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Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series

Elizabeth Bygarski14, Melanie Paterson2 and Edmond G Lemire23*

Author Affiliations

1 Department of Biology, John R. Brodie Science Centre, Brandon University, 270 18th Street, Brandon, MB R7A 6A9, Canada

2 Division of Medical Genetics, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada

3 Department of Pediatrics, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada

4 Department of Biology, University of Saskatchewan, W.P. Thompson Building, 112 Science Place, Saskatoon, SK S7N 5E2, Canada

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Journal of Medical Case Reports 2013, 7:117  doi:10.1186/1752-1947-7-117

Published: 26 April 2013



Congenital central hypoventilation syndrome is an autosomal dominant disorder that classically presents as sudden death in infancy secondary to central hypoventilation. Most cases are caused by polyalanine repeat mutations in the paired-like homeobox 2B gene, PHOX2B. More severe disease is typically associated with nonpolyalanine repeat mutations. We report the case of a family with nonpolyalanine repeat mutations that uncharacteristically has many individuals who were mildly symptomatic and only diagnosed after genetic testing. We highlight the highly variable clinical presentation of this condition and the need for clinicians to remain vigilant.

Case presentation

We identified 10 individuals in a large extended Caucasian family of German and Austrian background with congenital central hypoventilation syndrome.

Case 1: A 16-year old male proband presented for reproductive counseling. He had a previous history of apneic spells and Hirschsprung disease in the neonatal period. A PHOX2B nonpolyalanine repeat mutation was identified in the proband and used to screen his extended family.

Cases 2 to 10: Several mildly symptomatic family members (males aged 5, 13, 42 and 80 years; females aged 28, 44, 46 and 48 years) spanning four generations were identified after genetic screening. A newborn boy from this family was also recently diagnosed with Hirschsprung disease and went on to have an abnormal sleep study.


In this report, we highlight the significant phenotypic variability of congenital central hypoventilation syndrome, previously thought to be a rare genetic condition. Given the extreme clinical variability, it is possible that the prevalence of congenital central hypoventilation syndrome in the general population is much higher than previous estimates. This is of major importance to all clinicians who will need to maintain a high index of suspicion for this not so rare and highly clinically variable genetic condition that spans all ages. As the familial mutation has been identified, presymptomatic and prenatal diagnostic testing are available options for family members.