Congenital Central Hypoventilation Syndrome

Congenital central hypoventilation syndrome is a rare disorder of autonomic control of breathing in which the response to hypercapnia and hypoxaemia is absent or severely reduced, with hypoventilation most marked in sleep. It is caused by variants in the PHOX2B gene.

It is rare, with an estimated incidence of about 1 in 200 000 live births. Inheritance is autosomal dominant, but most cases arise de novo, and parental mosaicism occurs. Most patients have a polyalanine repeat expansion mutation (genotypes 20/24 to 20/33), and a minority have non-polyalanine repeat variants (which tend to cause more severe disease, with Hirschsprung disease and tumours).

Severity relates to genotype: longer expansions cause continuous ventilatory dependence, and shorter expansions may present late in childhood or adulthood, with sleep related hypoventilation.

Pathophysiology.

PHOX2B is a transcription factor required for development of the autonomic nervous system and the brainstem respiratory chemoreceptor neurons. Variants cause failure of autonomic control: hypoventilation, reduced heart rate variability, Hirschsprung disease and neural crest tumours.

Breathing is preserved during wakefulness in some, since voluntary respiration compensates, but fails in sleep.

• Newborn: cyanosis, apnoea or hypoventilation in sleep with normal lungs, failure to wean from ventilation, and shallow breathing.
• Absent perception of hypercapnia and hypoxaemia, so no dyspnoea.
• Autonomic dysfunction: poor heart rate variability, sinus pauses and bradycardia, temperature instability, abnormal sweating, abnormal pupil responses, and strabismus.
• Hirschsprung disease (about 20%), neuroblastoma and ganglioneuroma, and neurocognitive problems from hypoxia.

Red flags.

• Unexplained apnoea, cyanosis or hypoventilation in sleep with no lung, cardiac or neuromuscular cause.
• Associated Hirschsprung disease, or neural crest tumour.
• Cardiac pauses, seizures or neurological deficits.

• PHOX2B genetic testing: polyalanine repeat analysis (by PCR with fragment analysis), then sequencing and deletion analysis if negative. This is diagnostic.
• Exclude other causes: lung disease, cardiac disease, neuromuscular disease, brainstem lesion (MRI), metabolic disease and drug effects.
• Polysomnography with capnography showing hypoventilation in sleep, with PaCO2 over 60 mmHg or end tidal CO2 above 50 mmHg, without a response to carbon dioxide challenge.
• Evaluation of associated problems: rectal biopsy or contrast study for Hirschsprung disease, echocardiography, 72-hour Holter monitoring, and eye examination.

Differential diagnosis. Congenital heart or lung disease, brainstem malformation or injury (Chiari malformation, tumours), neuromuscular disease, metabolic disease, Prader-Willi syndrome, sedative drug effect and obstructive sleep apnoea.

Ventilatory support (lifelong).

• Infants: tracheostomy with positive pressure ventilation at night, and during the day in severe disease.
• Older children and adults: non-invasive ventilation by mask or diaphragm pacing during sleep, if the child is stable and can tolerate it.
• Target oxygen saturation of 95% or over and end tidal CO2 of 35 to 45 mmHg, with home monitoring (oximetry and capnography) continuously during sleep and during illness.
• Respiratory stimulants have no role.

Associated conditions.

• Cardiac: Holter monitoring and echocardiography at least annually, with pacemaker for significant pauses.
• Tumours: surveillance for neuroblastoma with chest radiograph and abdominal ultrasound or MRI and urinary catecholamines every 6 months in the early years for higher risk genotypes.
• Hirschsprung disease: surgical treatment.
• Neurocognitive: early developmental and educational support, with monitoring for pulmonary hypertension.

Precautions. Avoid sedatives, opioids, benzodiazepines and alcohol (respiratory depressants), and use extreme caution during anaesthesia and illness, because infections can cause decompensation. Parents need training in resuscitation, ventilator and tracheostomy care.

Monitoring. Ventilator settings, gas exchange, growth, development, cardiac rhythm and tumour surveillance.

Referral and escalation. Refer to a specialist centre for home ventilation, with 24-hour support and emergency plans.

Special groups. Late onset forms may be triggered by sedatives or respiratory illness, and heterozygous parents may carry mosaicism and need genetic testing.