Congenital Central Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS), also known as Ondine’s curse, is a rare neurological condition characterized by alveolar hypoventilation and autonomic nervous system dysregulation. CHHS is a life-threatening condition that causes an oxygen shortage and an accumulation of carbon dioxide in the blood. Usually, patients with CCHS require lifelong ventilatory support.  

CCHS affects the autonomic nervous system, which can cause an inability to control breathing, especially during sleep, thereby resulting in an imbalance of oxygen and carbon dioxide in the blood. Usually, when this occurs, the autonomic nervous system will correct by causing the individual to wake up or begin taking deeper breaths; however, in individuals with CCHS, the autonomic nervous system reaction is compromised.  

CCHS is caused by mutations in the PHOX2B gene, which is involved in the development of the nervous system in utero.  Although most cases of CCHS have been found to be spontaneous in nature (i.e., de novo), it is considered a dominant genetic condition, meaning that only one mutated gene needs to be present for the condition to occur. Therefore, both those assigned female and male at birth can be affected equally.  

Mutations in the PHOX2B gene can be due to repeat mutations, also known as polyalanine repeat expansion mutations (PARMS); or a gene mutation on the PHOX2B gene that isn’t repeating, known as non-polyalanine repeat expansion mutations (NPARMS). Regardless of the type of mutation, there is impaired function of the PHOX2B gene.  

Signs and symptoms of CCHS usually include reduced or shallow breathing related to the individual's inability to control their breathing. This impaired breathing will usually be seen during both REM and non-REM sleep but can also be present while awake. An individual may also experience blue discoloration in the skin and lips, which occurs when the oxygen levels in the blood are low.  

Other signs and symptoms can include impairment in the cardiovascular system, including temperature regulation issues, and alterations in heart rate and blood pressure, including prolonged sinus pauses and asystole in severe cases. Other symptoms suggesting autonomic dysregulation include seizures and altered pupillary reaction to light. Additionally, some children with CCHS can have abnormal development of neural-crest derived structures, leading to decreased gastrointestinal motility; gastrointestinal reflux; and Hirschsprung disease, which is a condition where nerve cells are not present in the large intestine thereby resulting in the inability to pass stool. Individuals may also have tumors of neural crest origin, such as neuroblastoma, ganglioneuroma, or ganglioneuroblastoma.

Treatment of CCHS is usually aimed at ensuring adequate ventilation, which includes mechanical ventilation with supplemental oxygen. A phrenic pacemaker can also be used to stimulate the phrenic nerve to contract the diaphragm and generate a breath. Those with CCHS need continuous monitoring of their oxygen saturation and carbon dioxide levels. Individuals should be assessed every six months for the first three years, then annually thereafter in a pediatric respiratory physiology laboratory. A child with CCHS who has cardiac involvement may need electrocardiography, echocardiography, Holter monitoring, implantable loop recorders, or even a cardiac pacemaker placement to monitor and treat changes in their cardiac rhythm. 

Management of CCHS usually requires a multidisciplinary approach and includes primary caregivers, pulmonologists, endocrinologists, gastroenterologists, ophthalmologists, oncologists, neurologists, neurodevelopmental psychologists, CCHS specialists, and social workers. Individuals or caretakers should be instructed to avoid swimming and breath-holding, alcohol, recreational drugs, and sedatives that could induce respiratory depression. Afflicted individuals and family members should also receive genetic counseling to understand how the condition could affect future pregnancies.