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congenital central hypoventilation syndrome

MIM.209880

Monday 20 September 2004

Congenital central hypoventilation syndrome (CCHS, Ondine’s curse) is a rare disorder of the chemical control of breathing.

Congenital central hypoventilation syndrome is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system.

Initially termed Ondine’s curse, CCHS is a rare, life-threatening condition characterised by abnormal ventilatory response to hypoxia and hypercapnia due to failure of autonomic respiratory control.

CCHS is not per se a neurocristopathy due to the involvement of both the central and peripheral autonomic nervous system. CCHS patients often present symptoms resulting from a broader dysfunction of the autonomous nervous system and predisposition to neural crest cell derived tumours (5–10% of CCHS cases, neuroblastoma, ganglioblastoma, ganglioneuroma).

Haddad syndrome (MIM 209880 [OMIM] ) is defined by the association of Hirschsprung disease and CCHS and is found in about 20% of CCHS patients.

In these cases, long form of Hirschsprung disease (including total colonic aganglionosis) is the most frequent, and the sex ratio is almost equal at variance to what is observed in isolated HSCR.

Pathology

- ASCL1-PHOX2A-PHOX2B developmental cascade anomalies

PHOX2B is the disease causing gene with de novo heterozygous mutation in the proband, the far most frequent being in frame duplication leading to polyalanine expansion.

Parents of patient with molecularly proven CCHS must be tested for accurate genetic counselling as about 10% carry a somatic mosaic and some parents may develop late onset CHS.

Genotype/phenotype correlations allow the detection of patients with a high risk to develop tumours (and carry a frameshift mutation) and reassurance about tumour predisposition to those carrying a polyalanine expansion.