Is a genetic test available?
A genetic test has been available since 2003 for the diagnosis of CCHS. The test finds an abnormality in every cell of the body of affected individuals, and this is never found in non-affected individuals. 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.
What does the genetic test find?
The most common mutation, found in the 90% of patients, consists of a longer stretch of alanines, one of the amino acids, or building blocks of the DNA spiral. The number of alanines is increased from 20 (normal) up to between 24 and 39 alanines on one of the pair of chromosomes. This produces pairs of chromosomes with 20/24 to 20/39 alanines (the normal being genotype 20/20).
There are other mutations found in under 10% of patients, which are known as missense, nonsense or frame shifts of the gene.
Does the type of mutation predict how the patient will be affected?
There is some relationship between some aspects of the clinical presentation and the type of mutation, including: 1) the risks of nerve cell tumours, like neuroblastoma or ganglio-neuroma; 2) the risks for Hirschsprung’s disease; 3) the severity of hypoventilation and the risk of 24-hour day mechanical ventilation; and 4) the presence of a disturbance of heart rhythm, a possible cause of sudden death.
For example, patients with a 20/25 genotype are unlikely to need 24 hours a day ventilation, whereas individuals carrying longer mutations have severe hypoventilation even when awake.
The presence of the second type of mutation can be associated with severe forms of CCHS, with both Hirschsprung’s disease (with extensive gut involvement) and tumors of the neural crest more commonly found.
How else does the genetic test help?
Knowledge of the PHOX2B mutation also allows identification of either asymptomatic parents carrying the mutation, who have a higher risk of recurrence in subsequent pregnancies, or adults with mild hypoventilation, which has not been previously observed or diagnosed.
What about diagnosis in pregnancy?
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.
Do parents carry the genetic mutation?
More than 90% of parents do not carry the genetic mutation. The genetic mutation is thought to occur spontaneously very early in pregnancy when the embryo is first formed. However, 5-10% of parents do carry the gene, so it is recommended that when the genetic mutation is found in an affected individual, the parents are tested.
Most parents carrying the mutation have not been studied to know whether they are affected by the genetic abnormality. Some only carry the abnormality in some cells of the body, a phenomenon known as mosaicism.
Who else needs genetic testing?
At present, only parents of affected or PHOX2B-positive individuals should be tested. Parents and affected young people should have genetic counselling to decide on who should have further PHOX2B testing.
To perform the analysis of the PHOX2B gene a sample of blood must be sent to one of the specialized genetic laboratories existing in Europe (link to the map). Such testing must be done with a referring physician in order that all clinical information is provided.
Can the genetic test identify patients in later childhood or adulthood?
With the introduction of genetic testing, it has been possible to diagnose some adult patients with hypoventilation as a result of CCHS.
Some adults with chronic hypoventilation or late-onset hypoventilation have been found to have a PHOX2B mutation. In addition, some adults with obstructive sleep apnoea or bad reactions to anaesthesia have been found to have PHOX2B mutations. The mutation commonly reported in such patients is the (shorter) expansion of alanines, with a 20/25 genotype. The mild condition associated with this mutation explains why the disease presents in adulthood or remained unrecognised before. Sometimes precipitating events like the use of sedative drugs or acute respiratory distress highlights the onset of hypoventilation.
Is the genetic test always positive?
No genetic test is currently available for diagnosis of ROHHAD syndrome (rapid onset obesity, hypoventilation, hypothalamic and autonomic dysfunction).
In central hypoventilation syndrome with a negative PHOX2B test, the diagnosis is not certain and other explanations need to be looked for.