Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in children

INTRODUCTION — Hypoventilation (ventilatory insufficiency) can result from disorders of the brain, spinal cord, nerves, muscles, heart, lungs, or airway. Sleep-related hypoventilation is a clinical pattern in which the ventilatory insufficiency occurs primarily during sleep. Affected individuals are at risk for hypoxemia and bradycardia because of the hypoventilation, and require continuous monitoring during sleep to monitor for these problems.

There are six subtypes of hypoventilation disorders recognized by the International Classification of Sleep Disorders: obesity hypoventilation syndrome (OHS), congenital central alveolar hypoventilation syndrome (CCHS), late-onset central hypoventilation with hypothalamic dysfunction, idiopathic central alveolar hypoventilation, sleep-related hypoventilation due to a medication or substance, and sleep-related hypoventilation due to a medical disorder [1].

In children, the most common cause of hypoventilation during sleep is obstructive sleep apnea (OSA), which is discussed in separate topic reviews. (See "Evaluation of suspected obstructive sleep apnea in children" and "Management of obstructive sleep apnea in children".)

Nonobstructive sleep-related hypoventilation is much less common, and is usually due to one of several rare genetic or neurologic disorders of ventilatory control, especially CCHS, late-onset central hypoventilation syndrome (LO-CHS), or rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome. These disorders will be discussed in this topic review.

DEFINITIONS

●Hypoventilation refers to a mismatch between elimination of carbon dioxide (CO₂) by the ventilatory apparatus and metabolic production of CO₂. Conventionally, hypoventilation is defined as arterial blood gas partial pressure of CO₂ (pCO₂) above the normal levels of 35 to 45 mmHg in an awake patient. Hypoventilation is often, but not always, accompanied by hypoxemia. Clinicians may suspect hypoventilation on the basis of capillary or venous blood gas with unexplained elevations of CO₂ (>50 mmHg) and bicarbonate (>25 mEq/L), or pulse oximetry with a baseline oxygen saturation <96 percent at rest.

●Sleep-related hypoventilation refers to hypoventilation that worsens or exclusively occurs during sleep. Because the hypoventilation tends to occur during daytime naps as well as during nocturnal sleep, the term "sleep-related hypoventilation" is preferred over "nocturnal hypoventilation." During sleep, withdrawal of the wakefulness drive to breathe allows a rise in pCO₂ in the arterial blood (PaCO₂) to as high as 50 mmHg in healthy individuals.

During polysomnography in children, sleep-related hypoventilation is defined as arterial, end-tidal (P_ETCO₂), or transcutaneous CO₂ (P_TCCO₂) levels >50 mmHg for more than 25 percent of total sleep time [2]. P_ETCO₂ or P_TCCO₂ values are preferred, as these techniques are continuous, noninvasive, and do not awaken the child from sleep. However, these results should be interpreted with caution. In particular, P_ETCO₂ tends to provide falsely low values for patients with rapid, shallow breathing, those with nasal obstruction, and patients who are receiving supplemental oxygen.

●Central apneas are periods of absent airflow due to lack of respiratory effort. Healthy infants and children often have short central apneas lasting less than 20 seconds and without important dips in oxygen saturation or arousal from sleep, and these are not considered clinically significant. Prolonged central apneas that occur during sleep suggest impaired autonomic control of ventilation; they are a hallmark of sleep-related hypoventilation disorders and other causes of central nervous system (CNS) dysfunction.

CONGENITAL CENTRAL HYPOVENTILATION SYNDROME — Congenital central hypoventilation syndrome (CCHS; MIM #209880) is a rare genetic disorder characterized by sleep-related hypoventilation, autonomic nervous system dysfunction, and increased risk for Hirschsprung disease and tumors of neural crest origin (neuroblastoma, ganglioneuroma, or ganglioneuroblastoma) (table 1). It typically presents in the newborn period, but occasionally presents in older individuals.

CCHS presenting in a newborn infant was first described in 1970 [3]. Evaluation showed no evidence of heart, lung, or neurologic disease although there was a history of polyhydramnios. At that time, there were approximately 20 case reports of an idiopathic central hypoventilation syndrome (CHS) in adults. Since then, more than 1000 to 1200 cases of CCHS have been reported worldwide, according to the National Organization of Rare Disorders (NORD) [4,5].

Genetics

Genotypes — CCHS is most commonly caused by a genetic defect in PHOX2B (paired-like homeobox 2B gene), located on chromosome 4p12 [6,7]. Approximately 90 percent of reported cases are caused by a heterozygous 5 to 13 amino acid expansion of a 20 polyalanine tract in exon three (figure 1). These mutations are known as polyalanine repeat mutations (PARMs). The disorder can be categorized by the genotype:

●PARMs – In at least 80 percent of cases, the expansions involve 25 to 27 alanine repeats; these genotypes are abbreviated 20/25, 20/26, or 20/27. An additional 5 percent of cases are longer PARMs of 28 to 33 repeats [8]. The shorter PARMs (eg, 20/24 and 20/25) are thought to be underdiagnosed because the clinical abnormalities tend to be subtle or variably expressed.

●NPARMs – Approximately 10 percent of cases are caused by non-polyalanine repeat mutations (NPARM) mutations of PHOX2B; these are usually frameshift mutations in exon 3.

The ventilatory defect is more severe in patients with longer PARMs and NPARMs (table 2). Patients with NPARMs typically have a severe ventilatory defect, requiring artificial ventilatory support during both wakefulness and sleep. Patients with NPARMs are also more likely to have neural crest tumors and Hirschsprung disease (table 2).

Mutations in other genes have been identified in patients with CCHS, though rarer than PHOX2B: PHOX2A (11q13.4), GDNF (5p13.2), RET (10q11.21), ASCL1 (12q23.2), EDN3 (20q13.32), BDNF (11p14.1), and BMP2 (20q12.3) [9-11].

Inheritance — All of the known gene mutations have autosomal dominant inheritance. Over 90 percent of PHOX2B mutations are de novo mutations [4].

Importantly, screening of asymptomatic first-degree relatives including parents and siblings should be undertaken in all cases of CCHS [12]. Prenatal testing and genetic counseling should be offered to affected families for subsequent pregnancies.

PHOX2B is located at 4p12. PHOX2B PARM mutations are thought to usually occur by unequal sister chromatid exchange during paternal spermatogenesis (figure 1) [13,14]. A few occurrences of mother to child transmission have been documented. Familial occurrences primarily derive from two other mechanisms. Parental somatic mosaicism for a PHOX2B mutation explains cases in which an asymptomatic parent has a minority of cells expressing the mutant allele, but the child is affected. Autosomal dominant inheritance with reduced penetrance explains cases in which a parent is asymptomatic or mildly affected and a child is mildly affected. The latter cases usually result from 20/24 or 20/25 PARMs and may present as CCHS or late-onset CHS (LO-CHS). A few cases of presumed parental germline mosaicism have been reported [15].

Molecular mechanisms — PHOX2B is a homeobox gene that encodes a transcription factor for central and peripheral nervous system development, and is developmentally and spatially expressed and regulated. The known functions of PHOX2B explain the clinical features and comorbidities of CCHS:

●Hypoventilation – In rats, the retrotrapezoid nucleus (RTN) in the ventrolateral medulla is now considered a key site for central chemoreception transmission of a CO₂ /H⁺ dependent signal to the central controller of breathing [16]. Increased levels of CO₂ /H⁺ cause PHOX2B containing RTN neurons to secrete the excitatory neurotransmitter glutamate with axons projecting to the pre-Boetzinger complex, the central controller of breathing. The molecule in the retrotrapezoid nucleus that senses CO₂ /H⁺ is GPR4 (G-protein coupled receptor 4) [17]. In mice that have a PHOX2B 20/27 defect, the RTN is absent and the animals have a phenotype similar to infants with CCHS: neonatal hypoventilation, apnea, and absent to diminished ventilatory response to CO₂. PHOX2B is also expressed in other central nervous system (CNS) sites involved with control of breathing, as well as in the carotid body, the peripheral chemoreceptor.

●Hirschsprung disease and neural crest tumors – The PHOX2B gene is expressed in both CNS and peripheral nervous system sites other than the RTN. The gene was originally identified in neuroblastoma cells, hence the alternative name, NBPhox (neuroblastoma paired-type homeobox gene). Embryologically, the PHOX2B gene is expressed in neural crest cells that give rise to the autonomic and enteric nervous systems. Hirschsprung disease, associated with CCHS in approximately 20 percent of cases, represents the failure of neural crest cells to innervate the distal intestine [18]. The transcription factor PHOX2B influences the RET proto-oncogene and endothelin 3 (EDN3) pathways and is required for development of the enteric nervous system [19].

●Other abnormalities – CCHS is also associated with abnormalities in cardiac and ophthalmic responses to stimuli. The cardiac findings are explained by the presence of PHOX2B in the precursors of autonomic ganglia innervating the heart. The ophthalmic findings are explained by PHOX2B expression in cranial nerve nuclei, including the trochlear (IV) and oculomotor (III) nuclei, and in the sympathetic and parasympathetic nervous systems derived from neural crest precursors.

Clinical features — The hallmark of CCHS is abnormal control of ventilatory function, with associated abnormalities of autonomic function and risk for Hirschsprung disease and neural crest tumors (table 1). The presentation and clinical phenotype are closely associated with PHOX2B genotype.

Presentation — Most patients with CCHS are born full term without abnormalities during pregnancy, labor, or delivery. Affected infants typically present in the neonatal period with cyanosis occurring primarily during sleep, indicating hypoventilation and hypoxemia, which can be confirmed by a blood gas measurement of partial pressure of carbon dioxide (pCO₂) and by pulse oximetry, respectively. Breathing during sleep is shallow, at or below anatomic dead space (approximately 2 cc/kg).

Despite hypoxemia and hypercapnia, the infant appears in no distress and does not seem to be trying to compensate for the severe blood gas abnormalities. There may or may not be associated Hirschsprung disease, neurologic abnormalities, or other organ dysfunction at the time of presentation. In some patients, the disorder will be recognized in the delivery room or in the neonatal nursery, but in others the diagnosis is delayed.

Most neonates with CCHS require intubation and mechanical ventilation. Because they have no intrinsic lung, chest wall, or airway abnormality they require minimal ventilator rates and pressures and little or no supplemental oxygen. If the infant is not artificially ventilated, blood gases show a respiratory acidosis, often compensated with a metabolic alkalosis, ie, elevations of PCO₂ and bicarbonate. Continuous monitoring with end-tidal (P_ETCO₂) or transcutaneous CO₂ (P_TCCO₂) demonstrates a marked worsening of hypoventilation during sleep.

Some individuals with CCHS present after the newborn period, with episodes of cyanosis, unexplained seizures, or unusual degrees of respiratory depression after anesthesia or in response to sedatives or anticonvulsant drugs. (See 'Late-onset central hypoventilation syndrome' below.)

Abnormal ventilatory and arousal responses — The hallmark of CCHS is diminished ventilation (table 1). This is usually present during wakefulness but is worse during sleep, particularly in non-rapid eye movement (NREM, also known as stage N or quiet) sleep, when breathing is under chemical rather than behavioral control. Both ventilatory and arousal responses to CO₂ and oxygen are abnormal in children with CCHS. A healthy child without CCHS will maintain normal levels of pCO₂ as the child transitions from wake to NREM sleep. In a child with CCHS, the polysomnogram demonstrates decreased depth of breathing, decreased rate of breathing, or both during sleep (particularly NREM sleep) without an arousal response, resulting in dramatic increases in PCO₂ and severity of hypoxemia (waveform 1) [20].

During wakefulness, the child with CCHS has an absent to diminished response to hypoxia and hypercapnia and has no subjective sensation of dyspnea or discomfort [21,22]. Similarly, a study in awake CCHS patients with PARMs of 20/25 to 20/27 showed diminished, but not absent, ventilatory, heart rate, and cerebrovascular responses to hyperoxic hypercapnia and other challenges [23].

Autonomic abnormalities — A wide variety of autonomic nervous system abnormalities have been documented in CCHS patients (table 1) [7,24]. CCHS patients have abnormalities in cardiovascular physiology, including blood pressure control and orthostatic hypotension, and in cardiac electrophysiology, including diminished heart rate variability, attenuated increase in heart rate to exercise, and sometimes prolonged QT_C intervals, prolonged sinus pauses, and heart block. Patients with genotypes 20/26 and 20/27 are more likely to have long sinus pauses than patients with genotype 20/25.

Some sudden unexpected deaths in CCHS patients may be due to cardiac asystole, and cardiac pacemakers have been recommended for patients with significant sinus pauses on Holter monitoring [25]. One study suggested that some symptomatic patients (most commonly presenting with symptoms of syncope) without significant sinus pauses on Holter monitoring may also require cardiac pacemakers [26].

Ophthalmic abnormalities — Ophthalmic abnormalities are common in children with CCHS. In one study, ocular abnormalities were noted in 27 of 37 children with CCHS; the defects included meiosis, strabismus, and convergence insufficiency [27]. Pupillometry has detected abnormalities in the sympathetic (meiosis) and parasympathetic (constriction after a light stimulus) control of pupil diameter, and these abnormalities were proportional to PARM length [28].

Cognitive abnormalities — Several studies have reported cognitive deficits in children with CCHS, including learning disabilities, limitations in perceptual skills, vocabulary and abstract reasoning, and mean scores more than 1 standard deviation (SD) below the population on Wechsler intelligence scales [29].

The range of neurocognitive functioning in patients with CCHS is quite wide. Children with CCHS are usually able to participate in age-appropriate classes, but often require special educational support services. A study of 31 preschool-aged children with CCHS reported modest deficits in mental development (mean scores 83.5 ± 24.75) and motor development (mean scores 73.33 ± 20.48), compared with the normative mean score of 100 [30]. The neurocognitive deficits were associated with more severe clinical manifestations of CCHS: severe cyanotic breath-holding spells, the need for 24 hours per day artificial ventilation, seizures and prolonged sinus pauses requiring a cardiac pacemaker. Children with the shortest PHOX2B PARM genotype (20/25) had no significant cognitive deficits. Of note, scores in the mid-average range were found in one-third of these preschool-aged children, suggesting the potential for good cognitive outcomes.

It remains uncertain to what extent cognitive deficits are determined by the type of PHOX2B mutation, versus intercurrent events such as hypoxia, comorbid disorders, complications, and lack of access to normal childhood activities and environment. Despite the uncertain mechanisms, knowledge that these children are at risk mandates vigilant developmental screening and prompt referral for remedial services.

Neural crest derived tumors — CCHS is associated with tumors of neural crest origin (primarily neuroblastomas). The risk is strongly associated with PHOX2B genotype: these tumors develop in approximately 50 percent of patients with NPARM genotype, but only 1 percent of those with PARMs. When they do occur in the setting of PARMs, they are almost always with long 20/29 or 20/33 genotypes and tend to be ganglioneuromas and ganglioneuroblastomas (table 2) [4].

Hirschsprung disease — All patients with CCHS and constipation should be evaluated for Hirschsprung disease. Hirschsprung disease is present in approximately 17 to 32 percent of individuals with CCHS, and the co-occurrence of the disorders is known as Haddad syndrome [18].

The prevalence of Hirschsprung disease is highest in those with NPARM genotypes. A 2010 review that included 559 patients with CCHS identified Hirschsprung disease in 80 percent of patients with NPARM genotypes and 19 percent of patients with PARM genotypes [4]. In a subsequent single-center series of 72 patients with CCHS, the overall prevalence was 32 percent (23 of 72 cases) [31]. PARM genotypes with 27 or longer alanine repeats accounted for 20 of 23 cases; one 20/25 PARM case and two NPARM cases had Hirschsprung disease. Of 25 patients with a 20/27 PARM mutation, 56 percent had Hirschsprung disease. Thus, clinicians should have a high index of suspicion for Hirschsprung disease in CCHS patients with either PARM or NPARM genotypes. (See "Congenital aganglionic megacolon (Hirschsprung disease)".)

Children with and without Hirschsprung disease have a high prevalence of other gastrointestinal disorders that may require evaluation and treatment as well. These include gastroesophageal reflux disease (GERD), functional constipation, achalasia, esophageal dysmotility with dysphagia, and colonic myopathy [4,31,32].  

Diagnosis — CCHS is suspected based upon the clinical presentation of a patient with ventilatory dysfunction, especially during sleep, without evidence of primary respiratory, cardiac, or neurologic disorders. The diagnosis is supported by typical findings on polysomnography, including elevations of pCO₂, hypoxemia, and shallow breathing, particularly during NREM sleep. The diagnosis is confirmed by CCHS gene panel testing, including PHOX2B mutations.

Clinical evaluation — Hypoventilation in an infant typically presents with cyanosis, and is confirmed by pulse oximetry demonstrating hypoxemia and blood gas measurements demonstrating severe respiratory acidosis, with CO₂ values typically above 60 mmHg during sleep.

In infants presenting with hypoventilation, the first step is to do a basic evaluation for primary respiratory, cardiac, or neurologic disorders that can cause hypoventilation. The main considerations are listed in the table (table 3). The evaluation should include a focused history, physical examination, and plain chest radiograph.

Most infants suspected of having CCHS will be admitted to a neonatal intensive care unit (NICU) where close observation, monitoring, and routine blood and radiographic testing will suggest the diagnosis. In particular, increased work of breathing suggests a primary lung, heart, or obstructive airway problem rather than CCHS. Most neurologic disorders have associated findings such as hypotonia, weakness, abnormal reflexes, convulsions, or diminished level of consciousness. Genetic, systemic, and infectious disorders also usually have other manifestations and/or increased work of breathing that are not characteristic of CCHS.

If the basic evaluation outlined above is consistent with CCHS, we suggest sending blood for a PHOX2B molecular testing, as outlined below (see 'Molecular diagnosis' below). In addition, we perform the following evaluations, either before the molecular testing or while awaiting results:

●Polysomnography – Polysomnography is the most accurate and comprehensive method to assess sleep and breathing in a child with CCHS (waveform 1). Polysomnographic evaluations should be performed as part of the initial evaluation to document breathing during sleep and wakefulness, and should be repeated periodically thereafter. Particular attention should be directed to sleep state because ventilation and gas exchange will often be considerably worse in NREM sleep compared with REM sleep in patients with CCHS. Continuous recording of oxygen saturation and P_TCCO₂ and P_ETCO₂, respiratory efforts, and respiratory airflow are essential. For pediatric patients, hypoventilation is defined as P_ETCO₂ or P_TCCO₂ is >50 mmHg for more than 25 percent of total sleep time [2]. (See 'Definitions' above.)

●Brain imaging – Neuroimaging, ideally with magnetic resonance imaging (MRI), is performed to exclude brainstem malformations that might impair ventilatory control, including Chiari malformations. Patients with CCHS do not have gross lesions of the brainstem, but may have nonspecific findings on MRI including reduced gray matter volume of the caudate nuclei and elsewhere [33-37]. The authors speculate the findings could be due to hypoxic or ischemic events or to consequences of the PHOX2B mutation.

●Cardiac evaluation – The cardiac evaluation should include an echocardiogram to detect structural and functional cardiac abnormalities, and an electrocardiogram. The electrocardiogram should also be recorded during polysomnography. If CCHS is ultimately diagnosed, a more comprehensive evaluation of cardiac rhythm may be warranted. (See 'Autonomic abnormalities' above.)

●Neuromuscular evaluation – A comprehensive neurologic examination should be performed, with electroencephalography, electromyography, and nerve conduction studies if indicated to exclude neuromuscular disease including spinal muscle atrophy. Ultrasound, fluoroscopy and/or phrenic nerve conduction testing can be used to diagnose phrenic nerve injury. CCHS patients typically have normal electromyograms and nerve conduction studies, have appropriate diaphragmatic movement during inspiration when awake, and can generate normal peak inspiratory and expiratory pressures when stimulated.

●Screen for inborn errors of metabolism – Initial evaluation includes plasma glucose, electrolytes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Infants with hypoglycemia, elevated ALT and AST, or persistent acidosis despite adequate ventilatory support warrant a more detailed evaluation for inborn errors of metabolism. Urine organic acids, plasma amino acids, and serum ammonia are usually included in the initial metabolic evaluation. (See "Inborn errors of metabolism: Identifying the specific disorder".)

●Observe for Hirschsprung disease and other gastrointestinal disorders – Newborns with suspected CCHS should be closely observed for symptoms of Hirschsprung disease. These include delayed passage of meconium (failure to pass meconium within the first 48 hours of life), constipation, abdominal distension, tight anal sphincter, or symptoms of enterocolitis (fever, vomiting, abdominal distension, and explosive diarrhea). Infants with any of these symptoms warrant an urgent full evaluation, usually consisting of a contrast enema and rectal suction biopsy.

An evaluation for Hirschsprung disease is also warranted for infants with confirmed CCHS with PHOX2B genotypes NPARM or PARM 20/26 or longer, regardless of symptoms [4], and any older children with constipation [31]. (See "Congenital aganglionic megacolon (Hirschsprung disease)".)

Symptoms and signs of other gastrointestinal disorders should also be closely monitored, including GERD, constipation, achalasia, esophageal dysmotility, and colonic myopathy [4,31,32].

When evaluating a complex and challenging infant with unexplained respiratory failure, early involvement of pediatric specialists is essential. Such specialties will usually include pediatric sleep clinicians, pulmonologists, geneticists, neurologists, neuroradiologists, and others as clinically indicated.

Molecular diagnosis — CCHS gene panel testing, including the most common gene PHOX2B, should be undertaken to confirm CCHS if the above studies do not suggest an alternative diagnosis [10].

A two-stage evaluation has been suggested. The PHOX2B screening test consists of polyacrylamide gel electrophoresis of polymerase chain reaction (PCR)-amplified polyalanine repeat section of exon 3. This will identify 95 percent of CCHS cases, all PARMs, and some NPARMs [4,8,38]. Additionally, this test can detect somatic mosaicism (parental). For patients with negative results of the screening test but a high clinical suspicion for CCHS, sequencing of the entire coding regions of the PHOX2B gene should be performed; this test will detect 99 percent of mutations in probands. A list of laboratories that provide screening for CCHS is available at the Genetic Testing Registry website.

LO-CHS cases present in infancy, childhood, or adult life. These patients may be recognized when they cannot be extubated after a surgical procedure or medical illness, or may present with unexplained pulmonary hypertension. LO-CHS PHOX2B testing will usually reveal a 20/24 or 20/25 PARM. (See 'Late-onset central hypoventilation syndrome' below.)

Management — Treatment of CCHS requires prompt recognition, comprehensive evaluation, and multiple resources to monitor the patient and to support a patient who requires a complex medical home. The American Thoracic Society (ATS) has produced an excellent review with comprehensive recommendations for evaluation and management [4].

Ventilatory support — Infants presenting with CCHS require careful monitoring during wakefulness and sleep, including measures of oxygenation (pulse oximetry) and ventilation (eg, P_ETCO₂). Most will require endotracheal intubation and mechanical ventilation during the initial diagnostic process. Administration of supplemental oxygen without mechanical ventilation is not sufficient; although this strategy improves the oxygenation and relieves the cyanosis, it does not relieve the hypercarbia and associated risks for pulmonary hypertension.

In most cases, tracheostomy with positive pressure ventilation is considered the safest way to manage the infants in the hospital and at home. Ventilation and oxygenation must be monitored and assured to be adequate during wakefulness as well as sleep. In late infancy and early childhood, ventilation often becomes somewhat more stable and other options for lifetime support become feasible. In patients with a more severe ventilatory defect (typically found in patients with longer PARM and most NPARM mutations), assisted ventilation is needed during both wakefulness and sleep. In such patients, ventilation with tracheostomy during sleep and diaphragmatic pacing during wakefulness can improve quality of life and mobility [39,40] (see "Pacing the diaphragm: Patient selection, evaluation, implantation, and complications"). In milder cases, gas exchange during wakefulness can be adequate so that positive pressure assisted ventilation is required only during sleep. If ventilation is only required during sleep, noninvasive positive pressure ventilation with a mask is an option and is preferred by many families [41].

Monitoring and home care — Continuous pulse oximetry should be used for in-hospital and at-home monitoring of CCHS patients. At all times, a caregiver capable of evaluating and responding to such life-threatening events as ventilator disconnection, tracheostomy decannulation, or airway blockage must be immediately available in case of alarm. Adequacy of ventilation should be assessed intermittently with a P_ETCO₂ monitor, particularly if supplemental oxygen is being used; supplemental oxygen may obscure clinically significant hypoventilation. Downloads of data from the oximeter can provide assurance of adequate ventilatory support over longer periods.

Individuals with CCHS are at risk for episodes of hypoxemia that may be life-threatening [4,32]. Triggers include:

●Breath-holding spells – These tend to occur in young children, triggered by fear or anger, and sometimes require resuscitation by caregivers.

●Swimming – Swimming should be avoided or undertaken only with close supervision. Underwater swimming is particularly dangerous. Breath-holding may lead to drowning because the ability to sense asphyxia is impaired.

●Alcohol and drugs – CNS depressants, including alcohol, recreational drugs, and prescribed or non-prescribed sedatives may cause respiratory depression and should be avoided. General anesthesia should be undertaken with caution because individuals with CCHS may have delayed recovery of adequate spontaneous ventilation and increased risk for respiratory infection after anesthesia.

Surveillance — Mortality in the 2005 French CCHS Registry report was 38 percent from a variety of causes, including ethical decisions not to fully support severely affected infants [42]. That said, with appropriate ventilatory support, careful surveillance, and multidisciplinary care most infants will survive [4]. Surveillance practices suggested by the ATS include (table 4) [4]:

●Polysomnography – To assess ventilation during sleep and to permit ventilator adjustments. Adequacy of breathing during wakefulness should also be documented. Guidelines recommend performing this testing every six months for the first three years of life, then at least annually thereafter.

●Echocardiogram – To assess for cor pulmonale (recommended every six months for the first three years of life, then annually thereafter).

●Seventy-two-hour continuous electrocardiography (Holter monitoring) – To monitor for prolonged asystoles and associated risk for sudden death. Cardiac pacemakers have been recommended for patients with sinus pauses longer than three seconds on Holter monitoring [25]. Surveillance is recommended every six months for the first three years of life, then annually thereafter. Surveillance is recommended for all genotypes, although there is some evidence that patients with longer PARMs are at increased risk [4,25]. (See 'Autonomic abnormalities' above.)

●Complete blood count (CBC) and blood gas – To assess for polycythemia and a compensated respiratory acidosis, which could develop if the ventilatory support is inadequate (every six months for the first three years of life, then annually thereafter).

●Surveillance for neural crest tumors (see 'Neural crest derived tumors' above):

•For patients with PHOX2B NPARMs, close surveillance for neuroblastoma is recommended, consisting of chest and abdominal imaging and urine catecholamines (every three months until age two years, then every six months until age seven years).

•For patients with longer PARMs (20/28 and longer), surveillance for ganglioneuromas and ganglioneuroblastomas is recommended, consisting of annual chest and abdominal imaging.

•For patients with short PARMs (24 through 27 repeats), surveillance for neural crest tumors is not required.

●Neurocognitive testing – Neurodevelopmental screening is recommended, to monitor for progressive dysfunction (which might be caused by insufficient ventilation, recurrent hypoxemia, or by the underlying disorder), and to optimize support services. Surveillance is recommended every six months for the first three years of life, then annually thereafter. If abnormalities are detected, the patient should be referred for more detailed evaluation and specialist care as appropriate. (See 'Cognitive abnormalities' above.)

●Gastroenterology consultation – In patients with constipation, evaluation for possible Hirschsprung disease and other gastrointestinal dysmotility disorders should be performed.

●Ophthalmologic testing – A comprehensive ophthalmologic evaluation is recommended.

Burden of illness, quality of life, and long-term outcome — Caring for a child with CCHS requires a dedicated supportive homecare environment. Even a stable, financially secure two-parent family will require in-home nursing support.

Surveys of families with a child affected by CCHS report significant medical, financial, and psychosocial burdens. In a 2004 survey of nearly 200 children with CCHS, 61 percent of the children had a tracheostomy at the time of the survey [41]. A variety of approaches to respiratory support were used, reflecting a trend towards earlier and more widespread use of noninvasive ventilation. Parents reported that their lifestyle was strongly affected by the care of these medically complex children.

By contrast, a group of CCHS patients surveyed during late adolescence reported only moderate concerns about their health-related quality of life, primarily in the domains of physical functioning, general health, and anxiety [43]. The authors interpreted the findings as providing hope to parents with a child diagnosed with CCHS and to the patients themselves. Ethical considerations for life-long provision of care in children with CCHS have been thoughtfully addressed [44,45].

OTHER HYPOVENTILATION SYNDROMES

Late-onset central hypoventilation syndrome — Although most pediatric cases of central hypoventilation syndrome present at birth or in the neonatal period, others present later, in infancy, childhood, adolescence, or adulthood. Like CCHS, these late-presenting cases are caused by PHOX2B (paired-like homeobox 2B gene) mutations. Presenting characteristics may include [32]:

●Unexplained apnea, cyanosis, clinically significant and/or recurrent brief resolved unexplained events (BRUE) or life-threatening events (see "Acute events in infancy including brief resolved unexplained event (BRUE)")

●Unexplained seizures during sleep

●Respiratory depression or difficulty weaning from a ventilator after anesthesia or after an intercurrent infection

●Lack of ventilatory response (apparent distress) during exposure to hypercarbia or hypoxemia (prolonged underwater swimming, breath-holding, pneumonia)

●Unresolved central sleep apnea (CSA) after treatment for obstructive sleep apnea (OSA)

●Unexplained cognitive delay with a history of cyanosis

●Unexplained cor pulmonale

Patients with these features should undergo polysomnography and testing for PHOX2B mutations. Late-onset central hypoventilation syndrome (LO-CHS) cases most often have a PHOX2B PARM 20/24 or 20/25 genotype and a milder phenotype than do patients who present in the neonatal period [4,46,47]. Despite the milder phenotype, patients should undergo a thorough evaluation for ventilatory function, and for abnormalities of cardiac rhythm and function (see 'Surveillance' above).

Noninvasive positive pressure ventilation is the preferred method of supporting breathing for such patients that have adequate breathing during wakefulness but hypoventilation and hypoxemia during sleep.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) — This rare syndrome is characterized by Rapid-onset Obesity, Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). Because patients are also at risk for developing neuroendocrine tumors, some authors have suggested the expanded acronym ROHHAD(NET) [48,49].

ROHHAD and/or ROHHAD(NET) are rare, complex, multisystem disorders that have important consequences for patients and families. The syndrome appears to be autoimmune and paraneoplastic in at least a subset of patients, based on the identification of novel zinc finger and SCAN domain-containing protein 1 (ZSCAN1) autoantibodies in cerebrospinal fluid and/or serum in seven out of nine patients with ROHHAD in one series [50]. In addition to autoantibody detection in patient samples using radioactive ligand binding and cell-based assays, ZSCAN1 expression was demonstrated in both neuroblastic tumor samples of affected patients and in the human hypothalamic tissue lysates from healthy human brain [50].

ROHHAD(NET) syndrome usually presents in early childhood with the following sequence of symptoms (table 5) [49,51-54]:

●Rapid and dramatic gain in weight but not height (mean 3.1 years)

●Endocrinologic disorders, including hypothalamic dysfunction (4.0 years), and autonomic dysregulation (4.9 years)

●Lastly, central hypoventilation (5.3 years, or about 2 years after the initial rapid-onset obesity)

The first few years of life may be quite normal. The excessive weight gain is usually the first feature, and is often very rapid (eg, 20- to 40-pound gain over six months) and associated with hyperphagia. This is followed by a variety of associated abnormalities in the hypothalamic-pituitary function axis (including Cushing-like features, growth hormone deficiency, precocious puberty, hyperprolactinemia, central hypothyroidism, and/or hypernatremia with or without diabetes insipidus). Autonomic dysregulation includes temperature dysregulation (episodes of hyperthermia or hypothermia), eye abnormalities (eg, altered pupil response to light, strabismus), intestinal dysmotility (leading to chronic constipation; diarrhea), decreased pain sensation, and/or bradycardia.

Affected children may have behavioral issues, which may be severe, developmental delay, and/or seizures (perhaps triggered by hypoxemia or electrolyte imbalance). A high mortality rate is reported [4].

Tumors of neural crest origin (ganglioneuromas and ganglioneuroblastomas) are eventually diagnosed in approximately 50 percent of cases, with most (70 percent) diagnosed within two years of initial rapid weight gain [4,48,49]. Suggested evaluation for these tumors includes initial computerized tomography (CT) or magnetic resonance imaging (MRI) of the chest and abdomen. If these are negative, annual screening with chest radiography, adrenal ultrasonography, and urine catecholamines has been suggested [55]. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)

The breathing disorder may include OSA and mechanical effects of obesity (decreased in functional residual capacity and restrictive lung disease) [56]. The central hypoventilation may become more apparent after the obstructive component is treated. The central hypoventilation also may increase over time. As for other disorders of ventilatory control, children with ROHHAD(NET) fail to have symptoms in response to hypoxemia or hypercarbia, which might be induced by routine daily activities or acute respiratory illnesses. Therefore, it is important to perform periodic evaluations of their response to a ventilatory challenge (eg, exercise) [55]. Some children will require both daytime and nighttime home monitoring. Like patients with CCHS, children with ROHHAD(NET) have a complex, life-threatening disorder that requires multidisciplinary support, evaluation, and monitoring. A comprehensive review is available [55].

ROHHAD(NET) is distinguished from CCHS by the unique clinical characteristics and absence of mutations on CCHS gene panel testing including PHOX2B [54]. Although the pathogenesis and biology of ROHHAD(NET) is poorly understood, accumulating evidence supports an autoimmune, paraneoplastic mechanism in many patients with concurrent tumors [50,57-60]. Specifically, one study found evidence of autoantibodies to a tumor-associated protein, ZSCAN1, in seven of nine patients with ROHHAD [50]. However, a clinical test for ZSCAN1 antibodies has not yet been validated [50]. A few case reports have described some success with immunosuppressive therapy, particularly rituximab and cyclophosphamide [61-63]. Patients should be managed in a multispecialty and multidisciplinary setting, and clinicians are encouraged to collaborate with ongoing patient registries, clinical trials of immunosuppressive treatments, and investigations into the underlying biology.

Hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, eye abnormalities (HIDEA) — Hypoventilation and other sleep-related breathing disorders can be seen in children with HIDEA syndrome (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities), a rare autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the prolyl 4-hydroxylase transmembrane (P4HTM) gene on chromosome 3p21 (MIM 618493).

Although an initial description of a Finnish kindred with HIDEA did not include hypoventilation [64], subsequent reports described a range of respiratory abnormalities in affected children including bradypnea, hypoventilation, and obstructive or central sleep apnea, often requiring nocturnal noninvasive positive pressure ventilation [65-67]. Most patients have hypotonia and profound neurodevelopmental delay from infancy. Recurrent pneumonia and respiratory distress are a common cause of early death.

OTHER CAUSES OF CENTRAL SLEEP APNEA — Central sleep apnea (CSA) is much less common than obstructive sleep apnea (OSA) in children. Brief central pauses in respiratory effort (less than 20 seconds) that cause neither oxygen desaturation nor arousal from sleep are benign and are not clinically significant. In the pediatric age group, clinically significant CSA most often occurs in premature infants, or in the setting of systemic, genetic, or neurologic disorders affecting the brainstem or other central nervous system (CNS) sites involved in the control of breathing. Young infants with severe bronchiolitis may develop central apnea but respiratory distress clearly distinguishes the cause of the central apnea from central hypoventilation syndrome (CCHS). (See "Bronchiolitis in infants and children: Clinical features and diagnosis".)

In adults, CSA is often a consequence of heart failure or CNS lesions, particularly stroke and destructive brainstem lesions, but can also be idiopathic. (See "Central sleep apnea: Risk factors, clinical presentation, and diagnosis".)

Apnea in premature infants can persist until 44 weeks postmenstrual age. They are also at risk for apnea after surgery, particularly if they receive general anesthesia, and this risk continues until they are approximately 60 weeks postmenstrual age [68]. (See "Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity" and "Management of apnea of prematurity".)

In children, CSA is usually related to neurologic disease affecting central control of breathing, including brain tumors or malformations that impinge on the brainstem (eg, Chiari malformations, achondroplasia, some craniosynostosis syndromes, or osteopetrosis), as well as CNS depressant medications, epilepsy, or infections. Children with Down syndrome and Prader-Willi syndrome are at risk for both CSA and obstructive sleep apnea (OSA) [69-71]. As an example, in a study of 969 patients referred to a pediatric sleep laboratory, 52 (5.4 percent) had more than five central apneic events per hour of sleep [72]. Most of the patients with CSA had neurologic disorders, including myelomeningocele with Chiari II malformation, brainstem compression, encephalitis, tumors, and genetic syndromes. Brainstem and/or cranial nerve compression, stretching, or vascular insufficiency may cause either central or obstructive patterns. As an example, in a study of 83 children with myelomeningocele and Chiari II malformation who underwent polysomnography, 17 (20 percent) patients had moderately or severely abnormal sleep-disordered breathing [73]. The apneas were predominantly central in 12 patients, and predominantly obstructive in five patients. Similarly, in a study of 31 pediatric brain tumor survivors referred to a sleep laboratory (mostly for excessive daytime somnolence), OSA was found in 14 patients with sellar, parasellar, or hypothalamic tumors, while central apneas were found in four children with tumors of the brainstem, posterior fossa, or spine [74]. In patients with CNS disorders that predispose to brainstem compression, such as Chiari I or II malformations, achondroplasia, craniosynostosis syndromes or osteopetrosis, the presence of CSA raises the possibility of progressive brainstem impingement that might require surgical decompression. (See "Chiari malformations", section on 'Management of Chiari I'.)

Sleep-disordered breathing, including OSA and CSA, should be suspected in children with neurologic disease and witnessed apnea or cyanosis. Polysomnography is required to delineate the type and severity of sleep-disordered breathing. Conversely, a finding of unexplained CSA warrants a careful neurologic evaluation, with CNS imaging in selected patients [71,75]. (See "Overview of polysomnography in infants and children".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sleep-related breathing disorders including obstructive sleep apnea in children".)

SUMMARY AND RECOMMENDATIONS

●Definitions and causes – Hypoventilation (ventilatory insufficiency) is defined in children as sustained partial pressure of carbon dioxide (pCO₂) in arterial blood (PaCO₂) levels above 45 mmHg in the awake state, or above 50 mmHg during sleep. Sleep-related hypoventilation refers to hypoventilation that worsens or exclusively occurs during sleep. (See 'Definitions' above.)

Hypoventilation can be caused by disorders of the brain, spinal cord, nerves, muscles, lungs, or airway (table 3). In children without apparent abnormalities in these organ systems, and particularly in those with sleep-related hypoventilation or central sleep apneas (CSAs), a disorder of ventilatory control should be considered. Important causes of sleep-related hypoventilation in neonates are prematurity, an underlying brain disorder, or congenital central hypoventilation syndrome (CCHS).

●Congenital central hypoventilation syndrome (CCHS) – CCHS usually presents at birth or in the neonatal period with symptoms of hypoventilation (eg, cyanosis and shallow breathing), without apparent respiratory distress.

•CCHS is associated with a wide variety of abnormalities including neurocognitive deficits, Hirschsprung disease, neural crest derived tumors (primarily neuroblastoma), bradycardia, ophthalmologic abnormalities, and other autonomic system abnormalities (table 1). (See 'Clinical features' above.)

•CCHS is most commonly caused by mutation in the paired-like homeobox 2B gene (PHOX2B) gene, a transcription factor on chromosome 4p12 that controls neural development. (See 'Genotypes' above.)

•Diagnosis of CCHS requires exclusion of other causes of sleep-related hypoventilation and demonstration of a mutation in disease-causing gene. (See 'Diagnosis' above.)

•Treatment includes artificial ventilation during sleep and often during wakefulness. Monitoring of oxygen saturation, end-tidal CO₂ (P_ETCO₂), and extensive home care support are required, as well as regular reevaluation with polysomnography, cardiac testing, cognitive testing, and surveillance for neural crest tumors (table 4). (See 'Management' above.)

●Late-onset central hypoventilation syndrome (LO-CHS) – Like CCHS, LO-CHS is caused by PHOX2B mutations. The cases that present after the neonatal period usually have heterozygous 20/24 or 20/25 polyamine repeat mutations (PARMs). Patients with LO-CHS usually have milder phenotypes than CCHS patients presenting in the neonatal period. (See 'Late-onset central hypoventilation syndrome' above.)

●Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysfunction (ROHHAD) – ROHHAD typically presents in early childhood with rapid onset of obesity, followed by hypothalamic or pituitary endocrine disorders, nocturnal hypoventilation, and autonomic nervous system findings (table 5). Patients are also at risk for developing tumors of neural crest origin (ganglioneuromas and ganglioneuroblastomas), and as such, some authors have suggested the expanded acronym ROHHAD(NET). (See 'Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD)' above.)

●Other causes of CSA – CSA and sleep-related hypoventilation can be caused by neurologic disease affecting control of breathing in the central nervous system (CNS). Causes include brain tumors or brain malformations that impinge on the brainstem, such as Chiari malformations, and some skull malformations (craniosynostosis syndromes, achondroplasia, or osteopetrosis). Central control of breathing also may be affected by CNS depressant medications, epilepsy, or infections. (See 'Other causes of central sleep apnea' above.)