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Congenital Central Hypoventilation Syndrome

Disease Details

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Description: Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder that causes individuals to have difficulty sensing and responding to low oxygen and high carbon dioxide levels, leading to inadequate autonomic control of breathing, especially during sleep.
Type: Autosomal dominant.
Signs And Symptoms: 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. Patients with CHS 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, episodes of fainting, and temperature disregulation.
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 diaphragm pacing.
Onset: Congenital Central Hypoventilation Syndrome (CCHS) is typically present at birth or appears in the neonatal period. The genetic mutation causing CCHS is present from conception, leading to early onset of symptoms, primarily involving impaired control of breathing, especially during sleep.
Prevalence: The precise prevalence of congenital central hypoventilation syndrome (CCHS) is not well documented, but it is estimated to occur in about 1 in 200,000 live births.
Epidemiology: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder. The estimated incidence is approximately 1 in 200,000 live births. It is most commonly associated with mutations in the PHOX2B gene. Cases have been reported across various ethnicities and geographical regions. The exact prevalence may vary due to underdiagnosis or misdiagnosis.
Intractability: Congenital Central Hypoventilation Syndrome (CCHS) is often considered intractable in the sense that it is a lifelong condition requiring ongoing management. While the respiratory issues associated with CCHS can be managed with interventions such as ventilatory support, there is currently no cure. Treatment primarily focuses on maintaining adequate ventilation, particularly during sleep, through methods like mechanical ventilation, diaphragm pacing, or non-invasive positive pressure ventilation.
Disease Severity: Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder affecting the autonomic control of breathing, which can vary in severity. In severe cases, individuals may require ventilatory support 24 hours a day, while milder cases might need support mainly during sleep. The severity often depends on mutations in the PHOX2B gene, where longer polyalanine repeat expansions generally correlate with more severe symptoms. Early diagnosis and management are crucial to improve outcomes.
Healthcare Professionals: Disease Ontology ID - DOID:0060731
Pathophysiology: Congenital Central Hypoventilation Syndrome (CCHS) is caused by mutations in the PHOX2B gene, which plays a crucial role in the development of the autonomic nervous system. These mutations result in the failure of the central nervous system to properly regulate breathing, particularly during sleep. This leads to hypoventilation, where the body does not adequately respond to increased levels of carbon dioxide, causing insufficient ventilation and oxygenation. The condition is inherited in an autosomal dominant manner.
Carrier Status: Congenital Central Hypoventilation Syndrome (CCHS) is typically caused by mutations in the PHOX2B gene. It follows an autosomal dominant inheritance pattern, meaning that carrying just one copy of the mutated gene can cause the disorder. Carrier status, in the context of autosomal dominant conditions like CCHS, usually implies that the individual has one affected allele and can present with symptoms of the disorder. Since "nan" specifies no further details, there isn't additional relevant carrier status information to provide here.
Mechanism: Congenital Central Hypoventilation Syndrome (CCHS) is a rare disorder typically caused by mutations in the PHOX2B gene.

Mechanism:
CCHS primarily affects the autonomic control of breathing, where individuals fail to adequately sense and respond to high levels of carbon dioxide (hypercapnia) and low levels of oxygen (hypoxemia) during sleep and, in severe cases, even while awake. This condition results in hypoventilation, where there is insufficient alveolar ventilation to meet the body's metabolic demands.

Molecular Mechanisms:
The majority of CCHS cases are associated with heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene. Normally, the PHOX2B gene contains a sequence of 20 alanine repeats, but in CCHS patients, this sequence can be expanded to 24-33 repeats. These expansions disrupt the normal function of the PHOX2B protein, which plays a critical role in the development and function of neural crest-derived tissues, including those involved in respiratory control. There are also non-PARM mutations, which are less common but may cause more severe phenotypes, including frameshift, missense, and nonsense mutations affecting the PHOX2B gene.

The disrupted function of PHOX2B results in impaired autonomic regulation of respiration, as the neural circuits responsible for detecting and responding to changes in blood gases are not properly developed or maintained. This leads to the characteristic symptoms of hypoventilation, particularly noted during sleep when voluntary control of breathing is diminished.
Treatment: People 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 CHS include oxygen therapy and medicine for stimulating the respiratory system. Currently, problems arise with the extended use of ventilators, including fatal infections and pneumonia.
Compassionate Use Treatment: For congenital central hypoventilation syndrome (CCHS), compassionate use treatments and off-label or experimental treatments might include:

1. **Phrenic Nerve Pacing**: Electrical stimulation of the phrenic nerve can help stimulate the diaphragm to induce breathing. This is considered especially in patients who are dependent on mechanical ventilation.

2. **Diaphragm Pacing**: Similar to phrenic nerve pacing but involves direct stimulation of the diaphragm muscle. This can improve quality of life by reducing dependence on mechanical ventilators.

3. **Gene Therapy**: Experimental approaches are being explored to correct the underlying genetic mutations associated with CCHS.

4. **Medications**: Use of specific drugs like caffeine or theophylline, which act as respiratory stimulants. These are not standard treatments and are used off-label for their potential benefits.

5. **Advanced Ventilatory Support Systems**: Trials with newer, more sophisticated ventilators that can provide better regulation of breathing patterns and potentially reduce complications.

6. **Hypoglossal Nerve Stimulation**: Experimental in CCHS but used in obstructive sleep apnea, this involves stimulating the hypoglossal nerve to ensure the airway stays open during sleep.

Each patient's specific situation is unique, and these treatments might be considered on a case-by-case basis when standard care is insufficient. Always in collaboration with a specialized healthcare provider.
Lifestyle Recommendations: For individuals with Congenital Central Hypoventilation Syndrome (CCHS), lifestyle recommendations include:

1. Regular Monitoring: Frequent medical check-ups to monitor respiratory and cardiovascular function.

2. Ventilation Support: Adherence to ventilatory support, such as mechanical ventilation or diaphragm pacing, especially during sleep.

3. Healthy Diet: Maintain a balanced diet to ensure adequate nutrition and support overall health.

4. Physical Activity: Engage in appropriate physical activities while being mindful of the body's respiratory limitations and the need for oxygen monitoring.

5. Avoid Respiratory Infections: Take preventive measures like vaccinations and good hygiene to avoid respiratory infections.

6. Education: Educate family members and caregivers about the condition and emergency response procedures.

7. Compliance: Strict compliance with treatment and breathing support protocols.

8. Smoke-Free Environment: Avoid exposure to smoke and other respiratory irritants.

9. Environmental Control: Ensure a safe living environment with controlled temperature and humidity to avoid respiratory stress.

10. Psychological Support: Seek psychological support if necessary, as living with a chronic condition can be challenging for both patients and their families.

Always consult healthcare providers for personalized advice and adjustments to these recommendations based on individual health assessments.
Medication: Congenital Central Hypoventilation Syndrome (CCHS) is typically not treated with medication. Instead, management focuses on ventilatory support, which can include mechanical ventilation (especially during sleep), diaphragmatic pacing, or non-invasive positive pressure ventilation (NPPV). The primary aim is to ensure adequate breathing and oxygenation, particularly during sleep when hypoventilation is most likely to occur. Regular monitoring and follow-up with a specialist are crucial for managing this condition effectively.
Repurposable Drugs: Currently, there are no well-established repurposable drugs specifically for Congenital Central Hypoventilation Syndrome (CCHS). Treatment primarily focuses on supportive measures such as mechanical ventilation or diaphragmatic pacing to manage hypoventilation. Emerging therapies and drug trials are areas of ongoing research.
Metabolites: Congenital Central Hypoventilation Syndrome (CCHS) is primarily a genetic disorder, often caused by mutations in the PHOX2B gene. The specific metabolic profile associated with CCHS is not well-documented as the condition is largely attributed to genetic factors affecting respiratory control. However, since it impacts autonomic regulation, secondary metabolic imbalances such as hypercapnia (elevated blood CO2 levels) and potential hypoxemia (low blood oxygen levels) can occur due to inadequate ventilation. Metabolic acidosis may also be a consequence of persistent respiratory acidosis in affected individuals.
Nutraceuticals: There is no established evidence or specific nutraceuticals recommended for the treatment of Congenital Central Hypoventilation Syndrome (CCHS). The primary management for CCHS typically involves ventilatory support to ensure proper breathing during sleep, and sometimes during wakefulness. This is often achieved through the use of ventilators, diaphragmatic pacing, or other respiratory aids. Comprehensive care usually includes regular follow-ups with a multidisciplinary team to address associated symptoms and complications.
Peptides: Congenital Central Hypoventilation Syndrome (CCHS) does not have a well-established link with peptide treatments. CCHS is typically caused by mutations in the PHOX2B gene, which affects the autonomic control of breathing. Management focuses on ventilatory support rather than peptide therapy or nanotechnology-based treatments.