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 and reported to be associated with neuroblastoma. 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: central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (CCHS, MONDO:0800026) and Haddad syndrome (MONDO:0020493). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism(s) (PARM versus NPARMS) AND phenotypic variability underlying the two disease entities. PHENOTYPIC VARIABILITY includes that PHOX2B PARMs are mainly associated with isolated CCHS and lower rate of Hirschsprung disease; whereas PHOX2B NPARMs are associated with Haddad syndrome including a much higher rate of Hirschsprung disease and more frequent neuroblastoma. Therefore, we have split curations for the disease entities, PHOX2B PARMs-CCHS which is being curated here; PHOX2B NPARMs-Haddad syndrome (neuroblastoma, Hirschsprung disease in CCHS syndrome, susceptibility to) which has been curated separately. The mechanism for CCHS disease is unclear and could involve dominant-negative effect or toxic gain of function, and disrupted transcription activity of PHOX2B protein in cells is associated with disease (PMID: 15888479, 16249188). Four PARM variants reported in more than 200 probands in three publications (PMIDs:12640453, 15657873,15121777) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence. (5 points, PMIDs: 9374403, 10360575, 12640453, 18198276). Mice heterozygous for the CCHS-causing expanded alanine tract in the Phox2b gene had irregular breathing, did not respond to an increase in CO2, and died soon after birth from central apnea. In summary, PHOX2B-PARM is definitively associated with autosomal dominant CCHS syndrome. This has been repeatedly demonstrated in the research and clinical diagnostic settings, and has been upheld over time. Only 2 CCHS patients harboring a polyalanine tract expansion were diagnosed with ganglioneuroma, suggesting limited association between PHOX2B PARMs and tumors of the sympathetic nervous system.