What is Ondine's curse (Congenital Central Hypoventilation Syndrome), its clinical implications, and when is it typically diagnosed, particularly in pediatric patients?

Ondine's Curse (Congenital Central Hypoventilation Syndrome)

Ondine's curse, formally known as Congenital Central Hypoventilation Syndrome (CCHS), is a life-threatening genetic disorder characterized by absent or severely diminished automatic control of breathing, particularly during sleep, caused by PHOX2B gene mutations in 90% of cases. 1, 2

What It Is

CCHS results from malformation of neural crest tissue in the brainstem, leading to loss of CO2 chemoreceptor sensitivity and absent ventilatory responses to hypoxemia and hypercarbia. 2 The hallmark feature is profound alveolar hypoventilation with diminished tidal volumes and monotonous respiratory rates, most severe during non-REM sleep but also abnormal during REM sleep and wakefulness. 1

Key Pathophysiology

• Patients lack the normal physiologic responses to asphyxia—they do not experience increased work of breathing, retractions, or shortness of breath when hypoxemic or hypercarbic. 1
• Complete respiratory arrest or severe hypoventilation occurs at sleep onset, making continuous monitoring and ventilatory support mandatory for survival. 1
• 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

Clinical Implications and Associated Conditions

Autonomic Nervous System Dysregulation

Beyond respiratory control, CCHS causes widespread autonomic dysfunction: 1

• Hirschsprung disease (intestinal dysmotility)—particularly with PHOX2B genotypes 20/26 and higher 1
• Tumors of neural crest origin (neuroblastomas, ganglioneuromas, ganglioneuroblastomas)—especially with genotypes 20/28 to 20/33 1
• Cardiac abnormalities including abrupt sinus pauses that standard apnea/bradycardia monitors cannot detect 1
• Diminished pupillary light response, esophageal dysmotility, altered body temperature regulation, and lack of dyspnea perception 1

Genotype-Phenotype Correlation

The severity directly correlates with PHOX2B mutation type: 1

• 20/24 and 20/25 genotypes: Mildest phenotype, typically require ventilation only during sleep, may present later in life after anesthesia or severe illness
• 20/26 genotype: Variable awake ventilatory needs depending on activity level
• 20/27 to 20/33 genotypes and NPARMs (non-polyalanine repeat mutations): Most severe, typically require 24-hour mechanical ventilation

When We See This

Typical Presentation

Most cases are diagnosed in the newborn period when infants present with cyanosis, apnea, or hypoventilation during sleep in the absence of primary lung, cardiac, or neuromuscular disease. 1 However, recognition of milder genotypes has expanded the diagnostic timeline. 1

Late-Onset CCHS (LO-CCHS)

Patients with milder genotypes (particularly 20/24 and 20/25) may not present until: 1, 3

• After exposure to anesthesia or sedation
• Following severe respiratory illness
• During evaluation for unexplained seizures or neurocognitive impairment
• In adolescence or adulthood with subtle symptoms

Critical red flags in history include: 1

• Delayed "recovery" from anesthesia
• Unexplained neurocognitive impairment
• Documented prolonged sinus pauses on ECG
• Polycythemia (compensatory response to chronic hypoxemia)
• Elevated bicarbonate (compensated respiratory acidosis)
• Signs of right heart strain or pulmonary hypertension on imaging

Distinguishing from ROHHAD

CCHS must be distinguished from Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD), which presents between ages 1.5-7 years with rapid weight gain (20-40 pounds over 4-6 months) followed by hypoventilation. 1 ROHHAD does not have PHOX2B mutations and represents a completely different syndrome requiring different management. 1

Critical Management Principles

Monitoring Requirements

Standard apnea/bradycardia monitors are completely inadequate and have no role in CCHS management. 1 These monitors cannot detect:

• The hypoventilation (only detect apnea, not shallow breathing)
• Tracheal obstruction
• The characteristic abrupt sinus pauses
• Falsely elevated heart rates from diaphragm pacer artifacts 1

Mandatory monitoring includes: 1

• Continuous pulse oximetry (alarm set ≤85% SpO2)
• Continuous end-tidal CO2 monitoring (alarm set ≥55 mmHg PETCO2)
• Continuous observation by trained personnel during all sleep periods
• Ideally hourly checks during awake time

Ventilatory Support

Chronic home ventilatory support is mandatory for survival and must be initiated before each sleep episode. 1 Options include: 1

• Positive pressure ventilation via tracheostomy (recommended for infants and young children to ensure optimal neurocognitive outcome)
• Bilevel positive airway pressure (BiPAP)
• Diaphragm pacing (effective long-term option) 4
• Negative pressure ventilators

Oxygen alone without mechanical ventilation is inadequate and dangerous—it relieves cyanosis but allows persistent hypoventilation and leads to pulmonary hypertension. 1

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. 1
• Avoid all sedative medications and CNS depressants as they worsen hypoventilation. 1
• Prohibit underwater swimming competitions—patients lack asphyxia perception and will swim longer than normal children, dramatically increasing drowning risk. 1
• Metabolic alkalosis further inhibits central respiratory drive and must be corrected. 1

Required Surveillance Based on Genotype

The American Thoracic Society recommends genotype-specific annual testing: 1

• All genotypes: Comprehensive physiologic testing (awake/asleep), neurocognitive assessment, 72-hour Holter monitoring, echocardiogram
• 20/26 and higher: Add Hirschsprung disease assessment
• 20/28 to 20/33 and NPARMs: Add imaging for neural crest tumors (chest/abdominal imaging every 3 months in first 2 years, then every 6 months until age 7 for neuroblastomas) 1

Prognosis and Quality of Life

With appropriate ventilatory support and monitoring, patients can lead productive lives—attending school, working full-time, and participating in normal daily activities while ventilator-free during waking hours. 4 However, this requires specialized care at centers with extensive CCHS experience, as the nuances of management differ substantially from routine ventilator care. 1