Congenital Central Hypoventilation Syndrome (CCHS)

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Congenital central hypoventilation syndrome (CCHS) is a disorder that affects breathing. People with this disorder take shallow breaths (hypoventilate), especially during sleep, resulting in a shortage of oxygen and a buildup of carbon dioxide in the blood. Ordinarily, the part of the nervous system that controls involuntary body processes (autonomic nervous system) would react to such an imbalance by stimulating the individual to breathe more deeply or wake up. This reaction is impaired in people with CCHS, and they must be supported with a machine to help them breathe (mechanical ventilation) or a device that stimulates a normal breathing pattern (diaphragm pacemaker). Some affected individuals need this support 24 hours a day, while others need it only at night.

Symptoms of CCHS usually become apparent shortly after birth. Affected infants hypoventilate upon falling asleep and exhibit a bluish appearance of the skin or lips (cyanosis). Cyanosis is caused by lack of oxygen in the blood. In some milder cases, CCHS may be diagnosed later in life. In addition to the breathing problem, people with this disorder may have difficulty regulating their heart rate and blood pressure, for example in response to exercise or changes in body position. They may have abnormalities in the nerves that control the digestive tract (Hirschsprung disease), resulting in severe constipation, intestinal blockage, and enlargement of the colon. They are also at increased risk of developing certain tumors of the nervous system called neuroblastomas, ganglioneuromas, and ganglioneuroblastomas. Some affected individuals develop learning difficulties or other neurological problems, which may be worsened by oxygen deprivation if treatment to support their breathing is not completely effective.

Individuals with CCHS usually have eye abnormalities, including a decreased response of the pupils to light. They also have decreased perception of pain, low body temperature, and occasional episodes of profuse sweating.

People with CCHS, especially children, may have a characteristic appearance with a short, wide, somewhat flattened face often described as "box-shaped." Life expectancy and the extent of any cognitive disabilities depend on the severity of the disorder, timing of the diagnosis, and the success of treatment.

Contents

How common is CCHS?

CCHS is a relatively rare disorder. Approximately 1,000 individuals with this condition have been identified. Researchers believe that some cases of sudden infant death syndrome (SIDS) or sudden unexplained death in children may be caused by undiagnosed CCHS.

What genes are related to CCHS?

Mutations in the PHOX2B gene cause CCHS. The PHOX2B gene provides instructions for making a protein that acts early in development to help promote the formation of nerve cells (neurons) and regulate the process by which the neurons mature to carry out specific functions (differentiation). The protein is active in the neural crest, which is a group of cells in the early embryo that give rise to many tissues and organs. Neural crest cells migrate to form parts of the autonomic nervous system, many tissues in the face and skull, and other tissue and cell types.

Mutations are believed to interfere with the PHOX2B protein's role in promoting neuron formation and differentiation, especially in the autonomic nervous system, resulting in the problems regulating breathing and other body functions that occur in CCHS.

Read more about the PHOX2B gene.

How do people inherit CCHS?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

More than 90 percent of cases of CCHS result from new mutations in the PHOX2B gene. These cases occur in people with no history of the disorder in their family. Occasionally an affected person inherits the mutation from one affected parent. The number of such cases has been increasing as better treatment has allowed more affected individuals to live into adulthood.

About 5 to 10 percent of affected individuals inherit the mutation from a seemingly unaffected parent with somatic mosaicism. Somatic mosaicism means that some of the body's cells have a PHOX2B mutation, and others do not. A parent with mosaicism for a PHOX2B mutation may not show any signs or symptoms of CCHS.

Where can I find information about treatment for CCHS?

These resources address the management of CCHS and may include treatment providers.

  • Gene Review: Congenital Central Hypoventilation Syndrome
  • MedlinePlus Encyclopedia: Hirschsprung's Disease

You might also find information on treatment of CCHS in Educational resources and Patient support.

Where can I find additional information about CCHS?

You may find the following resources about CCHS helpful. These materials are written for the general public.

  • MedlinePlus - Health information (2 links)
  • Educational resources - Information pages (2 links)
  • Patient support - For patients and families (2 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

  • Gene Reviews - Clinical summary
  • Gene Tests - DNA tests ordered by healthcare professionals
  • ClinicalTrials.gov - Linking patients to medical research
  • PubMed - Recent literature
  • OMIM - Genetic disorder catalog

What other names do people use for CCHS?

  • congenital failure of autonomic control
  • Haddad syndrome
  • Ondine-Hirschsprung disease
  • Ondine Syndrome

See How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about CCHS?

  • See How can I find a genetics professional in my area? in the Handbook.
  • Ask the Genetic and Rare Diseases Information Center.
  • Submit your question to Ask the Geneticist.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

  • What does it mean if a disorder seems to run in my family?
  • What are the different ways in which a genetic condition can be inherited?
  • If a genetic disorder runs in my family, what are the chances that my children will have the condition?
  • Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.

  • Genetics and health
  • Resources for Patients and Families
  • Resources for Health Professionals

What glossary definitions help with understanding CCHS?

apnea ; autonomic nervous system ; autosomal ; autosomal dominant ; cell ; colon ; congenital ; constipation ; cyanosis ; diagnosis ; differentiation ; digestive ; embryo ; gene ; involuntary ; mosaicism ; mutation ; nerve cell ; nervous system ; neural crest ; neuroblastoma ; neurological ; neuron ; new mutation ; oxygen ; pacemaker ; perception ; protein ; pupil ; sign ; somatic mosaicism ; symptom ; syndrome ; tissue ; tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

See also Understanding Medical Terminology.

References

These sources were used to develop the Genetics Home Reference condition summary on congenital central hypoventilation syndrome.

  • Antic NA, Malow BA, Lange N, McEvoy RD, Olson AL, Turkington P, Windisch W, Samuels M, Stevens CA, Berry-Kravis EM, Weese-Mayer DE. PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood. Am J Respir Crit Care Med. 2006 Oct 15;174(8):923-7. Epub 2006 Jul 27. PubMed citation
  • Axelrod FB, Chelimsky GG, Weese-Mayer DE. Pediatric autonomic disorders. Pediatrics. 2006 Jul;118(1):309-21. Review. PubMed citation
  • Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006 Nov 15;174(10):1139-44. Epub 2006 Aug 3. PubMed citation
  • Gaultier C, Trang H, Dauger S, Gallego J. Pediatric disorders with autonomic dysfunction: what role for PHOX2B? Pediatr Res. 2005 Jul;58(1):1-6. Epub 2005 May 18. Review. PubMed citation
  • Gene Review: Congenital Central Hypoventilation Syndrome
  • Gronli JO, Santucci BA, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol. 2008 Jan;43(1):77-86. PubMed citation
  • Parodi S, Bachetti T, Lantieri F, Di Duca M, Santamaria G, Ottonello G, Matera I, Ravazzolo R, Ceccherini I. Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome. Hum Mutat. 2008 Jan;29(1):206. PubMed citation
  • Repetto GM, Corrales RJ, Abara SG, Zhou L, Berry-Kravis EM, Rand CM, Weese-Mayer DE. Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene. Acta Paediatr. 2008 Sep 16; [Epub ahead of print]. PubMed citation
  • Todd ES, Weinberg SM, Berry-Kravis EM, Silvestri JM, Kenny AS, Rand CM, Zhou L, Maher BS, Marazita ML, Weese-Mayer DE. Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology. Pediatr Res. 2006 Jan;59(1):39-45. Epub 2005 Dec 2. PubMed citation
  • Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Rand CM. Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): Kindred disorders of autonomic regulation. Respir Physiol Neurobiol. 2008 May 23; [Epub ahead of print]. PubMed citation
  • Weese-Mayer DE, Berry-Kravis EM, Marazita ML. In pursuit (and discovery) of a genetic basis for congenital central hypoventilation syndrome. Respir Physiol Neurobiol. 2005 Nov 15;149(1-3):73-82. Epub 2005 Jul 28. Review. PubMed citation
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