Heterozygous 24-polyalanine repeats in the PHOX2B gene with different manifestations across three generations

Pediatr Pulmonol. 2014 Feb;49(2):E13-6. doi: 10.1002/ppul.22731. Epub 2013 Mar 4.

Abstract

Congenital central hypoventilation syndrome (CCHS) is an uncommon genetic disorder that is characterized by alveolar hypoventilation and autonomic dysregulation. More than 90% of the patients are heterozygous for polyalanine repeat expansion mutations in the paired-like homeobox 2b (PHOX2B) gene. The normal genotype has a 20-polyalanine sequence whereas expanded alleles are usually 25-33. Heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene has rarely been reported. We report three consecutive generations harboring heterozygous 24-polyalanine repeats in the PHOX2B gene with manifestations ranging from apparently asymptomatic to alveolar hypoventilation and apnea requiring mechanical ventilation. The 3-year-old proband developed cor pulmonale and central hypoventilation following an upper respiratory tract infection. Our findings add to the accumulating evidence that the 24-polyalanine repeat in the PHOX2B is a disease-causing mutation. In addition, a high index of suspicion and careful monitoring after anesthesia, sedation, or respiratory illnesses should be exercised when evaluating asymptomatic family members with this genotype.

Keywords: PHOX2B; central hypoventilation syndrome; cor pulmonale.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Child, Preschool
  • DNA Repeat Expansion*
  • Female
  • Genetic Markers
  • Heterozygote*
  • Homeodomain Proteins / genetics*
  • Humans
  • Hypoventilation / congenital*
  • Hypoventilation / diagnosis
  • Hypoventilation / genetics
  • Peptides / genetics*
  • Sleep Apnea, Central / diagnosis
  • Sleep Apnea, Central / genetics*
  • Transcription Factors / genetics*

Substances

  • Genetic Markers
  • Homeodomain Proteins
  • NBPhox protein
  • Peptides
  • Transcription Factors
  • polyalanine

Supplementary concepts

  • Congenital central hypoventilation syndrome