Central alveolar hypoventilation …

William I Wooten III MD

Sleep Disorders

Updated 12.02.2025
Released 10.01.1993
Expires For CME 12.02.2028

Central alveolar hypoventilation

Author: William I Wooten III MD

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Editor: Bradley V Vaughn MD

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Central alveolar hypoventilation

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Introduction

Overview

Central alveolar hypoventilation, a disorder of impaired ventilatory response to hypercapnia and hypoxemia, may be congenital, acquired, or idiopathic. Congenital central hypoventilation syndrome is most often caused by mutation of the gene PHOX2B and generally presents during the first year of life as respiratory failure in a neonate necessitating mechanical ventilation. These patients exhibit hypoventilation, which is generally worsened in sleep, and they may also suffer from varying degrees of dysautonomia. The PHOX2B gene transcript is essential for development of neural crest derivatives, thus, mutations are also associated with neurocristopathies, including Hirschsprung disease and malignancies of neural crest origin. Evidence is emerging linking PHOX2B mutations to structural changes within the central nervous system in patients affected by congenital central hypoventilation syndrome. The idiopathic form is characterized by decreased alveolar ventilation that leads to sleep-related hypercapnia in individuals who have no lung disease, obesity, skeletal malformation, or neuromuscular disorder to account for the hypoventilation. Central hypoventilation may also arise as an acquired disease in the context of brainstem injury or structural disorder.

Key points

	• Central alveolar hypoventilation may be congenital (genetic), acquired, or idiopathic.
	• The underlying neurologic disorder involves an absent or reduced ventilatory response to carbon dioxide resulting in hypercapnia and hypoxemia.
	• A thorough evaluation should be performed in all cases to rule out other identifiable neuromuscular, cardiopulmonary, and skeletal etiologies.
	• Genetic testing and neurologic imaging are indicated in all suspected cases.
	• Early diagnosis is crucial, and initiation of nocturnal positive pressure ventilation is a key therapeutic strategy.

Historical note and terminology

Congenital central alveolar hypoventilation syndrome was first described in 1970, and the genetic etiology was finally elucidated in 2003 (69; 05). A full description may be found in the 2014 International Classification of Sleep Disorders—Third Edition Text Revision (ICSD-3TR) under the name congenital central alveolar hypoventilation syndrome (02).

The term Ondine’s curse, which was first applied to the condition of central alveolar hypoventilation in a 1962 case series of three adult patients with high cervical and brainstem lesions following surgery, is derived both from an 1811 novella, Undine, by the German writer Friedrich de la Motte Fouqué and from a subsequent reimagining of the story in the 1938 play “Ondine” by Jean Giradoux (92; 37). In this play, Ondine, a water nymph, falls in love with a knight named Hans. However, their love is ill-fated, and when Ondine is jilted by Hans, her uncle, the King of the Sea, curses Hans. Hans loses all automaticity: “I don’t see unless I tell my eyes to see… A moment of inattention and I forget to hear, to breathe…” When he finally falls asleep, Hans stops breathing and dies. Ondine’s curse, therefore, properly refers only to the condition where hypoventilation is restricted to the sleeping state.

The idiopathically acquired form of central alveolar hypoventilation is also described in the ICSD-3-TR under sleep-related hypoventilation disorders, including idiopathic central alveolar hypoventilation, and late onset central hypoventilation with hypothalamic dysfunction. These disorders share the characteristic of a blunted chemoresponsiveness in the absence of identifiable abnormalities (pulmonary, cardiac, neurologic, or muscular). When hypoventilation occurs during the day (in addition to nocturnal sleep), the condition is referred to as idiopathic (primary) alveolar hypoventilation.

Clinical manifestations

Presentation and course

	• Congenital central alveolar hypoventilation syndrome usually presents in the first year of life as respiratory distress, shallow breathing, and cyanosis that are most evident during sleep.
	• The phenotype can be incompletely penetrant, with some affected individuals being relatively asymptomatic and only incidentally diagnosed later in life.
	• Congenital and acquired forms of the disorder can cooccur with a variety of conditions, usually dysautonomia in the former case and lesions in the brainstem, spine, or respiratory neurons in the latter case.
	• In the case of congenital central alveolar hypoventilation, prognosis is usually good, with the benefit of earlier recognition and treatment with nocturnal assisted ventilation.

Congenital central alveolar hypoventilation syndrome is a rare genetic condition, which generally presents in the first year of life, although later presentations are reported (55; 18). Typically, the newborn presents with respiratory distress, shallow breathing, and cyanosis and requires mechanical ventilation and monitoring in an intensive care unit. Abnormal blood gases with respiratory acidosis and marked hypercapnia are a hallmark for this condition. Elimination of other causes of abnormal breathing, such as sepsis, cardiac malformation, seizure disorder, and neuromuscular disease is important. Congenital central hypoventilation syndrome is a dysfunction of the autonomic control of breathing, and the diagnosis may be confirmed by abnormal responses to hypercapnic challenge during sleep as noted in polysomnography, and the syndrome is definitively identified by genetic testing for PHOX2B mutation (104).

The spectrum of clinical presentation of congenital central alveolar hypoventilation syndrome is broad. Mild hypoventilation and shallow breathing during quiet sleep accompanying normal ventilation during wakefulness may be seen. In more severe cases, children demonstrate severe central apneas and hypoventilation during sleep and various degrees of hypoventilation during wakefulness, with the development of serious respiratory acidosis due to a partially or completely absent response to hypercapnia and hypoxemia. Autonomic and brainstem dysfunction are often found. Rarely, infants may present with a syndrome of Hirschsprung disease or neuroblastoma before the subsequent development of respiratory issues (13).

Prior to the discovery of PHOX2B and its role in congenital central hypoventilation syndrome, the diagnosis was made using clinical criteria, including (1) persistent hypoventilation during quiet (non-REM) sleep with PaCO2 greater than 60 mmHg; (2) symptoms during the first year of life; and (3) an absence of lung, cardiac, or neuromuscular disease (03). The 2010 revised recommendations now also require PHOX2B gene mutation to confirm the diagnosis of congenital central alveolar hypoventilation syndrome (04). Genetic testing of parents with affected children is also recommended.

Congenital central alveolar hypoventilation may occur in association with the following disorders:

	• Autonomic nervous system dysfunction: Elevated heart rate levels and reduced heart rate variability (118; 106), abnormal circadian blood pressure pattern (104a), bradyarrhythmias from hypercapnic acidosis (96), and cerebral autoregulation dysfunction in the setting of orthostatic challenge, all of which are associated with structural changes in relevant areas of the cerebral cortex (06). Familial dysautonomia has also been reported.
	• Derivatives of neural crest malformation: Hirschsprung disease is a congenital aganglionosis of the intestines and occurs in 13% to 50% of patients with congenital central alveolar hypoventilation. Haddad syndrome is the combination of congenital central alveolar hypoventilation and Hirschsprung disease. Both entities belong to a family of disorders called neurocristopathies, referring to an early disturbance in neural crest cell development (111).
	• Derivatives of neural crest tumors: neuroblastoma and ganglioneuroma.
	• Ophthalmological abnormalities: cranial nerve palsies, Leber hereditary optic neuropathy (90) and convergence insufficiency, strabismus, and pupillary abnormalities (36).
	• Esophageal dysmotility: lower esophageal motility dysfunction (30).
	• Central nervous system malformation: Chiari II malformation and Leigh disease (44).

A variant of central hypoventilation, known as late-onset central hypoventilation syndrome, presents in previously healthy children and has features similar to congenital central alveolar hypoventilation. These children, adolescents, and adults typically present with milder disease but can have many of the same features. These patients may have shallow breathing and more obvious hypoventilation in sleep with symptoms of morning headache and sleepiness. These patients also may have aberrant control of glucose, bradycardia, gastrointestinal dysmotility, pupillary abnormalities, and dysautonomia including temperature dysregulation (07). Respiratory failure is usually precipitated following a respiratory tract infection, administration of an anesthetic or a hypnotic, or by adenotonsillar hypertrophy. These patients may also have greater likelihood of having neural crest tumors.

Neural crest tumors can be the presenting finding, and then the hypoventilation is discovered. The finding of hypoventilation, typically late onset, may not be revealed until the patient is undergoing therapy for the tumor. In one case, severe respiratory decompensation occurred with the administration of monoclonal antibody as part of therapy for a neuroblastoma (19).

Idiopathic central alveolar hypoventilation occurs because of reduced ventilation, which leads to nocturnal hypercapnia and hypoxemia. Unlike patients with congenital central hypoventilation syndrome, who, when properly ventilated at night, do not have sleep abnormalities, patients with idiopathic central alveolar hypoventilation typically exhibit sleep fragmentation (insomnia with frequent arousals and wake episodes) and lighter stages of sleep (08). Daytime symptoms include hypersomnolence, morning headaches, peripheral edema, polycythemia, and cor pulmonale, with abnormal pulmonary function tests.

Comparatively, the acquired form of central alveolar hypoventilation is typically caused by a structural lesion, which leads to the loss of control of automatic respiration. It occurs in all ages and may result from asphyxia, central nervous system infection, trauma, tumor, cerebral infarction, or intracranial hemorrhage. Following recovery from coma, hypercapnia is noted, sometimes along with brainstem lesions identifiable on MRI. The acquired form may be most evident in obese, middle-aged subjects, with an estimated prevalence of 0.3% in the general population (74).

Patients have an attenuated sense of breathlessness following exercise, particularly underwater swimming. The condition often becomes apparent after acute respiratory failure requiring intubation followed by carbon dioxide retention or difficulty weaning from the ventilator and can be unmasked in the setting of standard administration of sedatives.

Numerous case reports of association with other disorders or other acquired forms are described:

	• Acute respiratory failure in obese males induced by infection, trauma, or high altitude (68).
	• Bilateral cervical cordotomy, more commonly performed in the 1960s (53).
	• Neurosarcoidosis with diaphragmatic paresis secondary to sarcoid lesion (51).
	• Cervical anterior spinal artery syndrome presumably secondary to a reticulospinal pathway lesion, which normally activates ventilatory muscles during sleep (66).
	• Resolution of Ondine curse in a 72-year-old woman after suboccipital decompression (39).
	• Eventration of the diaphragm as a result of birth injury, cardiothoracic operation, or part of a congenital condition affecting phrenic nerve (34).
	• Medullary thyroid cancer (84).
	• Cerebral venous thrombosis (12).
	• Vascular bilateral posterolateral medullary infarcts, visible on MRI (23), Leigh syndrome, or other metabolic disorders (21).
	• Bilateral medullary plaques caused by multiple sclerosis (09).
	• Alternative ptosis of both the right and left eyes and esotropia (70).
	• Following Haemophilus influenzae type b meningitis and extensive herpes simplex infection with subsequent brainstem and cervical cord injury (103).
	• Bilateral medullary myeloma lesions with clinical response to chemotherapy but persistent hypoventilation and central sleep apnea (86).
	• Central apneas and hypoventilation in sleep secondary to interictal epileptiform discharges (61).
	• Central hypoventilation, drowsiness, hypoxia, falls, and upper extremity weakness and numbness in the setting of os odontoideum (14).
	• Central alveolar hypoventilation caused by aneurysmal megadolichobasilar artery (41).
	• Development of central alveolar hypoventilation approximately four years after the onset of progressive supranuclear palsy (43).
	• Central alveolar hypoventilation secondary to a lateral medullary infarction after endovascular patent artery occlusion for vertebral artery dissecting aneurysm (102).
	• Ondine’s curse co-occurring with temporal lobe seizures related to para-neoplastic antibodies (anti-Hu and Zic4) in the context of small cell lung cancer (50).

Prognosis and complications

In the case of congenital central hypoventilation syndrome, morbidity and mortality are related to timely diagnosis and referral to an experienced pediatric center. Serious complications include cardiac arrhythmias, lethargy, respiratory arrest, and, most seriously, death during sleep. The prognosis is generally worse in patients with Hirschsprung disease, ganglioneuroma, or neuroblastoma. Prolonged survival and an overall good quality of life are possible today, and with earlier recognition of the syndrome, serious complications can be avoided.

Children and adolescents with congenital central hypoventilation syndrome may also have developmental and cognitive problems that require special attention. Studies have demonstrated problems in attention, working memory, processing speed, perceptual reasoning, visuographic skills, and executive functions, resulting in issues with interpersonal communication and daily living skills in this population (117; 121). In a study comparing congenital central hypoventilation syndrome patients to their parents, the children scored significantly below their parents in indices of intelligence, vocabulary, and abstraction, as well as below population normative data for IQ, reasoning, processing speed, and working memory (120). Measures of neurocognitive function may already be reduced in preschool-age children (16).

Clinical vignette

A full-term infant born by cesarean section to non-consanguineous parents underwent further evaluation when he did not pass meconium in the first 24 hours of life. Work-up revealed signs of intestinal obstruction and prompted colonic biopsy that showed findings consistent with Hirschsprung disease. The patient was intubated and sedated for an ileostomy and successfully discharged home afterwards.

However, at 4 weeks of life, he was noted to develop unusual pauses in breathing while sleeping, which prompted readmission to the hospital. Further work-up revealed that the patient was having oxygen desaturations associated with these pauses in breathing. Arterial blood gas analysis revealed a compensated respiratory acidosis. He was intubated and ventilated. A diagnosis of congenital central hypoventilation syndrome was suspected and prompted PHOX2B mutation analysis. This revealed a heterozygous non-polyalanine repeat (NPARM) mutation. After discussion with family regarding the diagnosis of congenital central hypoventilation syndrome, the family agreed to placement of a tracheostomy.

Further review of family history revealed that the patient’s maternal uncle had also had Hirschsprung disease and died of a neuroblastoma at four years of age. The patient’s mother denied any history of sleep disturbance. She underwent genetic testing for PHOX2B mutation and was found to have the same NPARM mutation. Empiric evaluation of the patient’s mother’s sleep revealed mild central sleep apnea. The patient’s grandparents also underwent genetic testing, and the grandfather was found to also be heterozygous for the same mutation carried by his daughter and grandson.

This case is a modified version of a case reported by Low and colleagues in Pediatric Pulmonology (60). As discussed in this article, NPARM mutations account for roughly 10% of PHOX2B mutations and usually result in more severe, syndromic manifestations of the disease, as in this patient’s case—presenting with Haddad syndrome. However, this case also speaks to the variable penetrance of this mutation given a lack of symptoms in both the grandfather and the patient’s mother.

Biological basis

	• The main genetic mutation associated with congenital central hypoventilation is PHOX2B, which is believed to be involved in early neural crest cell migration with a central role in the generation of normal respiratory patterning and autonomic function.
	• Two types of PHOX2B mutations are described, including polyalanine repeat mutations (PARMs) and non-polyalanine repeat mutations (NPARMs), with more severe ventilatory defects associated with NPARMs and PARMs containing a higher number of polyalanine repeats.
	• Disruption of the upstream and downstream components of the PHOX2B pathway in the ventral medullary chemostatic centers likely explains the impaired ventilatory response, which is most evident in sleep due to the lack of volitional respiratory control.

Etiology and pathogenesis

Genetics. Congenital central hypoventilation syndrome is most often due to heterozygous mutations of the gene encoding paired-like homeobox 2b, PHOX2B, a transcription factor that maps to chromosome 4p12. PHOX2B is expressed in both the central and the peripheral autonomic nervous system during human embryonic development. It is believed to be involved in early neural crest cell migration with a central role in the generation of normal respiratory patterning and autonomic function. It is also the predisposing gene for occurrence of neuroblastoma in different mutational patterns, ganglioglioma, and Hirschsprung disease.

Function. PHOX2B expression in the brainstem respiratory network is preferentially associated with neurons involved in chemosensory integration, specifically by a chain of neurons involved in the integration of peripheral and central chemoreception. Studies in PHOX2B transgenic mice suggest that hypercapnic ventilatory response impairment in congenital central hypoventilation syndrome may be related to PHOX2B-expressing neuronal loss or maldevelopment in the nucleus tractus solitarius and retrotrapezoid nucleus, which are important centers of respiratory chemoreception and control (40; 35).

PHOX2B mutations disrupt breathing automaticity during sleep without causing major impairment of respiration during waking (99).

Genotype-phenotype correlations. Heterozygous mutations in PHOX2B are typically found in individuals with congenital central hypoventilation syndrome, with at least 90% of PHOX2B gene mutations consisting of polyalanine repeat mutations (PARMs) characterized by abnormal alanine expansions within a 20-repeat polyalanine expansion tract in exon 3 resulting from (GCN)n triplet repeat expansions (47). In a Japanese cohort of 92 subjects, 86 had polyalanine repeat mutations (PARMs) and six had nonpolyalanine repeat mutations (NPARMs). Of the subjects with PARMs, it was noted that all subjects with 26 or more repeats presented with hypoventilation at birth. Those with 25 or fewer repeats had hypoventilation at variable timepoints or not at all (95). As such, the association of increased number of repeats with more severe respiratory presentation has been suggested, though rare cases of delayed/adult presentations in individuals with more than six additional repeats suggest incomplete penetrance through a multitude of gene-gene interactions (48). Comparatively, NPARMs comprise less than 10% of PHOX2B mutations and are known to produce more severe disruption of PHOX2B function, usually presenting as a syndrome associated with Hirschsprung aganglionosis or other neurocristopathies (47). Increased prevalence of ventilatory dependence, Hirschsprung disease, and neural crest tumors were seen more frequently in the NPARM group as compared to those with polyalanine repeat mutations (13).

Other associated genes. Other mutations have been described in association with the congenital central hypoventilation syndrome phenotype, including genes involved in migration of neural crest origin, as well as genes upstream and downstream of PHOX2B in biological pathways such as RET, GDNF, EDNRB, EDN3, LBX1, and MYO1H (33; 42). The involvement of multiple genes suggests that the genetic involvement has a complex pattern of inheritance.

Pathophysiology. The primary factor controlling respiration is arterial carbon dioxide via brain tissue pH. Alveolar ventilation is principally a function of carbon dioxide, as oxygen tension is normally maintained at levels higher than those that induce stimulation of the respiratory system. Ventilatory responses to hypercapnia and to hypoxia are essential to maintain normal arterial blood gas tension (101). Peripheral chemoreceptors mediate responses to hypoxia, whereas central chemoreceptors mediate responses to carbon dioxide (via hydrogen ion concentrations). The central chemoreceptors are thought to be located near the surface of the fourth ventricle on the ventral side of the medulla oblongata, rostral and medial to the hypoglossal roots. Normally, progressive hypercapnia induces a linear increase in minute ventilation, whereas progressive hypoxia induces a hyperbolic increase. If a defect impairs the sensory system for monitoring carbon dioxide levels, ventilation is affected, particularly when sleep results in the loss of "wake stimuli" and volitional breath control, which facilitate control of ventilation during wakefulness (32).

In patients with congenital central alveolar hypoventilation syndrome, exposure to 100% oxygen results in further hypoventilation compared to baseline, suggesting that the peripheral chemoreceptors are functional. The extent of hypoventilation is also state dependent, being maximal during deep NREM sleep with relatively normal gas exchange during REM (94). During wakefulness, children with congenital central alveolar hypoventilation have absent rebreathing ventilatory responses to hypoxia and hypercapnia. During exercise, children with congenital central alveolar hypoventilation may become hypoxic and hypercapnic; they increase their minute ventilation primarily by an increase in respiratory rate rather than by tidal volume. Further, minute ventilation does not match carbon dioxide production.

Neuroimaging and structural correlates. In patients with congenital central alveolar syndrome, structural and functional imaging with MRI indicates abnormalities in both the forebrain and the brainstem (82). Whether these changes contribute to the pathogenesis or are a result of tissue hypoxia is unclear. Postmortem analysis of neonatal lethal cases has shown loss of neurons in the locus coeruleus. This is mirrored in abnormal development of the locus coeruleus in a transgenic mouse model of the same PHOX2B mutation (77). Although radiological evaluations of the brain have failed to identify a lesion to account for the clinical and physiological features, a functional MRI compared activity at baseline and at two minutes of hypoxic challenge (15% oxygen, 85% nitrogen) in patients with congenital central hypoventilation syndrome compared to controls. Results showed significant differences in the magnitude and timing of responses between the two groups indicative of deficient neurovascular activation in response to hypoxia (late or none) in patients with congenital central hypoventilation syndrome, specifically in the posterior thalamic, cerebellar, midbrain, and limbic structures (62). These findings partially explain the absent perception of air hunger and lack of discomfort in patients with congenital central hypoventilation syndrome.

Association of congenital central hypoventilation syndrome with the occurrence of Hirschsprung disease, congenital neuroblastoma, ganglioneuroblastoma, and benign ganglioneuroma suggests that the primary defect relates to neural crest cell migration and function. Vagal hyperresponsiveness, sinus pauses, bradyarrhythmia, and an attenuated response to endogenous sympathetic stimulation suggest a diffuse alteration in autonomic nervous system function (78). In line with this hypothesis is the finding that autonomic nervous system dysfunction was more common in relatives of the patients with the syndrome compared to control subjects (116).

Comparatively, idiopathic alveolar hypoventilation syndrome is not associated with structural lesions and does not appear to have an identifiable etiology.

Prevention

	• There are no known preventive strategies other than early detection and appropriate counseling of parents who are known to be carriers of the mutation.
	• Central nervous system depressants (including alcohol) should be avoided, whenever possible, due to the concomitant respiratory depression.
	• Due to the likelihood of dysautonomia, cardiology consultation is important for evaluation and determination as to whether a pacemaker is needed.

No means of prevention are known for congenital or idiopathic central alveolar hypoventilation. However, early recognition of the disease and associated risk factors can expedite interventions and possibly preserve neurocognitive function. Case reports of mother-daughter transmission, siblings, and twins with congenital central hypoventilation syndrome suggest that genetic counseling of parents and siblings is appropriate after identification of individuals with congenital central hypoventilation syndrome. This is particularly relevant given the association noted between sudden infant death syndrome (SIDS) and PHOX2B polyalanine length variants in certain populations (57). There are cases reported of severe adverse events, including coma and death, related to alcohol use in adolescents and young adults with congenital central hypoventilation. Patients should be advised to abstain from alcohol or other substances that are known to cause respiratory suppression (17). One of the more serious yet preventable complications of central hypoventilation syndrome is cardiac autonomic dysregulation, which can lead to sudden death (38). Early cardiac workup and prediction for the need of a pacemaker are crucial. When genetic testing reveals PHOX2B mutations in asymptomatic adult family members, these patients should be followed longitudinally for the development of respiratory and cardiac disturbances (47).

Differential diagnosis

Confusing conditions

The infant presenting with apnea or respiratory failure must have other more common etiologies rigorously excluded, including sepsis, pulmonary infections, cardiopulmonary and neurologic malformations, intoxication, trauma, and neuromuscular disease. Conditions in childhood that can be easily confusing include rapid onset obesity, hypoventilation hypothalamic dysfunction and autonomic dysregulation (ROHHAD), and Prader-Willi syndrome and demonstrate hypoventilation relatively early in the course (10). Other conditions that may cause clinically significant central alveolar hypoventilation include familial dysautonomia, Leigh syndrome, Chiari malformation type 1 and type 2, and achondroplasia.

In adults with unexplained respiratory failure and inability to wean from mechanical ventilation, the differential diagnosis includes obstructive and restrictive lung disease, severe ventilation-perfusion mismatch associated with pulmonary emboli or other causes, respiratory muscle weakness or fatigue, neuromuscular disease, and toxins affecting neuromuscular or central nervous system function. Adults with nocturnal hypoxemia or hypercapnia should also be considered for other disorders, such as obstructive sleep apnea syndrome, central sleep apnea syndrome, and obesity hypoventilation syndrome.

Associated or underlying disorders

The congenital form of central alveolar hypoventilation is associated with neurocristopathies including Hirschsprung disease and malignancies of crest cell origin, including congenital neuroblastoma, ganglioneuroblastoma, and benign ganglioneuroma. As a result of involvement of neural crest cells, dysautonomia – vagal hyperresponsiveness, sinus pauses, bradyarrhythmia, and/or an attenuated response to endogenous sympathetic stimulation – is frequently present, even in individuals who may not have significant respiratory symptoms (78; 54).

Lesions anywhere along the pathway from the chemoreceptive centers in the medulla, through the high cervical spine, to the phrenic nerves can result in an acquired form of central alveolar hypoventilation. As such, various disorders have been associated with the acquired form: vascular (medullary infarct, cervical anterior spinal artery syndrome, cerebral venous thrombosis), inflammatory/immunologic (neurosarcoidosis, multiple sclerosis, anti-Hu and Zic4 paraneoplastic antibodies), infectious (meningitis), traumatic (cordotomy, anatomic brainstem compression), oncologic (metastatic), and neurodegenerative (progressive supranuclear palsy).

Diagnostic workup

	• Genetic testing for the PHOX2B gene mutation is key to the diagnosis of congenital central alveolar hypoventilation.
	• Attended polysomnography is recommended at the time of initial investigation to demonstrate sleep-related hypoventilation and should be repeated at regular intervals to assess ventilatory needs that may change over time due to developmental and age-related changes in respiration.
	• Other diagnostic evaluations are used to rule out confounding conditions that may underlie the acquired form or can masquerade as the congenital form including primary pulmonary investigation with chest x-ray or computed tomography (CT) scan, neurologic evaluation including MRI and consideration of neuromuscular diagnostics, and structural and physiologic cardiac investigations.
	• Additional diagnostic tests should be considered to assess for neurocristopathies, including rectal punch biopsy for Hirschsprung disease, chest and abdominal imaging for neural crest tumors, and urine catecholamines for neuroblastomas.

According to consensus of the American Thoracic Society published in 1999, the diagnosis of congenital central alveolar hypoventilation syndrome required monitoring during sleep without mechanical ventilation. The 2010 American Thoracic Society policy statement concluded that suspected congenital central alveolar hypoventilation syndrome diagnosis is confirmed by demonstrating a PHOX2B gene mutation by sequential testing starting with a screening test that, if negative, should be followed by the sequel PHOX2B sequencing test in cases of high clinical suspicion. In addition to the genetic workup, other testing should be undertaken to rule out other etiologies of hypoventilation and to screen for associated conditions, such as autonomic dysfunction or intracranial lesions (115).

Cardiopulmonary evaluation. Electrocardiogram, echocardiogram, Holter monitoring, and chest x-ray or CT may be indicated to rule out autonomic dysfunction, right heart failure, pulmonary hypertension, and primary lung disease. In one retrospective study, congenital heart disease was found in 30% of patients with molecularly confirmed congenital central hypoventilation syndrome, primarily manifesting as anomalies of the proximal aortic arch and proximal coronary arteries (59). Furthermore, in a retrospective chart review of 72 congenital central alveolar hypoventilation patients, 22% (16) had evidence of potential life-threatening cardiac arrhythmias, most of which had significant sinus pauses on ambulatory monitoring without necessarily manifesting symptoms of syncope, dizziness, chest pain, tingling in the left arm, or palpitations (54).

Imaging studies. MRI of the brain should be performed to evaluate for intracranial lesions. The acquired forms are associated with intracranial hemorrhage, ischemic stroke, or tonsillar herniation. If Hirschsprung disease is suspected, MRI of the spine is indicated as well to evaluate the patient for ganglioneuromas.

Neurologic evaluation searching for hypotonia and neuromuscular disorders. Testing involves nerve conduction studies and electromyography. Muscle biopsy to look for myopathic disorders and pupillometry to assess for autonomic dysfunction may have a role as well (83). If diaphragmatic paresis is suspected, physicians should perform diaphragmatic fluoroscopy and ultrasound. If Hirschsprung disease is present, barium enema will show bowel distention, and colon biopsy will demonstrate an aganglionic colon.

Metabolic and mitochondrial disease screening. Late-onset congenital central hypoventilation syndrome in children may present with nonspecific signs, including cardiopulmonary compromise, autonomic dysregulation, and hypotonia, and it can masquerade as a metabolic syndrome (eg, Leigh disease, pyruvate dehydrogenase deficiency, and carnitine deficiency) (89). In the early stages of evaluation, consultation with a medical geneticist may be helpful.

Genetic workup. Clinical diagnostic testing for congenital central hypoventilation syndrome involves targeted mutation analysis or sequence analysis. Polyacrylamide gel electrophoresis PHOX2B screening testing is an appropriate first-line investigation. If negative in the setting of suspected congenital central alveolar hypoventilation syndrome, the sequel PHOX2B sequencing test should be performed (45). More information can be accessed at the following site: www.genetests.org.

Diagnostic polysomnography, including measures of pulse oximetry with either transcutaneous or end-tidal carbon dioxide, should be performed at the time of initial work-up to diagnose sleep-related hypoventilation and determine its severity. For infants diagnosed with congenital central hypoventilation syndrome, overnight polysomnography should be repeated on a regular basis to assess changes in ventilatory status. Respiratory support requirements often evolve during the first few years of life; thus, more frequent assessment is recommended every 2 to 6 months until 2 years of age and at least annually thereafter provided the patient is stable. The majority of patients require assisted ventilation throughout their lifetime, which necessitates close long-term follow-up of ventilatory status and assessment of potential complications (104).

Evaluation of patients with suspected idiopathic central hypoventilation. For older children and adults presenting with unexplained (idiopathic) hypoventilation or hypoxemia, infectious, cardiac, pulmonary, and neuromuscular causes must be excluded. Patients with idiopathic alveolar hypoventilation syndrome show evidence of abnormal pulmonary function with formal testing, as well as polycythemia, chronic hypoxemia, and hypercapnia, and it has been suggested that an elevated serum bicarbonate level may be of diagnostic value (67). If a mutation of PHOX2B is identified in a child, gene mutations should be systematically examined in any biological adult relative with unexplained central hypoventilation, and all, even apparently healthy, biological parents to determine if they harbor a somatic mosaic (108). One report indicates the possibility of germline mosaicism for PHOX2B mutations in parents, emphasizing the importance of screening subsequent pregnancies in families with a child that has congenital central hypoventilation syndrome (88). Adults who present with reduced cardiac baroreflex and blunted sympathetic mediated response should be suspected of having the adult-onset type of central alveolar hypoventilation (24). Polysomnography often demonstrates periods with reduced tidal volumes lasting several minutes along with sustained hypoxemia, which tends to worsen during REM sleep. Hypercapnia occurs during episodes of hypoventilation, due to a decreased minute ventilation. Polysomnography with the monitoring of blood gases by arterial catheter will typically demonstrate central apneas with hypercapnia that is greatest in NREM sleep, less pronounced in REM sleep, and least apparent during wakefulness. Apnea duration may increase at the end of the sleep period, reflecting further blunting by sleep fragmentation of already abnormal arousal responses.

Management

	• The goal of treatment is to ensure adequate ventilation, particularly during sleep.
	• Ventilation during sleep must be assessed regularly, and overnight monitoring with pulse oximetry and alarms should be used.
	• These patients often benefit from a multidisciplinary team approach to handle the many dimensions of health issues.
	• Tracheostomy is often required to provide a secure means of assisted ventilation; however, it introduces risks of infection and impairments of speech and swallowing. Transitioning to noninvasive positive pressure ventilation should be a therapeutic goal when safe and tolerable.
	• If ventilation is inadequate during both wakefulness and sleep, diaphragmatic pacing is a practical alternative once the patient is ambulatory.

The goal of treatment is to ensure adequate ventilation, particularly during sleep, due to the risk of severe hypoxemic episodes and because metabolic perturbations, especially in congenital central alveolar hypoventilation syndrome, have neurocognitive sequelae (119). These patients frequently require a coordinated multidisciplinary approach including pulmonologist, otolaryngologist, gastroenterologist, cardiologist, neurologist, sleep medicine physician, geneticist, respiratory therapist, psychologist, and social worker (49). Despite varying courses and severities among patients, lifelong follow-up is typically needed.

Chronic mechanical ventilation dependence is the norm and may be delivered via invasive or noninvasive means. Invasive ventilation via tracheostomy has been viewed as the most secure long-term option to provide ventilation, especially in young patients and those with severe disease. It is often capped during the day as tolerated and attached to a ventilator with humidified air during sleep. Early tracheostomy appears to promote improved neurocognitive function compared to delayed tracheostomy over 3 months of age or treatment with noninvasive means, based on a study of the neurocognitive function of 88 children with congenital central alveolar hypoventilation syndrome over the age of 6 years (79).

Despite the benefits of tracheostomy, this intervention involves significant drawbacks, including risks of morbidity and mortality. Tracheostomy may introduce airway infection, difficulties with speech and swallowing, complications related to the stoma, and negative effects on quality of life related to tracheostomy care and body image. Use of noninvasive positive-pressure ventilation in infants has been shown to avoid complications related to prolonged mechanical ventilation via tracheostomy; however, there is concern that a significant number of infants are unable to receive adequate ventilation via this modality and may eventually require tracheostomy (71; 20). Noninvasive ventilation has been increasingly implemented, especially for patients demonstrating clinical stability and those with milder phenotypes (85). In patients with tracheostomy, eventual transition to noninvasive ventilation may be possible during childhood using a cautious, stepwise approach (81). Clinicians and caregivers should be aware of potential complications of pseudoprognathism or midface hypoplasia, which are commonly associated with prolonged use of nasal masks for noninvasive positive pressure ventilation in children. Pressure-controlled ventilation is typically preferred to volume-controlled modalities because this option is effective at all ages and is better suited to compensate for air leaks. Optimal tidal volumes are achieved by adjustment of inspiratory and expiratory positive pressure settings along with maintaining an age-appropriate respiratory rate. Noninvasive positive airway pressure ventilation may be supplied using bilevel positive airway pressure in the spontaneous/timed mode (S/T) or intelligent volume-assured pressured support (iVAPS), with the latter being suggested in case reports as potentially useful for improving patient comfort and adherence compared to typical pressure-controlled means (110).

Negative pressure ventilation has been utilized in patients with congenital central hypoventilation syndrome; however, its use has become limited for a number of reasons, including discomfort and immobility of the patient, device portability, and potential to promote upper airway obstruction due to transmitting a negative pressure within the upper airway lumen. A cuirass or wrap enclosing the patient’s chest is often used to provide negative pressure ventilation and may be used in tandem with bilevel positive airway pressure if upper airway obstruction is a concern.

If central alveolar hypoventilation is a problem only during sleep, nocturnal ventilation is suitable. Because patients with congenital central hypoventilation are at risk for episodes of life-threatening hypoxemia, ventilation during sleep must be regularly assessed, and overnight pulse oximetry with alarms should be used. Transthoracic impedance monitors may fail to detect hypoventilation or obstructive apneas and, therefore, are not recommended. Adequacy of ventilation should be regularly assessed using measures of partial-pressure of carbon dioxide, which may be achieved using end-tidal, transcutaneous, or blood gas measurements. Because of the risk of hypoxemic events, a reliable caregiver with adequate training to respond to emergencies is essential (104).

If ventilation is inadequate during both wakefulness and sleep, diaphragmatic pacing is a practical alternative once the patient is ambulatory. Bilateral pacing is usually required, especially in infants and young children with congenital central hypoventilation syndrome, and it may be successfully implemented in children as young as 9 months of age (25). Diaphragmatic pacing can be utilized in patients either with or without tracheostomy. In a small cohort (N=23) of individuals implanted at a variety of ages and followed for up to 30 years, phrenic nerve pacing afforded independence from tracheostomy and noninvasive ventilation (109). Similar to negative pressure ventilation, there is potential for obstructive apnea to occur if pacing results in decannulation of tracheostomy due to creation of negative intraluminal pressure in the upper airway and vocal cord collapsibility has been observed during paced respiration in congenital central hypoventilation syndrome (26). Risk for obstructive sleep apnea should be assessed prior to decannulation, including consideration for adenotonsillectomy, especially in children. Overnight polysomnography should be considered, and airway obstruction may be mitigated by optimizing stimulator amplitude in response to polysomnographic findings (75; 114).

Overnight in-hospital respiratory evaluations are recommended at least annually in patients over 2 years of age for assessment of ventilator management, including measures of carbon dioxide via capnography or blood gas analysis, pulse oximetry, or polysomnography, and these evaluations often lead to adjustments in ventilator management (93; 27).

As a chronic, potentially life-limiting disease, the diagnosis of congenital central hypoventilation syndrome may significantly affect quality of life in affected patients and their caregivers. A cross-sectional study of quality of life in 271 adolescents and adults with congenital central hypoventilation syndrome demonstrated that the majority of patients reported a good quality of life, although with reduced physical, psychological, and social quality-of-life scores compared to healthy controls (87). Consideration should be given to social surroundings, family support, bed partner, age, life expectancy, and financial situation. Although the condition is serious, it can be controlled with prospects for optimal daytime performance, employment, and social life. Patients can be transitioned from one device to another to obtain optimal management, with consideration for noninvasive nocturnal ventilation or phrenic nerve pacing in those patients with stable alveolar hypoventilation syndromes (11; 109). It is important to remember that families need support with these therapies as parents and caregivers frequently have disturbed sleep (31).

Although congenital central hypoventilation syndrome is classically a permanent condition requiring assisted ventilation, cases have been reported in which clinical improvement or remission was possible using pharmacotherapy. Two children with congenital central alveolar hypoventilation syndrome were successfully weaned from mechanical ventilation with exogenous medroxyprogesterone, and clinical improvement with medroxyprogesterone was also observed in a patient with a right-sided pontomedullary stroke (72; 97). Another case report describes recovery of chemosensitivity to carbon dioxide in a woman with congenital central alveolar hypoventilation syndrome while receiving desogestrel, a potent oral contraceptive (100). This relationship was investigated in a mouse model, which suggested that desogestrel may improve resting ventilation in patients with congenital central hypoventilation syndrome by stimulating baseline respiratory frequency, a known physiological effect of progestins (46). In addition to restoring a degree of CO2 chemoresponsiveness, gonane progestins appear to increase the basal respiratory drive by modulating GABA and NMDA signaling in the respiratory network, medullary serotonergic systems, and supramedullary areas (58). Aside from progestins, the antiepileptic medication carbamazepine improved daytime apneic episodes in a single patient but had no overt effect on sleep-related hypoventilation (91). Although these cases show promise in the development of future pharmacotherapy, additional research is needed, and pharmacological management is unlikely to be sufficient for most patients who ultimately require ventilatory assistance during sleep.

In addition to hypoventilation, patients with congenital central hypoventilation syndrome are also at risk for life-threatening cardiac arrhythmias because of dysregulation of the autonomic system leading to sinus node dysfunction. Cardiac monitoring should be performed annually using routine ECG Holter for 48 to 72 hours to surveil for the emergence of abnormalities, particularly sinus pauses, which can manifest clinically as syncopal events and have been suggested as an independent risk factor for sudden death in congenital central hypoventilation syndrome (38; 104a). Implanted pacemakers may be required, and although there exists potential for electromagnetic interference with diaphragm pacers, these two devices have successfully been used in tandem in several cases (75; 52; 73). Routine pulse oximetry, end-tidal carbon dioxide levels, and frequent checks of the ventilatory system chosen are essential to ensure continued efficacy.

Finally, children with congenital central hypoventilation syndrome may experience progressive worsening of social cognition and executive function; therefore, close monitoring of developmental milestones and serial neurocognitive evaluation, paired with early intervention, should be implemented when needed (28).

Research continues to focus on possible strategies to correct the PHOX2B protein’s location and function. Exciting work in mouse models continues to investigate mechanisms to correct the PHOX2B protein by using molecules involved in protein formation, such as histone deacetylase inhibitors (01).

Outcomes

Over the last few decades, the presentation of central alveolar hypoventilation has evolved from a single disorder of high neonatal mortality to a spectrum of phenotypes, with some congenital cases sometimes being recognized later in life or occurring in association with precipitating CNS pathology. Despite some pharmacologic agents bearing benefits for ventilation (eg, carbamazepine and desogestrel), there is currently no cure for the condition. The mainstays of treatment are lifetime assisted ventilation and multidisciplinary care. However, with carefully coordinated care and safety precautions most individuals are expected to live reasonably normal lives, given that the focus of treatment is resolution of sleep-predominant inadequate sleep drive through invasive and noninvasive ventilatory support or neurostimulation. Patients can have good long-term outcomes with early diagnosis and strategies to optimize assisted ventilation, as shown in a 15-year review of 30 patients with congenital central hypoventilation syndrome (29). In their cohort, 28 received tracheostomy and 26 required assistance with ventilation only in sleep at 9 months of age, demonstrating good survival with close clinical follow-up and multidisciplinary care.

Among individuals with the mutation-based, congenital form of the disease, neurocognitive outcomes are often related to the nature and timing of ventilation. Nonetheless, most individuals generally demonstrate low-average intelligence (104b). Moreover, awareness of other associated conditions – from clinically significant dysautonomia (most importantly lethal asystole) to gastrointestinal dysmotility to neural-crest-cell-derived tumors – has led to a multidisciplinary approach that can effectively assess and manage all dimensions of care resulting in only a modest adverse impact of the condition on patient quality of life (112).

Special considerations

Pregnancy

Patients with congenital central alveolar hypoventilation syndrome often have children of their own. The theoretical hazard of reduced central ventilatory drive in congenital central alveolar hypoventilation syndrome, combined with the mechanical load of the enlarging uterus, mandates frequent respiratory monitoring with mechanical ventilation in sleep and during spontaneous breathing while awake (04). As such, in apparently healthy individuals, late-onset congenital central hypoventilation syndrome might be unmasked by an otherwise uncomplicated pregnancy (98). For patients who require Cesarean section, it is typically performed under general anesthesia, which carries risk. Alternatively, low-dose spinal epidural may be an alternative for some patients (56). In individuals with a known congenital central hypoventilation syndrome phenotype, prenatal PHOX2B gene testing of the fetus is also recommended to plan care of the newborn.

Anesthesia

Anesthesiologists should be made aware of the disorder to plan for appropriate postoperative airway and ventilatory management. Patients with congenital central hypoventilation syndrome are more likely to have an adverse event related to general anesthesia, which may lead to prolonged hospitalization or even tracheostomy (64). A case series of children undergoing diaphragmatic pacemaker placement found that over three fourths of the children had peri or intraoperative events of hypoxemia, hypotension, bradycardia, bronchospasm, hypoventilation, or developed pneumonia or atelectasis (15). One report highlights the following considerations regarding administration of anesthesia to central alveolar hypoventilation patients (76):

	• Regional anesthesia (eg, lumbar epidural) is preferred.
	• Spinal anesthesia should be avoided as it may precipitate hemodynamic instability.
	• Short-acting anesthetic agents are preferred.
	• Due to hypotonia, avoidance of neuromuscular blocker agents during intubation is advised.

In instances where general anesthesia is required, adjunct pharmacologic management may help with postoperative extubation. One case report suggested that caffeine may lead to a more rapid emergence from anesthesia through elevation of ionized cyclic adenosine monophosphate and blockade of the adenosine receptor (22). Comparatively, in individuals with TBI-related acquired central alveolar hypoventilation, a small case series suggested that treatment with 5HT3 receptor antagonist, ondansetron, helped improve ventilator synchrony, potentially through blockade of inhibitory neurons that terminate in the ventral respiratory group (65).

On occasion, congenital central hypoventilation syndrome or central hypoventilation due to brainstem lesions or compression may be unmasked with the use of anesthesia, necessitating anesthesiologists to maintain awareness regarding the condition (63; 113).

Parents of children with congenital central hypoventilation syndrome

Chronic respiratory disease in childhood can be a major stressor for families. The parents of children with congenital central hypoventilation syndrome have poor sleep quality, increased daytime sleepiness, and higher scores on a depression index than the parents of healthy subjects (80). In such cases, it is important to counsel parents and other caregivers on the importance of their own wellness as well as establish cautious but hopeful expectations regarding the efficacy of therapies.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

William I Wooten III MD

Dr. Wooten of East Carolina University has no relevant financial relationships to disclose.
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Editor

Bradley V Vaughn MD

Dr. Vaughn of UNC Hospital Chapel Hill and University of North Carolina School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Christian Guilleminault MD
Michael J Howell MD
James J Herdegen MD
Maha Alattar MD
Bharati Prasad MD
Kevin Gipson MD MS
Payal Kenia MD
Logan Schneider MD

Patient Profile

Age range of presentation: Congenital central alveolar hypoventilation

Typical: 0 months to 1 year

Atypical: 1 year to 65+ years

Acquired central alveolar hypoventilation

Typical: 0 months to 65+ years
Sex preponderance: no sex preponderance
Heredity: Congenital central alveolar hypoventilation

Heredity may be a factor

Autosomal dominant (negative dominant)

Acquired central alveolar hypoventilation

No heredity factors
Population groups selectively affected: Congenital central alveolar hypoventilation

Neonates and children

Acquired central alveolar hypoventilation

No population group selectively affected
Occupation groups selectively affected: Congenital central alveolar hypoventilation

No occupation group selectively affected

Acquired central alveolar hypoventilation

No occupation group selectively affected

ICD & OMIM codes

ICD-10: Congenital central alveolar hypoventilation syndrome: G47.35

Morbid (severe) obesity with alveolar hypoventilation: E66.2

Other specified respiratory conditions of newborn: P28.8

Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: G47.36

Respiratory failure, unspecified: J96.9

Sleep-related nonobstructive alveolar hypoventilation, idiopathic: G47.34
ICD-11: Idiopathic central alveolar hypoventilation: 7A42.3

Congenital central alveolar sleep-related hypoventilation: 7A42.1
OMIM: Central hypoventilation syndrome, congenital; CCHS: #209880

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Central alveolar hypoventilation

Associated Disorders

Congenital central alveolar hypoventilation
Familial dysautonomia
Ganglioneuroblastoma
Hirschsprung disease
Acquired central alveolar hypoventilation
- Brainstem glioma
- Chiari II malformation
- Leigh disease
- Multiple sclerosis
- Obesity

Differential Diagnosis

sepsis
pulmonary infections
cardiopulmonary and neurologic malformations
intoxication
trauma
- neuromuscular disease
- obstructive lung disease
- restrictive lung disease
- ventilation-perfusion mismatch associated with pulmonary emboli
- respiratory muscle weakness
- respiratory muscle fatigue
- neuromuscular disease
- toxins affecting neuromuscular or central nervous system function
- obstructive sleep apnea syndrome
- central sleep apnea syndrome
- Leigh syndrome
- brainstem lesion
- neurocristopathies including Hirschsprung disease
- malignancies of crest cell origin, including congenital neuroblastoma, ganglioneuroblastoma, and benign ganglioneuroma

Also Relevant

Central sleep apnea
Familial dysautonomia
Leigh disease
Parasomnias
Sleep disorders
- Sleep and chronic pulmonary disorders
- Sleep and medical disorders
- Sleep and multiple sclerosis
- Sleep and neuromuscular and spinal cord disorders
- Sudden infant death syndrome

Clinical Categories

Sleep Disorders

	• Incidence is estimated to be anywhere from 1 per 150,000 to 1 per 200,000 live births.
	• Disease prevalence may be underestimated due to variability in phenotype and penetrance and lack of widespread epidemiologic data for PHOX2B mutations.

Central alveolar hypoventilation

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Parents of children with congenital central hypoventilation syndrome

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

Sleep and parkinsonism

Sleep and alcohol use and abuse

Idiopathic hypersomnia

Jet lag disorder

Sleep and multiple sclerosis

Sleep and aging

Sleep and chronic pulmonary disorders

Environmental and behavioral sleep disorders

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