A 5-year-old female came to clinic for her pre-kindergarten health maintenance examination. She had moved to the area in the past month. She had congenital central hypoventilation syndrome (CCHS) and had received around the clock ventilatory support. “Before we even moved, we had meetings with the pulmonary specialists at the children’s hospital, along with the gastroenterologists. We are seeing you today and will see ophthalmology, endocrinology, and cardiology next week. School is still a few months away but again we are meeting with all the staff to update her IEP and plan for her medical needs at school,” the mother stated. She continued, “We’re going to need you to help us with her general pediatric problems like vaccinations and someone to help evaluate her when she gets sick. We’ve been fortunate that she had gotten some normal stuff like colds and ear infections, but she hadn’t been hospitalized for that, and only once for bad pneumonia.”
The past medical history revealed that the patient was diagnosed after she had respiratory distress after a 35 week gestation. She was not able to wean off her endotracheal tube which led to additional evaluation and eventually her diagnosis. She had some failure to thrive as an infant as well because of emesis. The family history was negative for genetic conditions, but was positive for obstructive sleep apnea in the paternal grandfather diagnosed in his 70s. The review of systems showed that she had some feeding difficulties with decreased intake, and her development was being monitored closely.
The pertinent physical exam showed a smiley, interactive female with normal vital signs. Her weight was at the 5th percentile and her height was 25%. HEENT showed a tracheostomy and trach cuff in place. Her lungs had some coarse breath sounds and her heart had no arrhythmias. The rest of her examination was normal.
The diagnosis of a kindergartener with CCHS was confirmed. The pediatrician and mother discussed her ongoing needs including updating her vaccinations, forms for school, and referrals for dental care, developmental monitoring and also recreational services in the community. Home health and nursing had already been well established for the family. “This town is very fortunate to have an active recreation program for all of its people including special programs for people with different needs. I know she can do most things, but they may also have ideas for other programs and also there may be a discount in the cost. I know you will also qualify for reduced or free public transportation as well. Do you need an updated handicapped parking sticker too?”, the pediatrician inquired.
Congenital central hypoventilation syndrome (CCHS) is an autosomal dominant with variable inheritance genetic disease caused by mutation in the Paired Like Homeobox B2 (PHOX2B) gene on chromosome 4. There are two other genes which may also cause CCHS. CCHS affects the chemoreceptor afferent ventilation pathways and is a neural crest migration problem of the autonomic nervous system. The incidence is unknown but a prevalence of 1 in 200,000 live births has been reported. Obviously it is a rarer phenomenon because of the general lethality of the syndrome.
Patients usually present at birth or soon afterwards, but older children and adolescents have been diagnosed. They can have apnea and cyanosis often right after birth. Frank respiratory arrest can occur also. Patients usually have a normal physical examination and often will not show tachypnea or nasal flaring even during times of abnormal gas exchange such as illnesses. Other presentations may include failure to wean from a ventilator, delayed anesthesia recovery, and near drowning. CCHS should be considered when there is “…evidence of hypoventilation without underlying cardiopulmonary, metabolic, neuromuscular or brainstem dysfunction….Signs of cor pulmonale or failure to thrive may be seen and are indicative of the chronicity and severity of the disease.”
Patients may or may not have adequate ventilation while awake, but have alveolar hypoventilation (decreased rate and/or tidal volume) while asleep or at other times when increased ventilation is expected such as during illnesses. “Central alveolar hypoventilation is diagnosed when the arterial PCO2 is > 45 mm Hg during wakefulness, due to decreased central ventilatory drive.”
Treatment for patients centers on maintaining adequate ventilation. This is usually done by tracheostomy, face mask or phrenic nerve stimulation. Currently central nervous system stimulant medication does not produce the necessary affects needed for adequate ventilation. This is a life-long condition and therefore the overall need for ventilatory support may change with time and the methods of providing it, but CCHS will always need to be treated.
Long term prognosis is better with earlier diagnosis and treatments for patients of all ages. Mortality still remains high (in the 30% range) in up to 3 month olds. “The main causes of death include cor pulmonale, pneumonia and aspiration.” Patients can and do have happy and fulfilling lives and can live to adulthood and have children themselves.
The potential concomitant problems are usually due to autonomic nervous system issues due to neural crest migration abnormalities. These include:
- Gastrointestinal problems – Hirschsprung disease occurs in up to 50% of patients and it tends to affect the colon extensively. Patients may also have failure to thrive or upper gastrointestinal problems.
- Eye disorders – anisocoria, abnormal pupillary light reflexes, ptosis and strabismus
- Congenital hyperinsulinism and related hypoglycemia
- Cardiac arrhythmias – bradycardia, sinus pauses, postural hypotension
- Tumors related to neural crest cells – gangioneuroma, ganglionneuroblastoma, neuroblastoma
- Central nervous system problems – Seizures are thought to be due to hypoxia, hypoglycemia and arrhythmias. Slight cognitive impairment also seen in some patients is also believed to be due to some of the same problems.
- Other autonomic features including profuse sweating and temperature instability/regulation
CCHS is the most commonly associated respiratory problem given the appellation of Undine’s or Ondine’s curse.
In mythology, the immortal nymph Ondine becomes human after falling in love with her husband who she later finds to have committed adultery. She curses him to be able to breath only while awake but not if he sleeps.
This poignant story is portrayed in many artistic forms in the written, visual and performing arts.
Other respiratory problems associated with Ondine’s curse include bulbar poliomyelitis, multiple sclerosis, other central nervous system degenerative diseases, and trauma, tumor and stroke occurring in loci that control ventilation are also causes of Ondine’s curse.
Questions for Further Discussion
1. What are some of the problems associated with chronic ventilatory support?
2. How does hypoventilation due to a congenital myopathy differ from CCHS?
- Disease: Congenital Central Hypoventilation Syndrome | Autonomic Nervous System Disorders
- Symptom/Presentation: Genetic Disorder | Health Maintenance and Disease Prevention | Respiratory Distress
- Age: School Ager
To Learn More
To view pediatric review articles on this topic from the past year check PubMed.
Information prescriptions for patients can be found at MedlinePlus for this topic: Autonomic Nervous System Disorders
To view current news articles on this topic check Google News.
To view images related to this topic check Google Images.
To view videos related to this topic check YouTube Videos.
Healy F, Marcus CL. Congenital central hypoventilation syndrome in children. Paediatr Respir Rev. 2011;12(4):253-263. doi:10.1016/j.prrv.2010.10.001
Demartini Z, Maranha Gatto LA, Koppe GL, Francisco AN, Guerios EE. Ondine’s curse: myth meets reality. Sleep Med X. 2020;2:100012. doi:10.1016/j.sleepx.2020.100012
Trang H, Samuels M, Ceccherini I, et al. Guidelines for diagnosis and management of congenital central hypoventilation syndrome. Orphanet J Rare Dis. 2020;15(1):252. doi:10.1186/s13023-020-01460-2
Ditmer M, Turkiewicz S, Gabryelska A, Sochal M, Bialasiewicz P. Adolescent Congenital Central Hypoventilation Syndrome: An Easily Overlooked Diagnosis. Int J Environ Res Public Health. 2021;18(24):13402. doi:10.3390/ijerph182413402
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa