Before the opportunity for genetic testing to confirm CCHS, and the description of the characteristic facies in CCHS, the diagnosis was essentially one of exclusion. CCHS was diagnosed in the absence of primary lung, cardiac, neuromuscular, or causative brainstem abnormalities.
The gold standard test to diagnose CCHS is genetic testing to identify mutations in the PHOX2B gene. This test has been available since 2003. There are 23 pairs of chromosomes (the genetic material in each cell) and the test finds an abnormality (mutation) in the chromosome number 4. The part of the chromosome where the genetic mutation exists is called PHOX2B.
To perform the analysis of the PHOX2B gene a sample of blood must be sent to one of the specialized genetic laboratories (see Resource Page). Such testing must be done with a referring physician in order that all clinical information is provided.
PHOX2B gene testing is appropriate for:
Most mutations occur de novo in CCHS, but 5 to 10% are inherited from a mosaic typically unaffected parent. A distinction is needed between germline inheritance and somatic occurrence of the PHOX2B mutation. Incomplete penetrance has been demonstrated when certain PHOX2B mutations are present in all the cells (including the reproductive cells of the germline) of individuals known to be unaffected. These latter PHOX2B mutations (20/24, 20/25, and a few NPARMs), although asymptomatic in some individuals, may be characterized by milder or variable phenotypic effects in the children affected with CCHS or other family members, respectively. In contrast, somatic mosaicism, due to postzygotic mutations, has been reported among a subset of parents of typical CCHS cases carrying PHOX2B polyalanine (PA).
It is possible to perform genetic testing of the fetus during pregnancy to provide prenatal diagnosis. Every affected individual has a 50% risk of transmitting the disorder to each child they have (autosomal dominant inheritance). As a consequence, a single mutation in one of the two PHOX2B genes is enough to cause the disease.