Congenital Central Hypoventilation Syndrome

Iris A. Perez, MD, FAAP, Emily S. Gillett, MD, PhD, FAAP, and Thomas G. Keens, MD, FAAP

Introduction/Etiology/Epidemiology

•Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by failure of automatic control of breathing and autonomic nervous system dysfunction.

•The most severe manifestation is profound alveolar hypoventilation during sleep, particularly non–rapid eye movement sleep; hypoventilation may extend into times when the patient is awake.

•It is most often caused by a mutation in the PHOX2B gene that affects neural crest cell migration and autonomic nervous system dysfunction.

•Most patients with PHOX2B gene mutations have a polyalanine repeat expansion mutation (PARM); 10% of cases are due to non-PARM (NPARM).

•Autosomal dominant inheritance occurs with variable penetrance.

•In France, the estimated incidence is 1 in 200,000 live births. In Japan, the incidence is 1 in 148,000 live births.

•Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD syndrome) is a rare and poorly understood syndrome that is similar to CCHS (see later discussion).

Clinical Features

•CCHS typically presents in the newborn period.

—Recurrent apnea and cyanosis

—Hypoventilation and hypoxemia without increase in breathing frequency

—Intubation and assisted ventilation in the nursery and failure to extubate

•Some patients with CCHS present in later infancy, childhood, and adolescence

—Recurrent apneas and apparent life-threatening events

—Diaphoresis and cyanosis during sleep

—Pulmonary hypertension

•Autonomic nervous system dysfunction is also a major manifestation; the presence and severity are dependent on PHOX2B gene mutation.

—Ophthalmologic abnormalities include sluggish pupils, strabismus, convergence insufficiency; Marcus Gunn jaw-winking phenomenon

—Cardiovascular: Sick sinus syndrome, reduced heart rate variability, decreased heart rate response to exercise, postural hypotension; decreased blood pressure response to head tilt and standing

—Gastrointestinal: Esophageal dysmotility, Hirschsprung disease (20%)

—Endocrine: Abnormal glucose metabolism that leads to hypoglycemia or hyperglycemia

—Tumors of neural crest origin: Ganglioneuromas and ganglioneuroblastomas (6%)

—Dysregulation of body temperature with decreased baseline body temperature; poor heat tolerance; sporadic profuse sweating (can be unilateral)

Diagnostic Considerations

•CCHS should be suspected in the presence of hypoventilation that is not explained by lung disease, ventilatory muscle weakness, or obvious neurological disorders.

•PHOX2B gene mutation is essential in establishing the diagnosis, predicting the severity of ventilatory and autonomic nervous system disorder, and associated complications.

•While waiting for gene mutation analysis results, perform tests to rule out other causes of hypoventilation.

—Neurological evaluation, including magnetic resonance imaging and/or computed tomography of the brain, to rule out gross anatomic lesions

—Metabolic screening

—Polysomnography (PSG) to establish the presence of hypoventilation and sleep-related breathing disorder

—Blood gas analysis performed while the patient is awake to document daytime hypoventilation

—Chest radiography

—Fluoroscopy of the diaphragm

—Echocardiography

—Muscle biopsy, as necessary

•Patients with CCHS require ventilatory support throughout life; weaning from ventilatory support is not realistic.

•The goal of ventilatory support is to ensure optimal ventilation and oxygenation both during sleep and while awake.

•Oxygen supplementation alone is not adequate and should be minimized because it does not alleviate the hypoventilation, and it can disarm providers and caregivers that may not be aware of clinically significant hypercapnia.

•There is currently no pharmacological treatment for management of respiratory insufficiency in CCHS.

•Most patients with CCHS have little or no lung disease; thus, there are different options for evaluation, including positive pressure ventilation (PPV) via tracheostomy, noninvasive PPV (NPPV), and diaphragm pacing.

—PPV via tracheostomy

▪PPV is most often prescribed in the first years of life because infants may be unstable, and minor respiratory infections may cause severe apneas and worsen respiratory failure.

▪Ventilatory support by using pressure control or assist control mode is provided to maintain end-tidal CO₂ pressure between 30 and 45 mm Hg and oxygen saturation at pulse oximetry (SpO₂) ≥95%.

▪Use of smaller tracheostomy tubes may decrease the risk for the development of tracheomalacia and allows a larger leak to assist with speech.

~Some CCHS centers prefer to treat patients with uncuffed tracheostomy tubes, and some centers suggest using cuffed tubes when the patient receives ventilation. There are advantages and disadvantages of the 2 approaches that are beyond the scope of this brief review.

—NPPV

▪NPPV is an option for stable older children who require ventilatory support only during sleep.

▪NPPV can be provided via bilevel positive airway pressure (BiPAP). NPPV can be provided with a variety of equipment and ventilator modes. Two common modes are BiPAP and average volume-assured pressure support ventilation, administered via nasal or full-face mask.

▪Patients with CCHS do not increase their respiratory rate with hypercapnia or hypoxemia; hence, an appropriate rate provided by spontaneous/timed or timed mode is necessary. Midface hypoplasia and dental malocclusion have been reported.

—Diaphragm pacing

▪Uses the patient’s own diaphragm as the ventilator pump

~Permits tracheostomy decannulation for those who are ventilator dependent only during sleep

~Permits freedom from the ventilator during the day in patients who are dependent on a ventilator full time; details of diaphragm pacing via phrenic nerve stimulation are discussed in Chapter 117.

•Patients with CCHS are biologically incapable of developing respiratory distress and are notorious for fooling families and health care providers because they always “look fine.” The only way to know if a patient with CCHS is being ventilated adequately is to monitor both pulse oximetry and partial pressure of carbon dioxide (PCO₂) by using capnography. Alarms are usually set at 85% for SpO₂ and 55 mm Hg for end-tidal CO₂ pressure. This minimizes nuisance alarms but still allows the caregiver to respond to emergencies.

Follow-up and Treatment of Associated Conditions

•Patients with CCHS should undergo yearly echocardiography to assess the presence of pulmonary hypertension or cor pulmonale.

•In patients with CCHS, pulmonary hypertension and cor pulmonale are likely caused by inadequate ventilation. Thus, patients with CCHS require yearly PSG (sleep study) to assess oxygenation and ventilation during sleep and adjust ventilator settings as necessary. Thus, pulse oximetry and PCO₂ monitoring (end tidal or transcutaneous) are necessary elements of PSG.

•Patients with CCHS should undergo a comprehensive eye examination to determine the nature of ophthalmologic involvement and allow for early intervention to avoid developing problems with learning.

•Patients with CCHS should undergo yearly monitoring to assess the presence of life-threatening cardiac sinus pauses—preferably at least 72 hours of recording time via Holter monitor or other portable electro-cardiographic device. More prolonged cardiac monitoring is becoming increasingly available, including 2-week monitoring systems and even subcutaneous cardiac monitoring that functions for years.

^a Children <3 years of age should undergo comprehensive evaluations every 6 months.

^b Annual chest and abdominal imaging should be performed to identify ganglioneuromas and ganglioneuroblastomas.

^c Abdominal imaging and urine catecholamine testing should be performed every 3 months in the first 2 years, then every 6 months until 7 years of age, to identify neuroblastomas.