Congenital Central Hypoventilation Syndrome

Individuals with Congenital Central Hypoventilation Syndrome (CCHS) generally have adequate ventilation when awake and hypoventilation with normal respiratory rates and shallow breathing during sleep.

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Individuals with Congenital Central Hypoventilation Syndrome (CCHS) generally have adequate ventilation when awake and hypoventilation with normal respiratory rates and shallow breathing during sleep.

Some affected children show symptoms of a generalized autonomic nervous system dysfunction including Hirschsprung Disease in 20%. Neural crest tumors are found in 6%. The condition is increasingly recognized in older children and adults.

In a few cases, CCHS is inherited in an autosomal dominant pattern, but the majority of cases are de novo. Approximately 92% of affected individuals have an in-frame expansion of a polyalanine repeat in exon 3 of the PHOX2B gene from the normal 20 repeats to 25-33 repeats. The remaining ~8% of patients have other mutations at the end of exon 2 or within exon 3.

The Ambry Test: Congenital Central Hypoventilation Syndrome includes full gene sequence analysis of PHOX2B, and alanine repeat numbers for the commonly-expanded region in exon 3 are determined and reported in all cases.

Disease Name 
Congenital Central Hypoventilation Syndrome
Disease Information 

Individuals with Congenital Central Hypoventilation Syndrome (CCHS) have adequate ventilation when awake and hypoventilation with normal respiratory rates and shallow breathing during sleep. In severe cases, hypoventilation can also occur while awake. Some children with CCHS also show symptoms of generalized autonomic nervous system dysfunction including Hirschsprung Disease in 20%.1 Neural crest tumors are found in 6%.1 Symptoms usually appear during the newborn period, although CCHS is increasingly recognized in older children and adults.

In a few cases, CCHS is inherited in an autosomal dominant pattern, but the majority of cases are de novo. Approximately 92% of affected individuals have an in-frame expansion of a polyalanine repeat in exon 3 of the PHOX2B gene from the normal 20 repeats to 25-33 repeats. The remaining ~8% of patients have other mutations at the end of exon 2 or within exon 3.1- 3 Mutation type and repeat length generally correlate with disease severity. Non-repeat mutations are associated with increased frequencies of Hirschsprung Disease, neural crest tumors, and continuous ventilator dependence compared to patients with polyalanine repeat expansions.1- 3  Similarly, large repeat expansions correlate with a more severe respiratory phenotype and higher risk of Hirschsprung Disease and tumors than short expansions.2 Late-onset CCHS patients without Hirschsprung Disease are typically found to have small repeat expansions.

Testing Benefits & Indication 
  • Diagnostic confirmation in patients suspected to have congenital or late-onset CHS
  • Define level of suspicion for other autonomic dysfunction and tumors
  • Parental testing to rule out risk for late-onset symptoms
Test Description 

The Ambry Test: CCHS is full gene sequence analysis 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 family mutations is also available.

Mutation Detection Rate 

Approximately 99% of PHOX2B mutations are detectable by this test.

Specimen Requirements 

Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice.  
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

Billing Codes 
Test Code Technique
1580 PHOX2B Gene Sequence Analysis    

 

Turnaround Time 
Technique Days
PHOX2B Gene Sequence Analysis     10-21

 

Specialty 
Genes 
References 

1. 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]

2. 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]

3. 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]