In 2003, the disease-causing gene for congenital central hypoventilation syndrome (CCHS) was discovered in the pairedlike homeobox gene PHOX2B, located at exon 3 on chromosome 4. According to American Thoracic Society (ATS) guidelines, a mutation in the PHOX2B gene is required for the diagnosis of CCHS. The normal PHOX2B contains a 20-alanine coding repeat region (20/20). An increased number of polyalanine repeats in this region is referred to as polyalanine repeat expansion mutation (PARM). There can also be nonpolyalanine repeat mutations (NPARMs), which consist of missense, nonsense, or frameshift mutations. Over 90% of patients with CCHS are heterozygous for a PARM in the PHOX2B gene, which can range from 24-33 alanines, the most common being 25, 26, and 27, referred to as 20/25, 20/26, 20/27, respectively. The remaining 10% have anNPARM. [1]

Studies have shown a correlation that with increasing expansion of alanines, the need for continuous ventilatory support increases. In general, individuals with 25-PARM rarely require 24-hour ventilatory support, those with 26-PARM have a variable need for ventilatory support during the awake periods based on their activity levels, and those with 27-33–PARMs require 24-hour ventilatory support. Mild- and late-onset CCHS has been associated with 24-polyalanine and 25-PARMs. [2]

Individuals with NPARMs have a more severe phenotype, which may require continuous ventilatory support, and they are also at higher risk of having Hirschsprung disease and neural crest tumors.

The PHOX2B gene codes for a transcriptional factor responsible for regulating expression of genes involved with the development of the autonomic nervous system, such as dopamine-β-hydroxylase (DBH), PHOX2A, and TLX-2. [1] Increased PRAM has been shown to impair the PHOX2B protein's ability to regulate the transcription of these genes. The mutated PHOX2B protein also interferes with the activity of the normal PHOX2B on the other chromosome. [3]

Genetics

CCHS can be from autosomal dominant inheritance or a de novo mutation. Some parents of CCHS patients have been found to have a somatic mosaicism for the PHOX2B mutation. [4] In one study looking at 45 CCHS families, nearly 20% of patients inherited the mutation from somatic mosaicism. [5]

Certain PARMs, such as 24 and 25, have an autosomal dominant inheritance with incomplete penetrance. [1, 6] Therefore, the degree to which family members of individuals with CCHS may have evidence of respiratory control or autonomic dysfunction remains uncertain. [7] The extreme variability that can be seen in a family is demonstrated by a case series in which the initial patient is found to have CCHS with an NPARM and most other members with the same mutation are mildly affected (constipation, autonomic dysfunction, sleep apnea) and identified later in childhood or after the initial patient was diagnosed. [8]

A disturbance of cardiac autonomic regulation in CCHS may indicate the possibility of PHOX2B genotype in relation to the severity of dysregulation, predict the need for cardiac pacemaker, and offer the clinician the potential to avert sudden death. [9]

Environmental influences have been suggested to affect the presentation of siblings with CCHS. One study of monozygotic term male twins with identical 25-PARMs showed differing clinical courses, with twin B having more severe respiratory compromise at birth and twin A exhibiting a relatively benign course until beginning to require more noninvasive ventilator support at around age 5 years. [10]

Structural central nervous system abnormalities

Based on the initial premise that CCHS is associated with a centrally located defect, multiple attempts have been made over the years to identify structural CNS abnormalities. Research in rodent models, indicating the retrotrapezoid nucleus (RTN) as the main area of PHOX2B activity, has been confirmed with PHOX2B immunoreactivity in human fetuses and infants. [11]

MRI changes indicating alterations or injury have been observed in the caudate nuclei in patients with CCHS. [12] Reduced gray matter volume over time in areas regulating autonomic, mood, motor, and cognition functions have been shown in CCHS patients. These areas include the prefrontal and frontal cortex, caudate nuclei, insular cortex, and cerebellar regions. [13] The pathologic process leading to these brain injuries is unknown but is thought to be caused by hypoxic mechanisms or due to sustained perfusion issues. The MRI scan of a premature infant with PHOX2B mutation showed deep cerebral white matter destruction with lesions concentrated in the internal capsule and corpus callosum. The infant’s pattern of damage (which is usually seen in patients with some degree of birth asphyxia) suggests that these signs of restricted cerebral perfusion may be a byproduct of autonomic neural dysfunction in CCHS resulting in impaired vascular control. [14]

Physiologic abnormalities of ventilatory control

Most patients with CCHS are able to maintain adequate spontaneous ventilation during wakefulness as a result of residual peripheral chemoreceptor function in these patients.

CCHS is characterized by dysfunction in the metabolic control of breathing; therefore, more severe gas-exchange disturbances occur during non–rapid eye movement (REM) sleep. This is clearly in contrast with other respiratory disorders associated with sleep-disordered breathing, such as obstructive sleep apnea syndrome, in which gas-exchange abnormalities preferentially occur during REM sleep.

Ventilatory sensitivity to hypercarbia and hypoxemia in CCHS has been found to be detectable, but weaker than in controls. This is thought to be due to deficit of central chemosensors with preservation of peripheral chemosensors. Differences in the cerebrovascular responses of CCHS patients and controls during hypoxic hypercapnic challenges suggest there is a dysregulation of cerebral autoregulation in CCHS patients. They also appear to not react to hypercarbia and hypoxemia, while controls have labored breathing and anxiety. [15]

Findings during non-REM sleep suggest that the intrinsic defect in CCHS is always present but becomes more prominently expressed during conditions in which other redundant mechanisms are either less active or inoperative. [16]

In addition, noradrenergic dysregulation has been reported in human pathologies affecting the control of breathing, such as sudden infant death syndrome, congenital central hypoventilation syndrome, and Rett syndrome. Noradrenergic neurons are located predominantly in pontine nuclei. Severe respiratory disturbances associated with gene mutations affecting noradrenergic neurons have been reported (PHOX2 and MECP2).

Efforts are attempting to understand the biochemical basis for PHOX2B mutation. Task2 potassium channel expression in the RTN region appears to be affected by reactive oxygen species generated during hypoxia. [17]