Congenital Central Hypoventilation Syndrome

CCHS is also referred to as Ondine's curse. The literary misnomer Ondine's curse has been used in prior literature. In this German folk epic, the nymph Ondine falls in love with a mortal. When the mortal is unfaithful to the nymph, he is cursed by the king of the nymphs. The king's curse makes the mortal responsible for remembering to perform all bodily functions, even those that occur automatically, such as breathing. When the mortal falls asleep, he "forgets" to breathe and dies. Because it was the king, rather than Ondine, who cursed the mortal, and because patients with CCHS do not actually “forget” to breathe, the term Ondine's curse is a misnomer and should be avoided.

CCHS should be considered in children with episodic or sustained hypoventilation and hypoxemia in the first months of life without obvious metabolic, cardiopulmonary, or neuromuscular disease. Most patients breathe normally while awake but hypoventilate during sleep. In 1962, Severinghaus and Mitchell coined the term Ondine’s curse to describe a syndrome that manifested in 3 adult patients after high cervical and brainstem surgery. When awake and needing to breathe, these patients did so; however, they required mechanical ventilation for severe central apnea when asleep. In 1970, Mellins and colleagues first reported an infant with the clinical features of CCHS.

Although the cases described by Severinghaus and Mitchell were markedly different from the typical cases in infants with CCHS, the term Ondine’s curse gained wide acceptance to denote CCHS in infants and children, but the term has recently fallen out of favor. Children with CCHS have progressive hypercapnia and hypoxemia when asleep, along with markedly impaired responses to hypercapnia and hypoxemia. CCHS is also associated with generalized dysfunction of the autonomic nervous system, including cardiovascular and ophthalmic regulation. Hirschsprung disease is associated with 20% of CCHS cases, and when seen in combination is termed Haddad syndrome. Tumors of neural crest origin are associated with 5-10% of cases.

CCHS should be considered in a patient who presents with hypercapnia and hypoxemia when underlying cardiac, neurologic, pulmonary, and generalized disorders have been excluded. Ultimately, the diagnosis of CCHS is established in a symptomatic patient with a genetic defect in the PHOX2B (paired-like homeobox 2B gene) located on chromosome 4p12.

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 a NPARM mutation. ^[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. Among NPARMs, frameshift mutations are most common and the degree of shift can predict clinical presentation; two-step frameshifts are associated with classic, isolated CCHS, whereas one-step frameshifts are associated with a syndromic presentation (CCHS plus Hirschsprung disease and neural crest tumors) often termed Haddad syndrome. ^[3]

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 PARM 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. ^[4]

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. ^[5] In one study looking at 45 CCHS families, nearly 20% of patients inherited the mutation from somatic mosaicism. ^[6]  Genetic counseling is important for the parents of individuals diagnosed with CCHS, as there is a 50% chance of recurrence in future children. ^[7]

Certain PARMs, such as 24 and 25, have an autosomal dominant inheritance with incomplete penetrance. ^{[1, 8]} Therefore, the degree to which family members of individuals with CCHS may have evidence of respiratory control or autonomic dysfunction remains uncertain. ^[9] 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. ^[10]

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. ^[11]

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. ^[12]

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. ^[13]

MRI changes indicating alterations or injury have been observed in the caudate nuclei in patients with CCHS. ^[14] 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. ^[15] 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. ^[16]

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 (N-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, whereas controls have labored breathing and anxiety. ^[17]

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. ^[18]

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. ^[19]

PHOX2B is the main disease-causing gene for primary congenital central hypoventilation syndrome (CCHS), an autosomal dominant disorder with incomplete penetrance. However, about 20 patients have been identified with CCHS with mutations in other genes, usually in genes involved in the development of neural crest cells or components of the endothelin pathway. In some cases, non-PHOX2B gene mutations were accompanied by PHOX2B mutations, suggesting a role as modifier genes. ^[20]

Secondary central hypoventilation syndrome may result from other conditions or occurrences (eg, brainstem tumor or other space-occupying lesions, vascular malformations, CNS infection, stroke, neurosurgical procedures to the brain stem).

Patients with CCHS who develop malignant neural crest–derived tumors have either a missense or a frameshift heterozygous mutation in the PHOX2B gene. Therefore, a subset of patients with CCHS who are at risk for developing malignant tumors may be identified.

United States statistics

Congenital central hypoventilation syndrome (CCHS) was thought to be a very rare disorder with an estimated prevalence of 1 case per 200,000 live births. ^[21] However, the introduction of more extensive screening measures for detection of PHOX2B mutations has revealed that CCHS is not as rare as previously considered.

International statistics

Nearly 1000 children worldwide have PHOX2B mutation–confirmed congenital central hypoventilation syndrome (CCHS). However, some believe that this number is likely underestimated. ^[1]

Race-, sex-, and age-related demographics

No differences in the occurrence of congenital central hypoventilation syndrome (CCHS) are evident based on race.

Both sexes appear to be equally affected.

Congenital central hypoventilation syndrome (CCHS) is present at birth, although the diagnosis may be delayed because of variations in the severity of the manifestations or lack of awareness in the medical community, particularly in milder cases. Late-onset CCHS may present in the school-aged child to adult years as abnormal ventilatory response to a severe infection or after administration of an anesthetic or CNS depressant during a surgical procedure.

Overall, the prognosis of patients with CCHS is excellent if the diagnosis is prompt and medical management is appropriate; however, neurocognitive deficits of varying severity, stunted growth, cor pulmonale, and seizure disorders are frequent in older patients who may not have benefited from prompt recognition or intervention. Long-term prognosis is variable, but ventilator support is lifelong, as the disease does not improve with age.

Morbidity/mortality

The clinical outcome of children with congenital central hypoventilation syndrome (CCHS) has markedly changed since the description of the disorder. In the past, most patients presented with neurocognitive deficits, especially in visuoperceptual reasoning and visuographic speed, stunted growth, cor pulmonale, and/or seizure disorders. However, early diagnosis and institution of adequate ventilatory support to prevent recurrent hypoxemic episodes clearly offers the potential for improved growth and development and should be associated with normal longevity.

Mortality is primarily due to complications that stem from long-term mechanical ventilation or from the extent of bowel involvement when Hirschsprung disease is present. Nevertheless, stressing that the characteristic central hypoventilation during sleep is a life-long symptom is important.

Neural crest tumors such as neuroblastomas or ganglioblastomas have also been associated with CCHS. Therefore, the prognosis depends on adequate treatment of the underlying tumor.

Central sinus vein thrombosis has been detected in several patients, one a newborn and another in early childhood, who had CCHS. ^[22]  Of note, the thrombophilia screening in the former was unremarkable. At this time, no clear physiologic link between central sinus vein thrombosis and CCHS has been established, although it has been hypothesized that the thrombosis may be associated with cerebral blood flow stasis as a result of dysfunctional autonomic vasculature regulation.

Complications

The major complications of CCHS include death due to hypoxemia during sleep. Development of pulmonary hypertension or cor pulmonale due to recurrent hypoxemia, either from delayed diagnosis or inadequate ventilatory support, is one of the most severe morbidities associated with CCHS leading to early mortality.

Patients with CCHS are medically fragile and can have inherent risks of complications due to the likelihood that they go on to have surgical interventions. There can also be complications associated with procedures (eg, tracheostomy, gastrostomy tube, colostomy, pacemaker procedure) that should always be considered, as well as anesthesia complications given the abnormal respiratory drive.

About 5-10% of patients may develop neural crest–derived tumors (eg, ganglioneuroma, neuroblastoma, ganglioneuroblastoma), which require prompt treatment and are associated with increased morbitidy and mortality.

For patient education resources, see the Children's Health Center, http://www.cchsnetwork.org/, as well as Sudden Infant Death Syndrome (SIDS).

The CCHS family network provides community support for families and individuals affected by CCHS. There is a significiant emotional, social, and financial burden for patients with CCHS.