Congenital central hypoventilation syndrome without hypoventilation: is it congenital central hypoventilation syndrome?

Congenital central hypoventilation syndrome (CCHS) is a rare condition caused by pathogenic variants of the PHOX2B gene. There have been case reports describing variable phenotypes and mutations of the PHOX2B gene, not commonly tested for, that may challenge the classic definition of CCHS. We report on 3 family members with a rare heterozygous deletion encompassing the entire PHOX2B gene with variable phenotypes, including sleep-disordered breathing and autonomic nervous system involvement, but an unexpected lack of alveolar hypoventilation, which is usually a defining feature of CCHS. Our cases highlight the dilemmas in making a diagnosis of CCHS and emphasize the need for expanded genetic testing, including for PHOX2B gene deletion. More patients with variable phenotypes of CCHS may be identified through comprehensive genetic testing and warrant surveillance as they are still at risk for high-risk complications of CCHS.