Congenital central hypoventilation syndrome

Central hypoventilation syndrome (CHS) is a respiratory disorder that results in respiratory arrest during sleep. CHS can either be congenital (CCHS) or acquired (ACHS) later in life. The condition is fatal if untreated. It is also known as Ondine's curse. Central hypoventilation syndrome (CHS) is a respiratory disorder that results in respiratory arrest during sleep. CHS can either be congenital (CCHS) or acquired (ACHS) later in life. The condition is fatal if untreated. It is also known as Ondine's curse. ACHS can develop as a result of severe injury or trauma to the brain or brainstem. Congenital cases are very rare and involve 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 also were found to have CCHS, it may be that 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). 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. CHS 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 Ondine's curse 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 disregulation. CHS 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 Parkinson's disease, Multiple System Atrophy, or multiple sclerosis. Long and Allen (1984) were the first to report the abnormal brainstem auditory evoked responses in an alcoholic woman who recovered from Ondine's curse. 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. Children with CCHS 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.