Submission Details

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system characterized by an altered chemosensory response to hypercapnia and hypoxia, typically most pronounced during sleep. PHOX2B was first reported in relation to autosomal dominant congenital central hypoventilation syndrome (CCHS) in 2003 (Amiel et al., PMID: 12640453). PHOX2B encodes a highly conserved paired box homeodomain transcription factor, characterized by two polyalanine repeats of 9 and 20 residues in the C-terminal region. There are two types of PHOX2B mutations associated with CCHS: Polyalanine repeat mutations (PARMs) and nonpolyalanine repeat mutations (NPARMs). PARMs are in-frame nucleotide duplications inside the 20 alanine stretch, leading to expansions from +5 to +13 alanine residues, and are detected in about 90% CCHS patients. NPARMs include missense, nonsense and frameshift mutations, leading to different aberrant C-terminal of the protein, and are detected in about 8% CCHS patients. In MONDO, an assertion has been made for two disease entities: congenital central hypoventilation syndrome (CCHS) associated with PARMs and Haddad syndrome (CCHS occurs concurrently with Hirschsprung disease) associated with NPARMs demonstrating different molecular mechanisms. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism(s) AND phenotypic variability underlying the two disease entities. For phenotypic variability, PHOX2B PARMs are mainly associated with isolated CCHS; whereas PHOX2B NPARMs are associated with Haddad syndrome including a much higher rate of Hirschsprung disease and more frequent neuroblastoma. The estimated incidence of neuroblastoma in patients with NPARMs is 50% compared to 1% among patients with PARMs (Berry-Kravis et al., 2006 PMID: 16888290). Therefore, we have split curations for the disease entities, PHOX2B PARMs-CCHS; PHOX2B NPARMs-Haddad syndrome (neuroblastoma, Hirschsprung disease in CCHS syndrome, susceptibility to) being curated here. Six variants (missense, nonsense, frameshift, deletion) that have been reported in 9 probands in five publications (PMIDs:12640453, 15657873, 29543228, 29696799, 17637745) are included in this curation. This gene-disease association is also supported by function studies (PMIDs: 17637745, 15888479). In summary, PHOX2B-NPARM is definitively associated with autosomal dominant Haddad syndrome (neuroblastoma, Hirschsprung disease in CCHS syndrome, susceptibility to). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.