Variable phenotype in a novel mutation in PHOX2B

Rachel C. Lombardo, Elizabeth Kramer, James F. Cnota, Hemant Sawnani, Robert J. Hopkin

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


We evaluated a family with three siblings, two of whom ages 2 years and 19 months, had long segment colonic agangliosis and anisocoria. The mother also had anisocoria. All three affected family members were mildly dysmorphic with a flat facial profile, square appearance to the face, depressed nasal bridge, and anteverted nares. Genetic testing identified a novel heterozygous mutation, c.234C>G, resulting in a premature stop codon in exon 1 of the PHOX2B gene. Screening for neural crest tumors was performed in the siblings and to date has been negative. This family supports a strong association between non polyalanine tract mutations, autonomic dysfunction, and Hirschsprung disease, but suggests mutation outside of the polyalanine tract may not dictate severe phenotype with significant respiratory compromise. A unique finding in this family is the association of congenital heart disease in two of the affected patients. These malformations may be a sporadic isolated finding or the result of environmental factors or a modifying allele. Given the association between congenital heart disease and aberrant neural crest cell development, however, findings are suggestive that congenital heart disease may be a rare feature of PHOX2B mutation which has not been previously reported.

Original languageEnglish (US)
Pages (from-to)1705-1709
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Issue number6
StatePublished - Jun 2017
Externally publishedYes


  • congenital central hypoventilation syndrome
  • congenital heart disease
  • Hirschsprung
  • neuroblastoma
  • PHOX2B

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Variable phenotype in a novel mutation in PHOX2B'. Together they form a unique fingerprint.

Cite this