Congenital Central Hypoventilation Syndrome 

Updated: Apr 21, 2021
Author: Amy Brown, MD, MS; Chief Editor: Girish D Sharma, MD, FCCP, FAAP 

Overview

Practice Essentials

Congenital central hypoventilation syndrome (CCHS), also referred to as Ondine's curse, is a life-threatening disorder manifesting as sleep-associated alveolar hypoventilation. According to American Thoracic Society (ATS) guidelines, a mutation in the PHOX2B gene is required for the diagnosis of CCHS. Treatment is supportive and is based on an assessment of respiratory impairment, cardiac dysfunction, and gastrointestinal dysfunction, as well as surveillance for underlying oncologic manifestations.

Signs and symptoms

Sleep-dependent hypoventilation in the absence of neuromuscular, cardiac, metabolic, or pulmonary disease is the hallmark of CCHS. The severity of respiratory dysfunction may range from relatively mild hypoventilation during quiet sleep with fairly good alveolar ventilation during wakefulness to complete apnea during sleep with severe hypoventilation during wakefulness.

A characteristic facies has been described in patients with CCHS between the ages of 2 years and early adulthood that is characterized by a shorter and flatter face. Infants may be hypotonic, display thermal lability, and have occasional and sudden hypotensive events that are unexplainable based on the surrounding circumstances. Ocular findings (eg, abnormal pupils that are miotic, anisocoric, or abnormally responsive to light) can be found in 70% of cases.

See Presentation for more detail.

Diagnosis

The diagnosis of CCHS requires the exclusion of other causes of sleep-related hypoventilation and genetic studies that support a mutation in the PHOX2B gene.

Studies used in the evaluation include the following:

  • Genetic testing for a mutation in the PHOX2B gene
  • Polysomnography
  • Brain magnetic resonance imaging (MRI)
  • Chest radiography and computed tomography (CT) scanning
  • Diaphragm fluoroscopy, ultrasonography, or both
  • Echocardiography
  • Comprehensive testing for neuromuscular disorders and inborn errors of metabolism
  • Serial monitoring of complete cell blood (CBC) counts
  • Blood gas analysis

See Workup for more detail.

Management

No cure or gene therapy exists for CCHS, which is a lifelong condition. Treatment is entirely supportive. Tracheostomy may be indicated for ventilatory support, and diaphragmatic pacing should be considered for appropriate patients.

See Treatment and Medication for more detail.

Background

CCHS is also referred to as Ondine's curse. The literary misnomer Ondine's curse has been used in prior literature. In this German folk epic, the nymph Ondine falls in love with a mortal. When the mortal is unfaithful to the nymph, he is cursed by the king of the nymphs. The king's curse makes the mortal responsible for remembering to perform all bodily functions, even those that occur automatically, such as breathing. When the mortal falls asleep, he "forgets" to breathe and dies. Because it was the king, rather than Ondine, who cursed the mortal, and because patients with CCHS do not actually “forget” to breathe, the term Ondine's curse is a misnomer and should be avoided.

CCHS should be considered in children with episodic or sustained hypoventilation and hypoxemia in the first months of life without obvious metabolic, cardiopulmonary, or neuromuscular disease. Most patients breathe normally while awake but hypoventilate during sleep. In 1962, Severinghaus and Mitchell coined the term Ondine’s curse to describe a syndrome that manifested in 3 adult patients after high cervical and brainstem surgery. When awake and needing to breathe, these patients did so; however, they required mechanical ventilation for severe central apnea when asleep. In 1970, Mellins and colleagues first reported an infant with the clinical features of CCHS.

Although the cases described by Severinghaus and Mitchell were markedly different from the typical cases in infants with CCHS, the term Ondine’s curse gained wide acceptance to denote CCHS in infants and children, but the term has recently fallen out of favor. Children with CCHS have progressive hypercapnia and hypoxemia when asleep, along with markedly impaired responses to hypercapnia and hypoxemia. CCHS is also associated with generalized dysfunction of the autonomic nervous system, including cardiovascular and ophthalmic regulation. Hirschsprung disease is associated with 20% of CCHS cases, and when seen in combination is termed Haddad syndrome. Tumors of neural crest origin are associated with 5-10% of cases.

CCHS should be considered in a patient who presents with hypercapnia and hypoxemia when underlying cardiac, neurologic, pulmonary, and generalized disorders have been excluded. Ultimately, the diagnosis of CCHS is established in a symptomatic patient with a genetic defect in the PHOX2B (paired-like homeobox 2B gene) located on chromosome 4p12.

Pathophysiology

In 2003, the disease-causing gene for congenital central hypoventilation syndrome (CCHS) was discovered in the pairedlike homeobox gene PHOX2B, located at exon 3 on chromosome 4. According to American Thoracic Society (ATS) guidelines, a mutation in the PHOX2B gene is required for the diagnosis of CCHS. The normal PHOX2B contains a 20-alanine coding repeat region (20/20). An increased number of polyalanine repeats in this region is referred to as polyalanine repeat expansion mutation (PARM). There can also be nonpolyalanine repeat mutations (NPARMs), which consist of missense, nonsense, or frameshift mutations. Over 90% of patients with CCHS are heterozygous for a PARM in the PHOX2B gene, which can range from 24-33 alanines, the most common being 25, 26, and 27, referred to as 20/25, 20/26, 20/27, respectively. The remaining 10% have a NPARM mutation.[1]

Studies have shown a correlation that with increasing expansion of alanines, the need for continuous ventilatory support increases. In general, individuals with 25-PARM rarely require 24-hour ventilatory support, those with 26-PARM have a variable need for ventilatory support during the awake periods based on their activity levels, and those with 27-33–PARMs require 24-hour ventilatory support. Mild- and late-onset CCHS has been associated with 24-polyalanine and 25-PARMs.[2]

Individuals with NPARMs have a more severe phenotype, which may require continuous ventilatory support, and they are also at higher risk of having Hirschsprung disease and neural crest tumors. Among NPARMs, frameshift mutations are most common and the degree of shift can predict clinical presentation; two-step frameshifts are associated with classic, isolated CCHS, whereas one-step frameshifts are associated with a syndromic presentation (CCHS plus Hirschsprung disease and neural crest tumors) often termed Haddad syndrome.[3]

The PHOX2B gene codes for a transcriptional factor responsible for regulating expression of genes involved with the development of the autonomic nervous system, such as dopamine-β-hydroxylase (DBH), PHOX2A, and TLX-2.[1] Increased PARM has been shown to impair the PHOX2B protein's ability to regulate the transcription of these genes. The mutated PHOX2B protein also interferes with the activity of the normal PHOX2B on the other chromosome.[4]

Genetics

CCHS can be from autosomal dominant inheritance or a de novo mutation. Some parents of CCHS patients have been found to have a somatic mosaicism for the PHOX2B mutation.[5] In one study looking at 45 CCHS families, nearly 20% of patients inherited the mutation from somatic mosaicism.[6]  Genetic counseling is important for the parents of individuals diagnosed with CCHS, as there is a 50% chance of recurrence in future children.[7]

Certain PARMs, such as 24 and 25, have an autosomal dominant inheritance with incomplete penetrance.[1, 8] Therefore, the degree to which family members of individuals with CCHS may have evidence of respiratory control or autonomic dysfunction remains uncertain.[9] The extreme variability that can be seen in a family is demonstrated by a case series in which the initial patient is found to have CCHS with an NPARM and most other members with the same mutation are mildly affected (constipation, autonomic dysfunction, sleep apnea) and identified later in childhood or after the initial patient was diagnosed.[10]

A disturbance of cardiac autonomic regulation in CCHS may indicate the possibility of PHOX2B genotype in relation to the severity of dysregulation, predict the need for cardiac pacemaker, and offer the clinician the potential to avert sudden death.[11]

Environmental influences have been suggested to affect the presentation of siblings with CCHS. One study of monozygotic term male twins with identical 25-PARMs showed differing clinical courses, with twin B having more severe respiratory compromise at birth and twin A exhibiting a relatively benign course until beginning to require more noninvasive ventilator support at around age 5 years.[12]

Structural central nervous system abnormalities

Based on the initial premise that CCHS is associated with a centrally located defect, multiple attempts have been made over the years to identify structural CNS abnormalities. Research in rodent models, indicating the retrotrapezoid nucleus (RTN) as the main area of PHOX2B activity, has been confirmed with PHOX2B immunoreactivity in human fetuses and infants.[13]

MRI changes indicating alterations or injury have been observed in the caudate nuclei in patients with CCHS.[14] Reduced gray matter volume over time in areas regulating autonomic, mood, motor, and cognition functions have been shown in CCHS patients. These areas include the prefrontal and frontal cortex, caudate nuclei, insular cortex, and cerebellar regions.[15] The pathologic process leading to these brain injuries is unknown but is thought to be caused by hypoxic mechanisms or due to sustained perfusion issues. The MRI scan of a premature infant with PHOX2B mutation showed deep cerebral white matter destruction with lesions concentrated in the internal capsule and corpus callosum. The infant’s pattern of damage (which is usually seen in patients with some degree of birth asphyxia) suggests that these signs of restricted cerebral perfusion may be a byproduct of autonomic neural dysfunction in CCHS resulting in impaired vascular control.[16]

Physiologic abnormalities of ventilatory control

Most patients with CCHS are able to maintain adequate spontaneous ventilation during wakefulness as a result of residual peripheral chemoreceptor function in these patients.

CCHS is characterized by dysfunction in the metabolic control of breathing; therefore, more severe gas-exchange disturbances occur during non–rapid eye movement (N-REM) sleep. This is clearly in contrast with other respiratory disorders associated with sleep-disordered breathing, such as obstructive sleep apnea syndrome, in which gas-exchange abnormalities preferentially occur during REM sleep.

Ventilatory sensitivity to hypercarbia and hypoxemia in CCHS has been found to be detectable, but weaker than in controls. This is thought to be due to deficit of central chemosensors with preservation of peripheral chemosensors. Differences in the cerebrovascular responses of CCHS patients and controls during hypoxic hypercapnic challenges suggest there is a dysregulation of cerebral autoregulation in CCHS patients. They also appear to not react to hypercarbia and hypoxemia, whereas controls have labored breathing and anxiety.[17]

Findings during non-REM sleep suggest that the intrinsic defect in CCHS is always present but becomes more prominently expressed during conditions in which other redundant mechanisms are either less active or inoperative.[18]

In addition, noradrenergic dysregulation has been reported in human pathologies affecting the control of breathing, such as sudden infant death syndrome, congenital central hypoventilation syndrome, and Rett syndrome. Noradrenergic neurons are located predominantly in pontine nuclei. Severe respiratory disturbances associated with gene mutations affecting noradrenergic neurons have been reported (PHOX2 and MECP2).

Efforts are attempting to understand the biochemical basis for PHOX2B mutation. Task2 potassium channel expression in the RTN region appears to be affected by reactive oxygen species generated during hypoxia.[19]

Etiology

PHOX2B is the main disease-causing gene for primary congenital central hypoventilation syndrome (CCHS), an autosomal dominant disorder with incomplete penetrance. However, about 20 patients have been identified with CCHS with mutations in other genes, usually in genes involved in the development of neural crest cells or components of the endothelin pathway. In some cases, non-PHOX2B gene mutations were accompanied by PHOX2B mutations, suggesting a role as modifier genes.[20]

Secondary central hypoventilation syndrome may result from other conditions or occurrences (eg, brainstem tumor or other space-occupying lesions, vascular malformations, CNS infection, stroke, neurosurgical procedures to the brain stem).

Patients with CCHS who develop malignant neural crest–derived tumors have either a missense or a frameshift heterozygous mutation in the PHOX2B gene. Therefore, a subset of patients with CCHS who are at risk for developing malignant tumors may be identified.

Epidemiology

United States statistics

Congenital central hypoventilation syndrome (CCHS) was thought to be a very rare disorder with an estimated prevalence of 1 case per 200,000 live births.[21] However, the introduction of more extensive screening measures for detection of PHOX2B mutations has revealed that CCHS is not as rare as previously considered.

International statistics

Nearly 1000 children worldwide have PHOX2B mutation–confirmed congenital central hypoventilation syndrome (CCHS). However, some believe that this number is likely underestimated.[1]

Race-, sex-, and age-related demographics

No differences in the occurrence of congenital central hypoventilation syndrome (CCHS) are evident based on race.

Both sexes appear to be equally affected.

Congenital central hypoventilation syndrome (CCHS) is present at birth, although the diagnosis may be delayed because of variations in the severity of the manifestations or lack of awareness in the medical community, particularly in milder cases. Late-onset CCHS may present in the school-aged child to adult years as abnormal ventilatory response to a severe infection or after administration of an anesthetic or CNS depressant during a surgical procedure.

Prognosis

Overall, the prognosis of patients with CCHS is excellent if the diagnosis is prompt and medical management is appropriate; however, neurocognitive deficits of varying severity, stunted growth, cor pulmonale, and seizure disorders are frequent in older patients who may not have benefited from prompt recognition or intervention. Long-term prognosis is variable, but ventilator support is lifelong, as the disease does not improve with age.

Morbidity/mortality

The clinical outcome of children with congenital central hypoventilation syndrome (CCHS) has markedly changed since the description of the disorder. In the past, most patients presented with neurocognitive deficits, especially in visuoperceptual reasoning and visuographic speed, stunted growth, cor pulmonale, and/or seizure disorders. However, early diagnosis and institution of adequate ventilatory support to prevent recurrent hypoxemic episodes clearly offers the potential for improved growth and development and should be associated with normal longevity.

Mortality is primarily due to complications that stem from long-term mechanical ventilation or from the extent of bowel involvement when Hirschsprung disease is present. Nevertheless, stressing that the characteristic central hypoventilation during sleep is a life-long symptom is important.

Neural crest tumors such as neuroblastomas or ganglioblastomas have also been associated with CCHS. Therefore, the prognosis depends on adequate treatment of the underlying tumor.

Central sinus vein thrombosis has been detected in several patients, one a newborn and another in early childhood, who had CCHS.[22]  Of note, the thrombophilia screening in the former was unremarkable. At this time, no clear physiologic link between central sinus vein thrombosis and CCHS has been established, although it has been hypothesized that the thrombosis may be associated with cerebral blood flow stasis as a result of dysfunctional autonomic vasculature regulation.

Complications

The major complications of CCHS include death due to hypoxemia during sleep. Development of pulmonary hypertension or cor pulmonale due to recurrent hypoxemia, either from delayed diagnosis or inadequate ventilatory support, is one of the most severe morbidities associated with CCHS leading to early mortality.

Patients with CCHS are medically fragile and can have inherent risks of complications due to the likelihood that they go on to have surgical interventions. There can also be complications associated with procedures (eg, tracheostomy, gastrostomy tube, colostomy, pacemaker procedure) that should always be considered, as well as anesthesia complications given the abnormal respiratory drive.

About 5-10% of patients may develop neural crest–derived tumors (eg, ganglioneuroma, neuroblastoma, ganglioneuroblastoma), which require prompt treatment and are associated with increased morbitidy and mortality.

Patient Education

For patient education resources, see the Children's Health Center, http://www.cchsnetwork.org/, as well as Sudden Infant Death Syndrome (SIDS).

The CCHS family network provides community support for families and individuals affected by CCHS. There is a significiant emotional, social, and financial burden for patients with CCHS.

 

Presentation

History

Sleep-dependent hypoventilation in the absence of neuromuscular, cardiac, metabolic, or pulmonary disease is the hallmark of congenital central hypoventilation syndrome (CCHS). In severe cases, hypoventilation is also present during wakefulness. The clinical presentation of patients with CCHS may vary and depends on the severity of the hypoventilation.

Some infants do not breathe at birth and require assisted ventilation in the newborn nursery. Most infants who present in this manner do not spontaneously breathe during the first few months of life but may mature and have a pattern of adequate breathing during wakefulness over time; however, apnea or central hypoventilation persists during sleep. This apparent improvement over the first few months of life is believed to result from normal maturation of the respiratory system and does not represent a true change in the basic deficit in respiratory control.

Other infants may present at a later age, with cyanosis, edema, and signs of right-sided heart failure as the first indications of CCHS. These symptoms in infants have often been mistaken for those of cyanotic congenital heart disease; however, cardiac catheterization reveals only pulmonary hypertension. Infants with less severe CCHS may present with tachycardia, diaphoresis, and/or cyanosis during sleep.

Presumably, if the diagnosis is not made, right-sided heart failure develops as a consequence of repeated hypoxemic episodes during sleep. Still, others may present with unexplained apnea or an apparent life-threatening event or some may even die and be categorized as having sudden infant death syndrome (SIDS). Thus, the wide spectrum of severity in clinical manifestations dictates the age at which recognition of CCHS takes place.

Late-onset central hypoventilation syndrome has also been described, for which symptoms present in late childhood or adulthood.[23]  Patients may present with hypoventilation or an altered response to hypoxemia or hypercarbia after an inciting event such as respiratory infection, sedation, anesthesia, or sleep apnea.

CCHS patients also have disorders of autonomic nervous system control. They may have cardiac dysfunction in the form of arrhythmias, primary sinus bradycardia and transient asystole, decreased heart rate variability, and alterations in blood pressure. Blood pressure values are lower during wakefulness and higher during sleep, indicating attenuation of the normal sleep-related blood pressure decrement in CCHS. They may also exhibit dysfunction in thermoregulation such as profuse sweating, decreased body temperature, or inability to mount a fever during an infection. They may also have blunted pupillary light responses.

About 20% of patients with CCHS also have Hirschsprung disease, which is referred to as Haddad syndrome.[24]

Neural crest tumors, such as neuroblastoma, are seen in 5-10% of CCHS patients.

Mild intellectual or cognitive deficits are also common.[25] However, the range of functioning defects makes it likely that environmental factors may also be playing a role.[26] There did not appear to be any correlation with PHOX2B genotype and disease severity. However, a study by Charnay et al that reported on neurodevelopmental impairment in preschool patients with CCHS found that among the children with the three most common polyalanine repeat expansion mutation genotypes, the motor and mental scored varied with normal scores reported in children with the 20/25 genotype but lower scores in the other genotype groups. These lower scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 hour/day artificial ventilation, and seizures.[27]

Physical Examination

The initial physical examination of a patient with suspected CCHS, if performed while the patient is awake, may be normal. Depending on the degree of impairment, digital clubbing of the nailbeds from long-standing hypoxia or the presence of cardiac murmurs associated with cor pulmonale may be noted. The head and neck examination is generally normal. Patients who have already undergone therapeutic interventions may have a tracheostomy in place. The chest examination for these patients generally reveals normal lung fields and a normal shape to the chest wall. In patients at high risk for neuroblastoma (NPARM genotype), abdominal palpation may reveal a mass consistent with neural crest tumor.

A characteristic facies has been described in patients with congenital central hypoventilation syndrome (CCHS) between the ages of 2 years and early adulthood that is characterized by a shorter and flatter face. This characteristic box-shaped face is seen in patients with polyalanine repeat expansion mutations (PARMs).

Infants may be hypotonic, display thermal lability, and have occasional and sudden hypotensive events that are unexplainable based on the surrounding circumstances. These manifestations usually improve over time. Autonomic nervous system dysfunction may also be seen with dysrhythmias, alterations in blood pressure, and ophthalmic findings.

Ocular findings (eg, abnormal pupils that are miotic, anisocoric, or abnormally responsive to light) can be found in 70% of cases. Abnormal irides (60% of cases); strabismus (50% of cases); and, on occasion, lack of tears during crying, can also be found. Thus, referring children with CCHS for a thorough ophthalmologic evaluation is important.

The severity of respiratory dysfunction may range from relatively mild hypoventilation during quiet sleep with fairly good alveolar ventilation during wakefulness to complete apnea during sleep with severe hypoventilation during wakefulness.

Gastroesophageal reflux and decreased intestinal motility with constipation are often present in younger patients.

 

 

DDx

Diagnostic Considerations

Diagnosis of CCHS requires exclusion of other causes of sleep-related hypoventilation and genetic studies supporting a mutation in the PHOX2B gene. 

Differential Diagnoses

  • Apnea of Prematurity

  • Aspiration Syndromes

  • Assisted Ventilation of the Newborn

  • Childhood Sleep Apnea

  • Late Onset Central Hypoventilation Syndrome (LO-CHS)

    This disease is very similar to CCHS in that it is caused by the same mutation in the PHOX2B gene; however these patients have heterozygous mutations for PARM 20/24 or 20/25 and overall present with a milder phenotype than CCHS patients, usually at a much later age.

  • Obesity in Children

  • Pediatric Botulism

  • Pediatric Obesity-Hypoventilation Syndrome

  • Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysfunction (ROHHAD)

    This is a disorder of early childhood that may have an overlap with CCHS but it is distinct entity. Patients present with rapid onset of obesity, hypothalamic or pituitary endocrine disorders, sleep related hypoventilation and abnormalities of the autonomic nervous system. There is also an associated with neural crest tumors.

 

Workup

Approach Considerations

In a patient with suspected congenital central hypoventilation syndrome (CCHS), even while awaiting genetic testing results, understanding the degree of systemic impact can help with early management. Steps to further evaluate the impairment of the patient with suspected CCHS to guide management include the following: 

  • Polysomnography is used to assess sleep-related gas exchange during staged sleep (REM vs NREM). Once the degree of hypoventilation is quantified, the next steps can be made for supportive care, which most often includes tracheostomy with ventilatory support during sleep. 
  • Brain imaging can be helpful to exclude malformations that may affect ventilation. Note that a patient with CCHS may have completely normal MRI findings or may present with non-specific findings on MRI or can present with gray matter volume reduction. [15]  It is unclear whether these gray matter changes, when seen, are primary lesions or secondary lesions related to hypoxic events from the underlying disorder. 
  • Cardiac dysfunction can occur in CCHS patients, and echocardiography can be used to assess baseline structural and functional cardiac activity. A baseline electrocardiogram can also be performed during wakefulness and also as a component of polysomnography. Once the diagnosis of CCHS is confirmed it is important to note that more prolonged cardiac electrophysiologic activity with a Holter monitor is suggested. 
  • Comprehensive testing for neuromuscular disorders and inborn errors of metabolism should also be performed while awaiting confirmation of the PHOX2B gene mutations. 
  • Close gastrointestinal monitoring of infants presenting with suspected CCHS should also take place, given the increased risk of Hirschsprung disease in these patients. Once the diagnosis is confirmed, if patients have the NPARM or PARM >20/26 phenotype, an evaluation for Hirschsprung disease should take place regardless of associated symptoms. 

Because the evaluation of patients with CCHS is complicated, it is best that testing be done in a coordinated fashion with pediatric specialists. Specialists involved in the patient's care usually include pediatric pulmonologists, cardiologists, gastrointestinal specialists, geneticists, neurologists, and dedicated pediatric sleep specialists. Pediatric surgeons may be involved in patient cases owing to the likely need for interventions such as tracheostomy for ventilatory support or gastrointestinal-related procedures if there is associated Hirschsprung disease. 

Laboratory Studies

Many commercial laboratories are now performing PHOX2B screening testing via fragment analysis or sequencing tests. However, if the screening test is negative and the patient’s clinical manifestations support the diagnosis of congenital central hypoventilation syndrome (CCHS), one can contact Rush University Genetics Laboratory to perform the actual sequencing to identify the subset of nonpolyalanine repeat expansion mutation (NPARM). Because more than 90-95% of individuals with CCHS have a PHOX2B polyalanine expansion mutation (PARM) and because PHOX2B polyalanine expansion testing is a more sensitive test for detection of mosaicism, such testing should be performed first.

Multiplex ligation-dependent probe amplification was introduced by Rush University to identify those patients with alveolar hypoventilation or suspicious apparent life-threatening events who test negative for PARM and NPARM.[28] Multiplex ligation-dependent probe amplification has been used to identify specific exon or whole-gene deletions in the PHOX2B gene that have not been detected by current means of commercial screening. Four cases of either single exon or complete PHOX2B gene deletion have been reported, suggesting that a subset of patients may demonstrate a degree of alveolar hypoventilation without the full spectrum of autonomic dysregulation characteristic in CCHS.

Urine collection for amino acids and organic acids may be considered for evaluation of metabolic disorders.

A hypercoagulability workup is indicated if neural imaging shows evidence of thrombosis.

Serial monitoring of complete cell blood (CBC) counts at least annually is suggested to evaluate for polycythemia that can result in response to hypoxic conditions. Additionally, blood gas analysis to assess for both acute and chronic respiratory acidosis can be done during the initial evaluations and annually to assess for chronic carbon diocide retention. 

Imaging Studies

Imaging studies of the central nervous system (CNS) are strongly recommended to rule out causative gross anatomic brain or brainstem lesions.

The American Thoracic Society (ATS) recommends performing imaging for neural crest tumors in individuals at greatest risk based on PHOX2B mutation.[1]

Obtain chest radiography and CT scanning to evaluate for a primary pulmonary problem.

As part of the cardiac evaluation, obtain an echocardiogram.

Perform diaphragm fluoroscopy, ultrasonography, or both to rule out unilateral or bilateral diaphragmatic paralysis or paresis.

Other Tests

Polysomnography is useful in determining respiratory patterning and gas-exchange abnormalities during different sleep states. Because many infants may not be sufficiently stable to undergo polysomnographic studies while spontaneously breathing, documenting the changes in cardiorespiratory behavior and related consequences by performing brief discontinuations of mechanical ventilatory support during each sleep stage is important. It is important to periodically repeat these studies because significant developmental changes occur in sleep and respiratory patterns during the first year of life. Therefore, a repeat sleep study should be performed every 3-4 months during the first 2 years of life and every 6 months until the child is aged 5-6 years. Annual evaluation after age 6 years is usually adequate if the patient is stable.

Although hypercapnic ventilatory challenges are not specifically included in the diagnostic criteria, they are a component for the diagnosis of CCHS. Steady-state or rebreathing approaches are similarly valid. For steady-state challenges, the use of 3%, 5%, and 7% carbon dioxide balance in oxygen for 20-30 minutes at each level is usually appropriate; it is also easier to deliver when patients are mechanically ventilated. In infants, the use of calibrated respiratory inductance plethysmography is helpful to determine whether a ventilatory increase is apparent during spontaneous breathing, during wakefulness in milder patients, or as a ventilatory change from the stable ventilation provided by the mechanical ventilatory settings.

Two case reports have described a tentative diagnosis of CCHS made by measuring the electrical activity of the diaphragm using a catheter with a sensor placed just above the gastroesophageal junction. During sleep, the electrical activity of the diaphragm was low, if not absent, indicating central apnea, but there was a good diaphragmatic activity while awake.[29, 30]

If extensive hypotonia is present, nerve conduction studies and electromyography (EMG) may be appropriate after extensive clinical neurologic assessment.

Perform an ophthalmologic examination (ie, careful pupillary assessment) to assess for autonomic ophthalmologic abnormality.

Neurocognitive assessment is used to determine baseline function.

Procedures

If extensive hypotonia is present, muscle biopsy may be required after extensive clinical neurologic assessment.

If Hirschsprung disease is suspected, consider rectal biopsy.

Since this is a lifelong disease of ventilatory impairment, invasive ventilation via a tracheostomy is the mechanism of choice to secure ventilatory support. 

 

Treatment

Approach Considerations

There is no cure or gene therapy for congenital central hypoventilation syndrome (CCHS). Treatment is entirely supportive and is based on assessment of respiratory impairment, cardiac dysfunction, and gastrointestinal dysfunction, as well as surveillance for underlying oncologic manifestations.

Medical Care

Congenital central hypoventilation syndrome (CCHS) is a lifelong condition. A multidisciplinary approach to provide for comprehensive care and support of every child is needed.

General measures

CCHS patients require biannual then annual evaluation to assess their ventilatory needs not only while awake and in all stages of sleep, but also with varying levels of activity while awake. Ventilatory response to different physiologic challenges while awake and asleep should also be assessed. Other testing that should be done on a semi-annual basis until age 3 and an annual basis after includes 72-hour Holter monitoring, echocardiography, assessment of autonomic nervous system dysregulation, formal neurocognitive assessment, polysomnography, and blood work (hemoglobin, hematocrit, reticulocyte count, and bicarbonate.) Surveillance based on mutation type is also recommended. Patients with long PARM mutations (28 repeats and longer) and NPARM mutations require chest imaging, abdominal imaging and urine catecholamine monitoring every 3 months until age 2 and every 6 months until age 7 to rule out neuroblastomas and other neural crest cell tumors.[1]

Ophthalmoplegia and other ocular anomalies have long been recognized to be occasionally present; therefore, a thorough and periodic (ie, every year) ophthalmologic evaluation is necessary

Reports of dysregulation in glucose homeostasis in patients with CCHS have been published. Patients can have asymptomatic episodes of hypoglycemia, which are thought to be due to hyperinsulinism. An observational study in France found that half the patients had either abnormal glucose values (mostly postprandial hyperglycemia) or impaired glucose tolerance.[31, 32] Autonomic nervous system abnormalities can affect glucose concentrations (either hyperglycemia or hypoglycemia) in CCHS; therefore, glucose monitoring should be considered.

Gastrointestinal problems

Infants with CCHS may have significant hypotonia and temporary feeding difficulties. In addition, moderate-to-severe gastroesophageal reflux is frequently present and may require early administration of prokinetic agents and antireflux medications, especially in patients with hypotonia, temporary feeding difficulties, and gastroesophageal reflux. Surgical procedures (such as percutaneous gastrostomy tube feeding insertion, antireflux surgical procedures, or both) may be necessary if these problems are severe or persistent.

For patients with Hirschsprung disease, surgical intervention and, sometimes, colostomy to relieve the distal intestinal obstruction, may be required. For patients with a history of constipation, consider barium enema, manometry, or full-thickness rectal biopsy.

Medications

Pharmacologic approaches to enhance the respiratory stability and promote eucapnia in patients with CCHS have been unsuccessful. Therefore, respiratory stimulants have no current role in the treatment of CCHS.[20]

Case reports have described progesterone, a known respiratory stimulus, establishing ventilatory response to carbon dioxide in patients with CCHS.[33] In vitro studies have described the use of 17-AAG and curcumin, used for treatments of tumors, as effective in promoting the clearance of mutant PHOX2B aggregates and restoring the activity of PHOX2B with the largest polyalanine expansion.[34]

Invasive mechanical ventilatory support

To date, most centers that provide long-term home care for children with CCHS use positive-pressure ventilation through a permanent tracheostomy. Depending on the severity of alveolar hypoventilation, some patients only need ventilatory support at night, while others may need it around the clock.

Ventilators should be used in the spontaneous intermittent mandatory ventilation (SIMV) mode. Because an uncuffed tracheostomy should be used to minimize granuloma formation, ventilator settings should compensate for air leaks around the tracheotomy tube by increasing volume and peak airway pressure as necessary.

The recent availability of continuous-delivery compressors in home ventilators now permits domiciliary and ambulatory administration of ventilator modes traditionally reserved for intensive care units. Mildly hyperventilating patients with CCHS during their sleep to achieve PCO2 near 30-35 mm Hg is recommended. Mild nighttime hyperventilation results in better daytime spontaneous ventilation and gas exchange ("sprinting").

Noninvasive ventilatory support

Although there have been some favorable reports of negative-pressure ventilation (NPV) in CCHS patients, this modality is also cumbersome and requires significant equipment adjustments over time. In addition, NPV may be associated with upper airway obstruction during sleep in younger children with CCHS. In addition, NPV relies on the ability of chest wall movement; therefore, patients with chest wall deformity may not be good candidates for NPV.

Nasal mask ventilation has been proven to be a less invasive modality that is effective in patients with CCHS who are older than 7-8 years and who are nocturnally dependent on the ventilator. It is not only effective but is the preferred mode of ventilatory support by parents and patients, and even children who are established on other modes of ventilatory support can be successfully weaned onto mask ventilation within a short period.[35]

The transition of a children from invasive mechanical ventilation (IMV) to noninvasive mechanical ventilation (NMV) should be performed in a stepwise function. First, the identification of eligible patients, then the initiation of airway rehabilitation, weaning from IMV, trial with NIV, and finally decannulation. Only attempting NIV on patients who are stable at baseline is crucial. The following criteria has been proposed for eligibility to transition from IMV to NIV: (a) patient's normal consciousness state; (b) intact cough reflex and managing respiratory secretions; (c) need of suction of the trachea less than or equal to 1 time/day; (d) daytime tolerated tracheostomy capping; (e) IMV dependency only during sleep; (f) integrity of upper and lower airways on bronchoscopy assessment; (g) patient and family's motivation. [36]

Diaphragm pacing

Daytime diaphragm pacing in children with CCHS provides greater mobility than mechanical ventilation.[37] Thus, candidates for diaphragm pacing are potentially ambulatory patients who require ventilatory support 24 h/d via tracheotomy and who do not exhibit significant ventilator-related lung damage. Diaphragm pacer settings must provide adequate alveolar ventilation and oxygenation during rest and daily activities. Long-term outcome appears good, especially quality of life.[38]

Potential risks may be associated with surgical implantation and possible need for surgical revisions because of pacer malfunction. Diaphragm pacing requires increased level of fitness of the diaphragm. This is achieved by gradually increasing the length of time the child is paced. Most children can tolerate approximately 12-14 hours of pacing per day. Despite these limitations, most parental reports regarding diaphragm pacing are favorable. Development of a quadripolar electrode offers several advantages that primarily include greater durations of diaphragmatic pacer support at diminished risk of phrenic nerve damage, decreased diaphragmatic fatigue, and optimization of pacing requirements during exercise. Therefore, as equipment improves, the need to replace components is lessened.

Some families attempt diaphragmatic pacing during sleep to facilitate tracheal deaccannulation. Relying on diaphragmatic pacing as full life support during sleep requires extreme caution. Sleep endoscopy data from children with CCHS who use diagragmatic pacing reveals varying degrees of airway obstruction coupled with inadequate gas exchange in many cases. If parents and patients desire decannulation, sleep-state breathing may be better supported by noninvasive mask ventilation rather than diaphragmatic pacing in many cases. [39]

Deciding on the most appropriate type of ventilatory support requires referral to specialized centers with personnel experienced in diaphragm pacing.

Medicolegal concerns

The major medicolegal situations that may develop primarily involve the delayed diagnosis of CCHS or the assignment of causal relationships between CCHS and any type of fetal exposure.

For example, legal issues may arise from the potential association between ingestion of any given medication or exposure to a particular environmental situation; however, no current evidence links a particular teratogen to CCHS. Thus, although the embryology of the neural crest is still actively researched and is clearly linked to CCHS, no associations between exposure to chemicals during a particular phase of pregnancy and ultimate development of CCHS are noted.

A more frequent, albeit less argumentative, issue involves the recognition and diagnosis of CCHS. Infants who develop apnea or apparent life-threatening events during early postnatal life could have a mild variant of the wide clinical spectrum of CCHS and ultimately die of sudden infant death syndrome (SIDS). Because the manifestations in cases of SIDS/CCHS are subtle, diagnosing CCHS and preventing SIDS would be impossible.

On the other side of the severity spectrum, multiple unsuccessful trials to wean mechanical ventilation in an otherwise full-term baby should raise the suspicion for central hypoventilation syndrome, either congenital or secondary to other conditions. Early recognition of the appropriate diagnostic entity using the diagnostic approach elaborated in Workup prevents unnecessary delays in tracheotomy and in the institution of mechanical ventilatory support using a home ventilator, thereby accelerating the discharge process and preventing iatrogenic complications (eg, self-extubation, acute and chronic tracheal injury) that arise from ventilatory support using an endotracheal tube.

Surgical Care

Tracheostomy may be indicated for ventilatory support. Colostomy is sometimes required when Hirschsprung disease is present. When feeding problems arise, particularly during infancy, gastrostomy tube placement with or without antireflux procedures may be required.

Usual postoperative follow-up care for these procedures is necessary but does not differ from the care needed by any other patient.

Diaphragmatic pacing should be considered in appropriate patients. Those patients that may be candidates are patients who are ventilator dependent only during sleep and without significant co-morbidities.[40]  Obesity seems to be an unfavorable co-morbid condition to successful diaphragmatic pacing.  

Consultations

The diagnostic evaluation of patients with congenital central hypoventilation syndrome requires a multidisciplinary approach involving many specialists, such as the following:

  • Pulmonologist

  • Neurologist: Consultation with a pediatric neurologist is recommended in the evaluation of hypotonia or seizure activity; seizures can occur in some children with congenital central hypoventilation syndrome (CCHS) spontaneously or as a result of acute hypoxia. Nerve conduction studies, electromyography (EMG), muscle biopsy, auditory-evoked potentials, EEG, and imaging studies of the CNS may be necessary.

  • Cardiologist: Evaluation by a cardiologist is suggested to exclude any cardiac involvement.

  • Gastroenterologist: Evaluation by a gastroenterologist is suggested to rule out bowel hypomotility, to evaluate for gastroesophageal reflux, and to assist in management of Hirschsprung disease.

  • Hematologist: Evaluation by a hematologist is suggested in patients with a history of thrombosis or hypercoagulability.

  • Ear, nose, and throat (ENT) specialist: Evaluation by an otolaryngologist is suggested for tracheostomy evaluation, surgery, and regular postoperative and long-term care.

  • Social worker, speech therapist, respiratory therapist, and other healthcare specialists: Evaluation by these specialists is suggested to provide multidisciplinary care and follow-up.

  • Child behavior specialist: Periodic developmental assessment by a child behavior specialist is suggested.

Activity

Children with congenital central hypoventilation syndrome (CCHS) can lead active lives and are not restricted from any of the usual activities engaged in by healthy children. In water activities, such as swimming, special protective devices are required for the tracheostomy tube to prevent aspiration. Nevertheless, many children with CCHS participate in aquatic activities without any identifiable adverse consequence. Patients require close supervision by the parents or caretakers while swimming or while playing in swimming pools or similar situations. This is because these children do not sense air hunger while diving and can therefore become severely hypoxic underwater and lose consciousness.

Because of an absent or negligible respiratory drive, it is recommended that patients with CCHS monitor pulse oximetry and end-tidal carbon dioxide, particularly during asleep states, because they may develop profound hypoxemia and hypercarbia.[1]

 

Guidelines

Guidelines Summary

The following guidelines summary is adapted from the American Thoracic Society (ATS) 2010 Practice Guidelines[1] :

1. A PHOX2B mutation is required to make the diagnosis of CCHS. 

2. Because CCHS is a disease of autosomal dominant inheritance, patients with CCHS who plan to have children should consider genetic counseling. If the diagnosis is confirmed in a patient with CCHS, genetic counseling for testing should be offered to the parents and siblings of the patient when deemed appropriate. 

3. A high suspicion for CCHS should be considered in patients with unexplained alveolar hypoventilation and delayed recovery from sedative procedures and anesthesia, especially those with a history of neurocognitive delays. 

4. CCHS is a lifelong disease. Patients do not outgrow CCHS. There is a need for lifelong ventilatory support. 

5. CCHS is not a disease of the lung parenchyma; it is a disease of abnormal brain communication with the lungs (central drive) to control ventilation. To provide ventilatory assistance, use of a tracheosomy to a ventilator, or invasive ventilation, is recommended. 

6. We are leaning more, but there is still a knowledge gap about the genotype CCHS mutation and the associated phenotype. 

7. For families who have lost loved ones to CCHS, obtaining tissue samples via autopsy may be helpful to provide more information about biologic abnormalities in these patients. 

 

 

 

Medication

Medication Summary

Congenital central hypoventilation syndrome (CCHS) patients do not respond to pharmacological respiratory stimulants. Use of medications is restricted to the treatment of associated diseases. These patients frequently have problems with gastroesophageal reflux.

Prokinetic agents

Class Summary

These agents are useful in the management of gastroesophageal reflux, which is a frequent manifestation in patients with congenital central hypoventilation syndrome (CCHS), particularly during their younger years.

Metoclopramide (Reglan, Clopra, Maxolon)

Metoclopramide improves GI motility by releasing acetylcholine from the myenteric plexus, resulting in contraction of the smooth muscle. It is available in 5- and 10-mg tablets, 5-mg/mL syrup, and 5-mg/mL injection. Administer 30 minutes before eating.

Cisapride (Propulsid)

Cisapride indirectly improves GI motility by promoting acetylcholine release from postganglionic nerve endings in the myenteric plexus. It accelerates gastric emptying and enhances lower esophageal sphincter tone.

Cisapride was withdrawn from the US market on July 14, 2000. The manufacturer may make it available to certain patients who meet clinical eligibility criteria for a limited-access protocol only. It is available in 10- and 20-mg tablets and an oral suspension (1 mg/mL).

Agents to Reduce Apnea

Carbamazepine

Carbamazepine has been associated with decreased apneic events in CCHS. Though the mechanism is not fully understood, this is an area for future study. [48]

 

Follow-up

Further Outpatient Care

Periodic follow-up is necessary and is usually more frequent in younger children with congenital central hypoventilation syndrome (CCHS). Follow-up incorporates multidisciplinary approaches, aiming to determine that all areas receiving care are addressed. The American Thoracic Society Statement from 2010 outlines the comprehensive monitoring that should take place at recommended intervals[1] :

  • Adequacy of ventilatory support must be established based on an overnight sleep study in the laboratory, which should be done periodically. Guidelines recommend testing with nocturnal polysomnography (NPSG) every 6 months of life for the first 3 years and then at least annually. 
  • Cardiac evaluation with an echocardiogram is recommended to assess for signs of cor pulmonale every 6 months for the first 3 years of life, with annual evaluations following. Cardiac evaluation should also include 72-hour continuous electrocardiography (Holter monitoring). 
  • Patients should have annual complete cell blood (CBC) counts to assess for polycythemia, which would result from untreated hypoxia. Patient should also have an annual blood gas analysis to detect respiratory acidosis, which suggests inadequate ventilatory support. 
  • Certain patients with high-risk mutations for neural crest tumors ( PHOX2B NPARMs, patients with PARMS 20/28 or greater) should be evaluated frequently for the respective associated malignancies. Surveillance for neuroblastomas (NPARM mutations) should take place every 3 months for the first 2 years of life and every 6 months until age 7 years. Evaluation consists of imaging of the chest and abdomen, as well as measurement of urine catecholamines. Surveillance for ganglioneuromas and ganglioneuroblastomas (PARM 20/28 and longer) is recommended annually with chest and abdominal imaging.  

The CCHS family network provides community support for families and individuals affected by CCHS. There is a significiant emotional, social, and financial burden for patients with CCHS. 

Further Inpatient Care

In the immediate neonatal period, many patients with CCHS often develop a constellation of symptoms suggestive of CCHS. The initial evaluation often takes place in the inpatient setting. Patients, however, may present at varying points, and the presentation may dictate whether inpatient management is warranted. Often, these patients are managed initially in the inpatient setting, not only because of the severity of their presentation, but also owing to the coordinated nature of the specialists who work together in the inpatient setting.

Initial inpatient management includes patient stabilization and treatment of the underlying conditions. The patient's absent or negligible respiratory drive warrants close monitoring of pulse oximetry and end-tidal carbon dioxide, particularly during asleep states, because the patient may develop profound hypoxemia and hypercarbia whenever he or she is hospitalized for any reason.