detection as no clinical markers for MR are available. Furthermore, multiplex ligation-dependent probe amplification has the advantage to identify female carriers that, depending on the deletion extension, have a high risk of giving birth to children with MR, AHC, glycerol kinase deficiency and Duchenne muscular dystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Hyperplasia, Congenital / genetics*
  • Adrenal Hyperplasia, Congenital / metabolism
  • Adrenal Hyperplasia, Congenital / physiopathology*
  • Adrenal Insufficiency
  • Adult
  • Child
  • DAX-1 Orphan Nuclear Receptor / genetics*
  • DAX-1 Orphan Nuclear Receptor / metabolism
  • Female
  • Gene Deletion*
  • Genetic Association Studies
  • Genetic Carrier Screening / methods
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Diseases, X-Linked / physiopathology*
  • Genetic Loci*
  • Humans
  • Hypoadrenocorticism, Familial
  • Infant
  • Interleukin-1 Receptor Accessory Protein / genetics
  • Interleukin-1 Receptor Accessory Protein / metabolism
  • Male
  • Mental Retardation, X-Linked / genetics
  • Mothers
  • Multiplex Polymerase Chain Reaction
  • Nucleic Acid Amplification Techniques
  • Oligonucleotide Array Sequence Analysis
  • Sweden


  • DAX-1 Orphan Nuclear Receptor
  • IL1RAPL1 protein, human
  • Interleukin-1 Receptor Accessory Protein
  • NR0B1 protein, human