The gold standard method to diagnose CCHS is through genetic testing. These tests are used to identify mutations in the PHOX2B gene found on chromosome 4. Genetic testing for CCHS has been available since 2003. Prior to that, diagnosis was based solely on clinical presentation.

What Does Genetic Testing Involve?

To perform analysis of the PHOX2B gene, a sample of blood must be sent to a specialized genetic laboratory. Click here for a list of approved laboratories. This test typically requires a physician’s order. With the commercialization of DNA testing, certain independent companies like 23andMe can also confirm Phox2B mutations when specifically requested. Genetic testing will determine the exact nature of the PHOX2B mutation and further distinguish between a polyalanine repeat mutation (PARM) or non-polyalanine repeat mutation (NPARM). This is important clinical information that can offer guidance on disease presentation, severity and treatment considerations. For instance, in patients with PARM diagnoses, expansion mutations will range from 20/25 to 20/33, indicating the number of alanine repeats as well as a spectrum of disease involvement. Click here to learn more about the role of genetics in CCHS.

Who Should Be Tested?

PHOX2B gene testing is recommended for:

  • infants with central hypoventilation at birth or in the first month of life
  • patients with unexplained central hypoventilation manifesting after the first month of life
  • hypoventilation manifesting in the setting of general anesthesia or sedative use
  • adults presenting with unexplained central sleep related hypoventilation
  • patients presenting with Hirschsprung’s disease and hypoventilation
  • patients presenting with dysautonomia and hyperventilation
  • patients presenting with neural crest tumors and hypoventilation
  • patients presenting with hyperinsulinism and hypoventilation
  • any child born to a parent with known CCHS
  • parents of children with CCHS 
  • patients with hypoventilation associated with rapid onset obesity and hormonal disturbance  

Clinical Diagnosis

A clinical diagnosis can be assigned in the absence of genetic confirmation based on the presentation of at least 3 of these 4 medical findings:

Chronic respiratory failure characterized by hypoxia (low oxygenation) and/or carbon dioxide retention​​

*Lack of confirming differential diagnosis (diagnosis by exclusion method)

Abnormality in central control of breathing, which is typically confirmed via a sleep study​
Clinically confirmed dysautonomia​

*2. i.e. metabolic, neuro-muscular, chronic lung disease, and obstructive airway disease is clearly ruled out as a cause of respiratory failure

Can CCHS Be Diagnosed During Pregnancy?

CCHS cannot be detected through prenatal ultrasound or standard prenatal testing. Given that the majority of cases are de novo (occur sporadically without known family history), most expecting parents do not have the foresight to test for this extremely rare condition.

Individuals diagnosed with CCHS need to consider the 50% risk of passing the disorder to each biological child (this is called autosomal dominant inheritance). Some may consider prenatal genetic testing of the fetus using amniocentesis or Chorionic Villus Sampling “CVS” prior to birth. More recently, in-vitro fertilization with preimplantation CCHS testing has become possible for some cases who prefer taking measures prior to conception.