What is congenital hypoventilation syndrome (CCHS, Ondine’s curse), how is it diagnosed, and what are the recommended management and treatment options?

Congenital Central Hypoventilation Syndrome (CCHS)

CCHS is a genetic disorder caused by PHOX2B mutations that results in absent ventilatory responses to hypoxemia and hypercarbia, requiring lifelong mechanical ventilatory support during sleep (and sometimes 24 hours/day), as pharmacologic stimulants are completely ineffective and the condition never resolves spontaneously. 1, 2

What is CCHS?

CCHS, also known as Ondine's curse, is a rare disorder resulting from malformation of neural crest tissue in the brainstem that causes loss of CO2 chemoreceptor sensitivity 3, 4. The disease-defining genetic mutation is in the PHOX2B gene, found in approximately 90% of patients 1, 4, 5.

Key pathophysiologic features:

• Patients have diminutive tidal volumes and monotonous respiratory rates both awake and asleep, with profound alveolar hypoventilation primarily during sleep 1
• Complete respiratory arrest or severe hypoventilation occurs at sleep onset 3, 2
• Patients lack arousal responses to hypoxemia/hypercarbia and do not experience dyspnea, increased work of breathing, or respiratory distress despite severe asphyxia 3, 6
• This is not solely a breathing disorder but represents diffuse autonomic nervous system dysregulation (ANSD) 1

Diagnosis

Genetic testing for PHOX2B mutations is essential for diagnosis and also directs disease management based on genotype-phenotype correlation. 1, 3, 5

Clinical Presentation

Neonatal-onset CCHS (most common):

• Presents in the newborn period with hypoventilation during sleep 1
• Diagnosis is one of exclusion after ruling out primary lung, cardiac, neuromuscular disease, or identifiable brainstem lesions 1, 6

Later-onset CCHS (LO-CCHS):

• Can present in infancy, childhood, or adulthood, particularly with genotypes 20/24 and 20/25 1
• Consider LO-CCHS in cases of centrally mediated alveolar hypoventilation and/or cyanosis or seizures after: (1) administration of anesthetics or CNS depressants, (2) recent severe pulmonary infection, or (3) treatment of obstructive sleep apnea 1

Diagnostic Evaluation

For suspected LO-CCHS, obtain: 1

• Careful history regarding past anesthesia/sedation exposure, delayed recovery from respiratory illness, unexplained seizures or neurocognitive impairment
• Review of frontal and lateral photographs (evaluate for characteristic facies; adult males often have moustache concealing "lip trait")
• 72-hour Holter monitoring (document prolonged sinus pauses)
• Physiologic evaluations documenting ventilation awake and asleep (for hypercarbia/hypoxemia)
• Hematocrit and reticulocyte count (for polycythemia and hypoxemia response)
• Bicarbonate level (for compensated respiratory acidosis)
• Chest x-ray, echocardiogram, ECG (for right chamber enlargement or pulmonary hypertension)
• Barium enema or manometry if constipation present (exclude Hirschsprung disease)

Critical distinction: Distinguish LO-CCHS from ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation), which presents between ages 1.5-7 years with rapid obesity (20-40 pound gain over 4-6 months) followed by hypothalamic disorders, and is PHOX2B-negative 1

Genotype-Phenotype Correlation

The severity of CCHS directly correlates with PHOX2B mutation type: 3

• Genotypes 20/26 and higher: Associated with Hirschsprung disease
• Genotypes 20/28 to 20/33: Associated with neural crest tumors (neuroblastomas, ganglioneuromas, ganglioneuroblastomas)
• Genotypes 20/24 and 20/25: Often require environmental cofactors to manifest phenotype and are likely underdiagnosed 1

Management and Treatment

Primary Treatment: Mechanical Ventilatory Support

All patients with CCHS require chronic home ventilatory support, as the condition does not resolve spontaneously, does not respond to pharmacologic respiratory stimulants, and does not improve with age except in rare anecdotal cases. 1, 2, 6

Available ventilation modalities: 1, 2, 6

• Positive pressure ventilation via tracheostomy (recommended for infants and young children in first several years of life to ensure optimal neurocognitive outcomes)
• Bilevel positive airway pressure (BiPAP)
• Diaphragm pacing (offers maximal mobility for full-time ventilatory patients and may permit tracheostomy decannulation in those requiring only sleep support) 7
• Negative pressure ventilators

Critical Safety Measures

Continuous monitoring is mandatory: 3, 2

• Continuous pulse oximetry during all sleep periods
• Continuous end-tidal CO2 monitoring during all sleep periods
• Continuous observation by trained personnel during all sleep periods
• Target parameters: SpO2 ≥95%, PETCO2 30-50 mm Hg
• Alarm settings: SpO2 ≤85%, PETCO2 ≥55 mm Hg

Ventilatory support must be initiated before each sleep episode, ideally before sleep onset, as patients may suffer complete respiratory arrest at sleep onset. 1, 3

Physiologic Assessment

Biannual (initially) then annual in-hospital comprehensive physiologic testing is required to assess ventilatory needs during varying activity levels, concentration, and all sleep stages. 1, 2 These multi-day hospitalizations should include constant supervision by highly trained personnel with continuous audiovisual surveillance and recording of respiratory inductance plethysmography, ECG, hemoglobin saturation, pulse waveform, end-tidal CO2, sleep state staging, blood pressure, and temperature 1.

Surveillance Based on Genotype

Annual testing required for all genotypes: 3

• Comprehensive physiologic testing
• Neurocognitive assessment
• 72-hour Holter monitoring
• Echocardiogram

Additional genotype-specific testing: 3

• Hirschsprung disease screening for genotypes 20/26 and higher
• Neural crest tumor surveillance for genotypes 20/28 to 20/33

Critical Pitfalls to Avoid

Never attempt to "wean" or "train" patients to breathe—this is not a realistic goal and wastes energy needed for development and activities. 3, 2

Never use oxygen supplementation alone without mechanical ventilation—this is inadequate and dangerous, as it improves cyanosis but allows persistent hypoventilation leading to pulmonary hypertension. 1, 2, 6

Never rely on apnea/bradycardia transthoracic impedance monitors—they cannot detect hypoventilation (do not determine obstructed breaths) and will not detect the characteristic abrupt sinus pauses that may spontaneously terminate before the averaging algorithm detects them. 1, 2

Avoid all sedative medications and CNS depressants—they worsen hypoventilation. 1, 2

Correct metabolic alkalosis—it further inhibits central respiratory drive. 2

Never rely on clinical appearance alone—patients lack typical respiratory distress signs (retractions, increased work of breathing, dyspnea sensation) despite severe hypoxemia/hypercarbia. 3, 2, 6

Emergency Preparedness

Mandatory emergency measures: 2

• Power generators for home use
• Placement on emergency lists for local power companies and fire departments

Long-term Prognosis

With modern home ventilation techniques and aggressive management in CCHS centers, most children can have prolonged survival with good quality of life 1. The mortality rate is low in aggressively managed patients, though continuous vigilance is necessary regarding physiologic monitoring, equipment maintenance, and battery replacement 1. As children advance into adulthood, transitional medicine programs in CCHS centers are essential 1.