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

Elizabeth Bygarski,Edmond G Lemire,Melanie Paterson

doi:10.1186/1752-1947-7-117

Abstract

IntroductionCongenital 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 presentationWe 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.ConclusionsIn 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.

Highlights

Congenital central hypoventilation syndrome is an autosomal dominant disorder that classically presents as sudden death in infancy secondary to central hypoventilation
A PHOX2B nonpolyalanine repeat mutation was identified in the proband and used to screen his extended family
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

Summary

Conclusions

We highlight the importance of considering CCHS in the differential diagnosis for HSCR or when the medical or family histories are suggestive of generalized autonomic nervous system dysregulation. The clinical variability demonstrated by this family suggests that CCHS is likely an unrecognized entity and that previous frequency measurements are probably underestimates. All clinicians must maintain a high index of suspicion for CCHS in order to diagnose and manage mildly symptomatic cases, to avoid the associated longterm morbidity and mortality, and to permit genetic testing and counseling for families. Consent Written informed consents were obtained from the patients and from the minors’ of kin for publication of this manuscript and accompanying images. Authors’ contributions EB reviewed the patient records, tabulated the clinical information and wrote the initial manuscript, which was submitted as part of an undergraduate student project. MP met with the family, provided genetic counseling and obtained patient consents. EGL supervised EB for her course work, examined the patients and modified the manuscript for publication.

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