Central Hypoventilation Syndrome, Congenital

Alternative Names

  • CCHS
  • Autonomic Control, Congenital Failure of
  • Ondine Curse, Congenital
  • Ondine-Hirschsprung Disease, Included
  • OHD, Included
  • CCHS with Hirschsprung Disease, Included
  • Haddad Syndrome, Included

Associated Genes

Paired-Like Homeobox 2B
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WHO-ICD-10 version:2010

Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified

OMIM Number

209880

Mode of Inheritance

Autosomal recessive vs. dominant with reduced penetrance (or paternal gonadal mosaicism)

Gene Map Locus

4p13,5p13.2,10q11.21,12q23.2,20q13.32

Description

Congenital central hypoventilation syndrome (CCHS) is a rare condition that usually presents soon after birth and is potentially life-shortening if not treated. The defining abnormality is a persistent hypoventilation, most pronounced during sleep, with relative insensitivity to hypercarbia and a lesser insensitivity to hypoxia, beginning in the neonatal period and requiring life-long ventilatory assistance. Changes in the integration of afferent inputs from central and peripheral chemoreceptors in the brainstem are the most likely disease mechanisms.

The association of congenital failure of autonomic control with congenital central hypoventilation syndrome was first reported in 1978. This syndrome is rare; only about 50 cases have been reported worldwide. Congenital failure of autonomic control is a condition caused by congenital absence of ganglion cells from the enteric nervous system, resulting in bowel obstruction ranging in severity from chronic severe constipation to complete obstruction and early neonatal death. It is thought to originate in a failure of migration of neural crest derived precursor cells, although this is controversial and a hostile gut microenvironment may also contribute.

Congenital failure of autonomic control can be caused by mutation in the paired-liked homeobox 2B (PHOX2B) gene as well as in several other genes, including RET, GDNF, EDN3, and BDNF. PHOX2B is the major disease-causing gene, mutated in half to two thirds of patients with congenital failure of autonomic control.

Epidemiology in the Arab World

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Other Reports

Oman

Al Rashdi et al. (2011) and Mahfouz et al. (2011) described a 6-year old Omani girl with congenital central hypoventilation syndrome. She was born to consanguineous parents through normal delivery. Her weight was below average due to dental conditions. She did not have any breathing problems during sleep, and she never complained about headache or visual changes. Her parents confirmed that she had no history of cardiac and pulmonary diseases. After she had a dental extraction surgery with general anesthesia, she suffered from shallow breathing and apnea. The results of the genetic test showed that the patient had a repeat expansion in the polyalanine tract of PHOX2B gene, causing congenital central hypoventilation syndrome. After 65 days in the ICU, she was discharged with portable ventilator for ventilator support during sleep.

Saudi Arabia

Mansoor and Zahrani (2002) analyzed 27 consecutive cases of endoscopic colonic biopsies and surgical colectomy specimens of both male and female cases who were received for investigation of ganglion cells for the Hirschsprung's disease and related disorders. In their study, Mansoor and Zahrani (2002) looked for only three symptoms and all the 27 patients presented with constipation, 15 (55.5%) patients had abdominal distension and no patient presented with diarrhea. Mansoor and Zahrani (2002) suggested that a wider population study for the genetic factors of this frequent congenital disease is highly recommended in the Saudi population.

Trivedi et al. (2011) presented four families with CCHS, three with autosomal dominant inheritance and familial clustering, and one with a de novo mutation resulting in CCHS. Mutations detected in all the families were repeat expansion in the polyalanine tract of PHOX2B gene. Trivedi et al. (2011) demonstrated that phenotypic variability in expression of disease is seen in families with the same mutations in PHOX2B gene. They also commented on the psychosocial costs of the disease and the unrecognized 'morbidity barter' that is part of current management needs to be factored into in all stages of management from childhood to adolescence to adulthood.

While presenting a case study, Al Saadi et al. (2011) linked the presence of congenital central hypoventilation syndrome in a Saudi child to a repeat expansion in the polyalanine tract of  PHOX2B gene.

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