Congenital central hypoventilation syndrome

Synonyms

3

Overview

Congenital central hypoventilation syndrome (CCHS, primary alveolar hypoventilation, Ondine's curse). CCHS is a respiratory disorder that is fatal if untreated. People afflicted with CCHS classically suffer from respiratory arrest during sleep.

CCHS is a very rare and serious form of central nervous system failure, involving a failure of autonomic control of breathing. In 2006, there were only about 200 known cases worldwide. As of 2008, only 1000 total cases were known. 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. However, as there have been cases where asymptomatic family members found to also have CCHS it may be these figures only reflect those found to require mechanical ventilation. In all cases, episodes of apnea occur in sleep, but in a few patients, at the most severe end of the spectrum, apnea also occurs while awake.

Although rare, cases of long-term untreated CCHS have been reported and are termed late onset CCHS (LO-CCHS). Cases that go undiagnosed until later life and middle age, although the symptoms are usually obvious in retrospect. There have, however, even been cases of LO-CCHS where family members found to have it have been asymptomatic. Again, lack of awareness in the medical community may cause such a delay.

CCHS susceptibility is not known to be affected by gender.

CCHS is congenital. By contrast, Acquired Central Hypoventilation Syndrome (ACHS) or alveolar hypoventilation secondary to neurologic disease, can develop as a result of severe injury or trauma to the brain or brainstem. Where the cause of an Acquired Central Hypoventilation Syndrome is unclear or unknown it is called idiopathic acquired central hypoventilation syndrome.

Symptoms

Congenital central hypoventilation syndrome is associated with respiratory arrests during sleep and, in some cases, to neuroblastoma (tumors of the sympathetic ganglia), Hirschsprung disease (partial agenesis of the enteric nervous system), dysphagia (difficulty swallowing) and anomalies of the pupilla. Other symptoms include darkening of skin color from inadequate amounts of oxygen, drowsiness, fatigue, headaches, and an inability to sleep at night. Those suffering from CCHS also have a sensitivity to sedatives and narcotics, which makes respiration even more difficult. A low concentration of oxygen in the red blood cells also may cause hypoxia-induced pulmonary vasoconstriction and pulmonary hypertension, culminating in cor pulmonale or a failure of the right side of the heart. Associated complications may also include gastro-esophageal reflux, ophthalmologic issues, seizures, recurrent pneumonia, developmental delays, learning disabilities and episodes of fainting and temperature dysregulation.

Causes

Congenital central hypoventilation syndrome is exhibited typically as a congenital disorder, but in rare circumstances, can also result from severe brain or spinal trauma or injury (such as after an automobile accident, stroke, asphyxiation, brain tumor, encephalitis, poisoning, as a complication of neurosurgery) or due to particular neurodegenerative conditions such as Parkinsons and Multiple Sclerosis. Long and Allen (1984) reported the abnormal brainstem auditory-evoked responses in an alcoholic woman who recovered from CCHS. These investigators hypothesized that their patient's brainstem was poisoned—not destroyed—by her chronic alcoholism.

Medical investigation of patients with this syndrome has led to a deeper understanding of how the body and brain regulate breathing on a molecular level. PHOX2B, a transcription factor involved in the development of neurons, can be associated with this condition. This homeobox gene is important for the normal development of the autonomic nervous system.

The disease used to be classified as a "neurocristopathy", or disease of the neural crest because part of the autonomic nervous system (such as sympathetic ganglia) derives from the neural crest. However, this denomination is no longer favored because essential neurons of the autonomic nervous system, including those that underlie the defining symptom of the disease (respiratory arrests), are derived from the neural tube (the medulla), not from the neural crest, although such mixed embryological origins are also true for most other neurocristopathies.

Prevention

Genetic consuling and prenatal testing for pregnancies at increased risk is possible if the causative variant has been identified in an affected family member.

Diagnosis

Children with congenital central hypoventilation syndrome develop life-threatening episodes of apnea with cyanosis, usually in the first months of life. Medical evaluation excludes lesions of the brain, heart, and lungs but demonstrates impaired responses to build-up of carbon dioxide (hypercapnia) and decreases of oxygen in the circulation (hypoxia), the two strongest stimuli to increase breathing rate.

Polysomnography shows that hypoventilation is most marked during slow-wave sleep. In the most severe cases, hypoventilation is present during other nonrapid eye movement sleep stages and even wakefulness. A subset of CCHS patients are at very high risk for developing malignant neural crest derived tumors, such as neuroblastoma.

The sequence of PHOX2B reveals mutations in 91% of the cases.

As in many disorders that are very rare, an infant with this unusual form of sleep apnea suffers from the probability that their physician has most likely never seen another case and will not recognize the diagnosis. In some locations, such as France, optimal management of patients, once identified, has been aided by the creation of a national registry and the formation of a network of centers.

Prognosis

Most people with CCHS (unless they have the Late Onset form) do not survive infancy, unless they receive ventilatory assistance during sleep. An alternative to a mechanical ventilator is Phrenic Nerve Pacing/diaphragm pacing.

Treatment

Patients generally require tracheostomy and lifetime mechanical ventilation on a ventilator in order to survive. However, it has now been shown that Biphasic Cuirass Ventilation can effectively be used without the need for a tracheotomy. Other potential treatments for Ondine's curse include oxygen therapy and medicine for stimulating the respiratory system. Currently problems arise with the extended use of ventilators, including fatal infections and pneumonia.