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

We describe 3 family members with PHOX2B gene deletion across 2 generations that experienced some of the known complications of CCHS yet hypoventilation was not a predominant feature. All 3 patients have severe obesity, which can contribute to their sleep-disordered breathing, complicating the major question: do all these patients have CCHS?

Genetic testing of PHOX2B gene mutation may start with fragment analysis for PARMs and Sanger sequencing for non-PARMs. If both steps are negative, but clinical suspicion remains high, a multiplex-ligation dependent probe amplification testing and/or chromosomal microarray analysis can be considered to identify patients with a partial or complete PHOX2B gene deletion with or without involving neighboring genes. Of note, next-generation sequencing-based technologies may not detect PHOX2B PARMs In our case, given the high clinical suspicion, the deletion was initially identified using exome sequencing data and was confirmed by chromosomal microarray analysis on the tumor sample. The availability of whole exome sequencing can help identify a subset of PHOX2B alterations.

There is limited literature describing phenotypes of PHOX2B gene deletion. While our patients may not have initially demonstrated CCHS defining feature of hypoventilation, they do demonstrate some of the high-risk complications of CCHS, including neural crest tumors and gastrointestinal dysmotility. Jennings et al3 described 4 patients with PHOX2B deletion ranging from a partial exon 3 deletion to whole gene deletion with variable phenotypes. Three patients showed hypoventilation and autonomic nervous system dysfunction and 1 patient presented with an apparent life-threatening event with need for ventilation just in the newborn period. Similar to our own findings, the parent of the patient in Case 4 in Jennings’ paper lacked hypoventilation on polysomnography. Hypoventilation is not a major finding in our series, even in the presence of autonomic nervous system involvement. This emphasizes the variable phenotype of PHOX2B gene deletion.

Our cases highlight the dilemmas in making a diagnosis in CCHS. These patients demonstrate some of the multi-system involvement of CCHS but were thought not to meet criteria for CCHS initially because of their lack of hypoventilation and significant central sleep apnea. Another significant challenge in making the diagnosis was limited genetic testing options when the index case first presented. While diagnostic capabilities have improved significantly today, this genetic finding may not have been made without awareness of previous patients with PHOX2B deletions and intentionally expanding our genetic testing.

https://jcsm.aasm.org/doi/full/10.5664/jcsm.10512