Congenital Central Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS) is an inherited pulmonary and neurologic condition that generally causes affected individuals, typically identified in the newborn period, to have adequate ventilation when awake, but low (hypo) ventilation during sleep.  People with CCHS are also at higher risk for other health concerns. Confirming a genetic diagnosis of CCHS can greatly affect a patient’s healthcare management. 

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Congenital central hypoventilation syndrome (CCHS) is an inherited pulmonary and neurologic condition that generally causes affected individuals, typically identified in the newborn period, to have adequate ventilation when awake, but low (hypo) ventilation during sleep.  People with CCHS are also at higher risk for other health concerns. Confirming a genetic diagnosis of CCHS can greatly affect a patient’s healthcare management. 

Ambry offers full sequencing of the gene causing CCHS in order to empower patients and their healthcare providers to make important decisions and plan their healthcare management.

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Disease Name 
Congenital Central Hypoventilation Syndrome
Disease Information 

Congenital central hypoventilation syndrome (CCHS) is an inherited lung and autonomic nervous system disorder that usually causes low (hypo) ventilation with normal respiratory rates but shallow breathing during sleep; proper ventilation usually occurs when awake. In severe cases however, hypoventilation can also occur while awake. After discovery of the gene that causes CCHS, PHOX2B, the condition is felt to be more common than originally thought.  No pan-ethnic prospective population studies have been done to date, however, so it is difficult to determine the actual incidence of CCHS.1

Symptoms usually appear during the newborn period, although CCHS is increasingly recognized in older children and adults. Various treatments may be used, including ventilator support, surgeries, and other options depending on the symptoms. Some children with CCHS also show other symptoms of autonomic nervous system dysregulation (ANSD). The autonomic nervous system controls several functions in the body, including heart rate, digestion, perspiration, and breathing. Individuals with ANSD may have problems with breathing, heart rate, constipation, as well as other symptoms.2

People with CCHS may also show signs of poorly developed neural crest structures.  The neural crest is a structure in a developing embryo that gives rise to many systems in the body, including the nervous system, gastrointestinal tract, and the heart. Because of this lack of proper development, people with CCHS are at a higher chance to develop Hirschsprung disease, which is a problem within the nerve tissue of the intestines that causes contents to not move through properly. About 20% of people with CCHS have Hirschsprung disease.2 In about 6% of people with CCHS, tumors of the neural crest develop, including brain/nerve tumors like neuroblastomas, ganglioneuromas, and ganglioneuroblastomas).2 In addition, cardiac arrhythmias are more common in people with CCHS.1,2

CCHS is inherited in an autosomal dominant pattern.3 However, the majority of cases are caused by de novo mutations, meaning they occur for the first time in the affected individual in that family. Approximately 92% of people with CCHS have a type of mutation called a polyalanine repeat expansion mutation (PARM).2,4 Within coding exon 3 of the PHOX2B gene, there is a repeating region that results in a string of an amino acid called alanine.  Normally, there are 20 alanine repeats or less in this exon of PHOX2B. In people with CCHS, there can be 25-33 repeats.  The remaining ~8% of patients have non-polyalanine repeat expansion mutations (NPARMs), including DNA sequence alterations or frameshift mutations.2-5

Genetic testing can be very useful, due to the strong genotype-phenotype correlations in CCHS. Mutation type and repeat length generally correlate with disease severity. NPARMs can cause more severe symptoms and are associated with increased frequencies of Hirschsprung disease, neural crest tumors, and continuous ventilator dependence.2-5 Similarly, large repeat expansions correlate with more severe respiratory concerns and a higher risk of Hirschsprung disease and tumors, when compared to shorter repeat expansions.2 Other genotype-phenotype associations exist as well, and can involve other organ systems.

Testing Benefits & Indication 
The American Thoracic Society has published a clinical policy statement regarding PHOX2B genetic testing in those suspected to have CCHS, as well as in their at-risk relatives.6  Benefits of genetic testing include:
  • Direct impact on prognosis/medical care/treatment/surveillance due to knowledge of the specific PHOX2B mutation a person has (because of the genotype-phenotype correlation in CCHS)  
  • Diagnostic confirmation in patients suspected to have congenital or late-onset CHS
  • Parental testing to rule out risk for late-onset symptoms
  • Screening to adjust medical management in at-risk relatives
Test Description 

Ambry’s PHOX2B full gene sequence analysis is performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 1-3 of the PHOX2B gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. Alanine repeat numbers for the commonly-expanded region in exon 3 are determined and reported in all cases. Specific mutation analysis for known PHOX2B familial mutations is also available.

Mutation Detection Rate 

Approximately 99% of PHOX2B mutations are detectable by this test (analytic sensitivity).  Clinical sensitivity is near 99% (~92% PPARMs and ~8% NPARMs).1

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TEST NAME TURNAROUND TIME (Days)
1580  PHOX2B Gene Sequence Analysis                                            10-21

 

Specialty 
Genes 
References 
  1. Weese-Mayer DE et al. Congenital Central Hypoventilation Syndrome. GeneReviews. 2004, updated 2014. Pagon RA, Adam MP, Ardiner HH et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2014. 
  2. Berry-Kravis EM et al. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006;174:1139-1144. [PMID: 16888290]
  3. Low KJ et al.  A case of congenital central hypoventilation syndrome in a three-generation family with non-polyalanine repeat PHOX2B mutation. Pediatr Pulmonol. 2014;49: E140–E143. [PMID: 24799442]
  4. Trochet D et al. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005;14:3697-3708. [PMID: 16249188]
  5. Trochet D et al. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am J Hum Genet. 2005;76;421-426. [PMID: 15657873]
  6. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H. ATS Congenital Central Hypoventilation Syndrome Subcommittee. An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med. 2010 Mar 15;181(6):626-44. [PMID: 20208042]