• congenital Central Hypoventilation syndrome (CCHS)
• genotype-phenotype correlation
• PHOX2B gene
• polyalanine expansion

• ANS, autonomic nervous system
• ANSD, ANS dysfunctions
• CCHS, congenital Central Hypoventilation syndrome
• HSCR, Hirschsprung’s disease
• LOCHS, late onset Central Hypoventilation syndrome
• SNP, single nucleotide polymorphism

Congenital Central Hypoventilation syndrome (CCHS (MIM 209880)) is a rare disorder, with fewer than 200 patients currently reported worldwide, characterised by absence of adequate autonomic control of respiration with decreased sensitivity to hypercapnia and hypoxia, in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion.¹ Children with CCHS show an adequate ventilation while awake but hypoventilate during sleep. More severely affected children hypoventilate both when awake and during sleep.¹ CCHS has been reported in association with several disorders, among which aganglionic megacolon (Hirschsprung disease, HSCR) and tumours of neural crest origin, reflecting a common molecular pathogenesis sustained by defects of one or more genes that control the correct development of neural crest derived cell lineages.^1–3

A genetic aetiology has long been hypothesised for CCHS based on recurrence reported in siblings, in half siblings and in affected children born to women with CCHS.^2–6 More recently, a generalised autonomic nervous system (ANS) imbalance has been observed among children with CCHS and an increased incidence of ANS dysfunctions (ANSD) reported among relatives of 56 patients with CCHS, as against relatives of 56 matched controls.⁷ A family transmission study has shown that the risk of developing an ANSD symptom including CCHS, regarded as the most severe expression of ANS imbalance, mainly depends on the genotype at a major locus, while significant residual variants could be due to additional minor genes, modifying loci effects or environmental factors.⁸

Genes involved in the ANS development, like the RET proto-oncogene, its ligand GDNF, the Endothelin 3 gene, the Brain Derived Neurotrophic Factor (BDNF) and the RNX genes, have been tested and a few mutations found, showing no cosegregation with the disease phenotype in CCHS families.^9–13

The PHOX2B gene encodes a 314 amino acids …