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Congenital central hypoventilation syndrome
CCHS primarily affects the nervous system's ability to regulate breathing, especially during sleep. Individuals with CCHS often require lifelong ventilatory support. It is a lifelong condition, typically identified shortly after birth.
Overview
Congenital central hypoventilation syndrome (CCHS) is a rare disorder that impacts the body's autonomic nervous system, specifically its ability to control breathing. Individuals with CCHS do not respond effectively to changes in carbon dioxide or oxygen levels in the blood, particularly during sleep. This can lead to dangerously low oxygen and high carbon dioxide levels if not managed [PMID:31536706].
Symptoms & clinical features
The primary symptom of CCHS is inadequate breathing, or hypoventilation, which is often most pronounced during sleep. Infants with CCHS may appear blue (cyanotic) due to low oxygen levels, particularly when sleeping. They might also exhibit shallow breathing or pauses in breathing. During wakefulness, breathing control can appear normal, but it may still be compromised, especially during illness or sedation [PMID:24765352]. Some individuals with CCHS may also experience impaired swallowing (dysphagia), gastrointestinal motility problems (such as Hirschsprung disease), irregular heart rhythms (arrhythmias), or sudden drops in blood pressure. Eye abnormalities and tumours of nerve tissue (neuroblastomas) are also sometimes associated with the condition.
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Affected organs
CCHS primarily affects the central nervous system, which controls involuntary functions like breathing and heart rate. This means the brainstem, responsible for regulating breathing, is significantly impacted. Other affected organs can include the heart, gastrointestinal tract, and eyes, reflecting the broad role of the autonomic nervous system [PMID:31536706].
Risks & severity
The severity of CCHS can vary, but it is always a serious condition requiring careful management. The main risk is life-threatening respiratory failure, especially during sleep. Most affected individuals require lifelong ventilatory support, such as a ventilator, even if they can breathe independently during the day. The risk of sudden death is significantly reduced with appropriate ventilatory assistance. The condition is typically diagnosed shortly after birth or in early infancy. Long-term health outcomes depend heavily on consistent and appropriate respiratory support.
Genetic causes
CCHS is most commonly caused by pathogenic changes in the PHOX2B gene. This gene provides instructions for making a protein that is vital for the development of nerve cells, particularly those involved in the autonomic nervous system and the parts of the brain that control breathing. Changes in PHOX2B can disrupt the normal development and function of these crucial nerve cells [PMID:24765352]. The PHOX2B gene is also essential for the formation of certain hormone-producing cells and nerve centres in the gut, which explains why some individuals with CCHS can also develop conditions like Hirschsprung disease, where nerve cells are missing from parts of the bowel.
- PHOX2B paired like homeobox 2B
Inheritance pattern
CCHS typically follows an autosomal dominant inheritance pattern. This means that only one copy of the altered PHOX2B gene in each cell is sufficient to cause the condition. In most cases, CCHS arises from a new (de novo) pathogenic variant in the PHOX2B gene, meaning it is not inherited from either parent. However, in a small number of cases, an affected parent may pass the altered gene on to their child. Each child of an individual with autosomal dominant CCHS has a 50% chance of inheriting the condition.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of CCHS is usually suspected in newborns or infants who experience unexplained breathing problems, particularly when asleep. Confirmation involves genetic testing to identify pathogenic variants in the PHOX2B gene [PMID:31536706]. This testing is often performed under the NHS Genomic Medicine Service (GMS) framework. Healthcare professionals, such as paediatricians or clinical geneticists, can refer individuals for genetic testing, which is covered by various NHS R-codes depending on the specific clinical presentation. Further investigations, such as sleep studies and assessments of autonomic function, may be carried out to evaluate the extent of breathing difficulties and other associated problems.
Management & lifestyle
Management of CCHS focuses on providing consistent ventilatory support and monitoring for associated health issues. Most individuals with CCHS will require ventilatory support, often mechanical ventilation via a tracheostomy or non-invasive ventilation, especially during sleep. This support is crucial for maintaining adequate oxygen levels and removing carbon dioxide. Ongoing care typically involves a multidisciplinary team, including paediatricians, respiratory specialists, neurologists, gastroenterologists, and genetic counsellors. Regular monitoring of respiratory function, heart rhythm, and other autonomic symptoms is essential. Individuals with CCHS and their families receive support and guidance through their NHS care pathway to ensure the best possible quality of life.
UK care pathway
In the UK, suspected cases of CCHS are typically referred to clinical genetics services or specialist paediatric centres for evaluation and genetic testing. Genetic testing for CCHS, specifically targeting the PHOX2B gene, is available through the NHS Genomic Medicine Service, with specific R-codes used to guide testing decisions. Genetic counsellors play a vital role in explaining the condition, its inheritance, and implications for families, as well as coordinating care within the NHS.
Frequently asked questions
How common is Congenital Central Hypoventilation Syndrome?
CCHS is a very rare condition, affecting approximately 1 in every 200,000 live births globally. Due to its rarity, exact prevalence figures can vary slightly.
Can someone with CCHS breathe on their own during the day?
Many individuals with CCHS can breathe independently while awake, though their breathing control may still be less efficient than usual. However, most will require mechanical assistance, such as a ventilator, during sleep to ensure adequate oxygen levels.
Is CCHS always inherited from a parent?
No, in most cases, CCHS results from a new genetic change in the PHOX2B gene that was not present in either parent. This is known as a de novo variant. In a smaller number of cases, it can be inherited in an autosomal dominant pattern from an affected parent.
What kind of support is available for families affected by CCHS?
Families in the UK can access support through the NHS, including specialist children's hospitals, respiratory teams, and genetic counselling services. Patient organisations and charities also offer valuable resources, information, and peer support for families living with CCHS.
Will a child with CCHS outgrow the need for ventilatory support?
CCHS is a lifelong condition, and the need for ventilatory support, particularly during sleep, typically does not resolve. Management focuses on optimising support to allow individuals to lead as full a life as possible, rather than outgrowing the condition.
References
- Trang H, Samuels M, Ceccherini I. Guidelines for diagnosis and management of congenital central hypoventilation syndrome. Orphanet journal of rare diseases. 2020. PMID: 32958024
- Kasi AS, Perez IA. Congenital Central Hypoventilation Syndrome and Disorders of Control of Ventilation. Clinics in chest medicine. 2024. PMID: 39069329
- Guyenet PG, Bayliss DA. Central respiratory chemoreception. Handbook of clinical neurology. 2022. PMID: 35965033
- Adam MP, Bick S, Mirzaa GM. Congenital Central Hypoventilation Syndrome. 1993. PMID: 20301600
- Kamihara J, Diller LR, Foulkes WD. Neuroblastoma Predisposition and Surveillance-An Update from the 2023 AACR Childhood Cancer Predisposition Workshop. Clinical cancer research : an official journal of the American Association for Cancer Research. 2024. PMID: 38860978
- Maloney MA, Kun SS, Keens TG. Congenital central hypoventilation syndrome: diagnosis and management. Expert review of respiratory medicine. 2018. PMID: 29486608
- Kasi AS, Perez IA, Kun SS. Congenital central hypoventilation syndrome: diagnostic and management challenges. Pediatric health, medicine and therapeutics. 2016. PMID: 29388615
- Amos L. Later Onset Congenital Central Hypoventilation Syndrome. The Medical clinics of North America. 2024. PMID: 37951652