Congenital Central Hypoventilation Syndrome
Author: Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Coauthor(s): Cyrus M Shahriary, MD, Fellow, Pediatric Pulmonology, University of California at Irvine, Miller Children's Hospital; David Gozal, MD, Vice-Chairman of Research and Director, Kosair Children's Hospital Comprehensive Sleep Medicine Center, Professor, Department of Pediatrics, University of Louisville
Contributor Information and Disclosures
Updated: Dec 19, 2008
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Overview
Differential Diagnoses & Workup
Treatment & Medication
Follow-up
References
Keywords
Introduction
Background
The preferred nomenclature for the disorder known as Ondine curse is congenital central hypoventilation syndrome (CCHS). The literary misnomer "Ondine's curse" has been used in prior literature. In the story of Ondine, a German folk epic, the nymph Ondine falls in love with a mortal. When the mortal is unfaithful to the nymph, the king of the nymphs places a curse on the mortal. 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.
Congenital central hypoventilation syndrome should be considered in children with episodic or sustained hypoventilation and hypoxemia in the first months of life without obvious cardiopulmonary or neuromuscular disease. Most patients breathe normally while awake but hypoventilate during sleep. In 1962, Severinghaus and Mitchell coined the term Ondine curse to describe a syndrome that manifested in 3 adult patients after high cervical and brainstem surgery. When awake and summoned 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 congenital central hypoventilation syndrome.
Children with congenital central hypoventilation syndrome have progressive hypercapnia and hypoxemia when asleep, particularly during quiet sleep and, to a lesser extent, during rapid eye movement (REM) sleep. Unfortunately, patients with congenital central hypoventilation syndrome also lack an arousal response to hypoxemia and hypercapnia. Therefore, mechanical ventilation is the only therapeutic option. However, ventilation can be adequate while the patient is awake.
Pathophysiology
Remarkable progress has been made in determining the genetic basis of congenital central hypoventilation syndrome and in recognizing that this disordered respiratory control syndrome actually represents a more global phenomenon of autonomic nervous syndrome (ANS) dysregulation.
A genetic defect for congenital central hypoventilation syndrome has been speculated because of its occurrence in certain families, suggesting a codominant Mendelian inheritance of a major gene. Vertical transmission has been reported in at least 5 women, and symptoms of ANS dysfunction in families are prevalent. Approximately 20% of all reported congenital central hypoventilation syndrome cases are accompanied by Hirschsprung disease. The association of these 2 relatively rare clinical entities suggests a possible common pathogenetic basis.
Initial attempts at identifying the gene were directed at genes known to be associated with Hirschsprung disease, including receptor tyrosine kinase (ret), endothelin-signaling pathway genes, glial-derived neurotrophic factor, and other genes involved in neural crest cell migration and ANS development. However, many of these mutations occur in family members who do not have congenital central hypoventilation syndrome. Although initial studies show mutation of PHOX2B in 62% of patients with congenital central hypoventilation syndrome in France and 40% in Japan, more recent studies have identified mutations of the PHOX2B gene in almost 93-100% of probands with congenital central hypoventilation syndrome.1,2 PHOX2B is located on chromosome 4p12 and was initially identified in mice deficient in PHOX2B that died in utero with absent ANS circuits. The specific mutation appears to be a polyalanine repeat expansion in the second polyalanine repeat sequence in exon3of PHOX2B.
Weese-Mayer et al (2004) reported on 20 individuals with unique protein-altering mutations in other genes, as follows:3
Eight unrelated individuals had ret mutations.
One individual had a GDNF mutation.
One individual had an EDN3 mutation.
One individual had a BDNF mutation.
Five individuals had HASH1 mutations.
One individual had a PHOX2A mutation.
One individual had a GFRA1 mutation.
One individual had a BMP2 mutation.
One individual had an ECE1 mutation.
Nine of 16 individuals evaluated had PHOX2B polyalanine repeat expansion mutations. Three of these 9 patients were identified as having ret mutations, 3 with HASH1 mutations, one with a GDNF mutation, one with a BDNF mutation, and one with a GFRA1 mutation. The PHOX2B repeat expansion mutations were associated with congenital central hypoventilation syndrome. Parental samples from these families were analyzed. The ret, GDNF, BDNF, and HASH1 mutations were not associated with congenital central hypoventilation syndrome. Therefore, the role of mutations in genes other than PHOX2B in congenital central hypoventilation syndrome causation is unclear.
Whether family members of people with congenital central hypoventilation syndrome are also affected is unclear. On one hand, family members of people with congenital central hypoventilation syndrome do not have evidence of respiratory control dysfunction. On the otherhand, many family members have some derangement in ANS function.
ANS dysfunction
Some investigators believe that ANS dysfunction is universally present in varying degrees in patients with congenital central hypoventilation syndrome.4 They cite reports that show abnormal development of neural crest-derived cells, decreased heart rate variability, diminished pupillary light responses, breath-holding spells, poor temperature regulation, sporadic profuse sweating episodes with cool extremities, blood pressure fluctuation, and abnormal esophageal motility. Vagally mediated syncope or asystole may also occur in children with congenital central hypoventilation syndrome, lending further support to the notion that significant dysregulation of central ANS control is common in patients with congenital central hypoventilation syndrome.
Research is now directed at correlating the gene defect with the complex phenotypic expression that indicates ANS imbalance. A disturbance of cardiac autonomic regulation in congenital central hypoventilation syndrome may indicate thepossibility 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.
Structural CNS abnormalities
Based on the initial premise that congenital central hypoventilation syndrome is associated with a centrally located defect, multiple attempts, albeit unsuccessful, have been made over the years to identify structural CNS abnormalities. Despite careful radiologic surveys of the brain in more than 20 patients with CCHS, no recognizable lesion accountable for the unique manifestations of this syndrome could be found. Noninvasive functional MRI approaches, which provide functional topographic maps of the brain in response to the application of specific ventilatory challenges, have been used to show that the extent and location of several neural sites undergoing neuronal activity increase during carbon dioxide challenge.
This increase markedly differs between control children and children with congenital central hypoventilation syndrome. Thus, more than one brain region is likely affected and accurate mapping of the several regions involved may provide some clues to the type and function of neurons affected by this condition. In one study using a 3.0-Tesla MRI unit, mean diffusivity (MD) values, which suggest regional alterations or injury, were increased in areas classically associated with autonomic and respiratory control, such as brainstem sites.5
Physiologic abnormalities of ventilatory control
Interestingly, despite absent rebreathing ventilatory responses to both hypercapnia and hypoxia, most patients with congenital central hypoventilation syndrome are able to maintain adequate spontaneous ventilation during wakefulness, and this ability probably relates to residual peripheral chemoreceptor function in these patients (ie, positive response to transient changes in carbon dioxide or oxygen concentration in respired gas).
Because chemoreceptors are considered to be important controllers of ventilation during exercise and because parents of children with congenital congestive hypoventilation syndrome do not report major limitations in the ability of their children to participate in regular physical activities, incremental exercise tests on a treadmill were performed in children with congenital central hypoventilation syndrome. These studies showed that movement of the lower limbs exerts a dominant influence on the respiratory rate and, consequently, on the increase of minute ventilation during exercise.
These findings were confirmed when similar increases in ventilation were found during application of passive motion in these children. Thus, in a setting of deficient integration of respiratory control inputs, mechanoreceptor afferent input from muscles and joints, rhythmic entrainment of respiration, or both take over and play a significant role in the modulation of breathing during exercise in children with congenital central hypoventilation syndrome.
Congenital central hypoventilation syndrome is characterized by dysfunction in the metabolic control of breathing; therefore, more severe gas-exchange disturbances occur during non-REM sleep. This is clearly in contrast with other sleep-disordered breathing, such as obstructive asleep apnea syndrome, in which gas-exchange abnormalities preferentially occur during REM sleep. These unique findings during non-REM sleep suggest that the intrinsic defect in congenital central hypoventilation syndrome is always present but becomes more prominently expressed at times when other overlapping mechanisms are less active or inoperative.6
Because ventilatory and arousal responses to respiratory stimuli may at least partially involve separate neural pathways, if children with congenital central hypoventilation syndrome have a disorder of chemoreceptor input integration, they may still arouse to respiratory stimuli. Marcus et al (1991) showed that most children with congenital central hypoventilation syndrome aroused to hypercapnia.7 This suggests that the most probable mechanism for congenital central hypoventilation syndrome is a brainstem lesion in the area where input from chemoreceptors is integrated.
Also, noradrenergic dysregulation has been reported in human pathologies that affects 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).
Frequency
United States
Congenital central hypoventilation syndrome is a very rare disorder with an estimated prevalence of 1 case per 200,000 live births.8
International
Some speculate that about 300 children worldwide have congenital central hypoventilation syndrome.3
Mortality/Morbidity
The clinical outcome of children with congenital central hypoventilation syndrome has markedly changed since the description of the disorder. In the past, most patients presented with neurocognitive deficits of varying severity, 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 have also been associated with congenital central hypoventilation syndrome. Therefore, the prognosis depends on adequate treatment of the underlying tumor.
Race
No differences in the occurrence of congenital central hypoventilation syndrome are evident based on race.
Sex
Both sexes appear to be equally affected.
Age
Congenital central hypoventilation syndrome 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.
Clinical
History
The clinical presentation of patients with congenital central hypoventilation syndrome (CCHS) may widely vary and depends on the severity of the hypoventilation disorder. Some infants do not breathe at birth and require assisted ventilation in the newborn nursery. Most infants with congenital central hypoventilation syndrome 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 (eg, improved respiratory mechanics, postnatal development and compensation) 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 heart failure as the first indications of congenital central hypoventilation syndrome. 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 congenital central hypoventilation syndrome may present with tachycardia, diaphoresis, and/or cyanosis during sleep.
Presumably, if the diagnosis is not made, right heart failure develops as a consequence of repeated hypoxemic and hypercapnic episodes during sleep. Still others may present with unexplained apnea or an apparent life-threatening event; some may even die and be categorized as having sudden infant death syndrome. Thus, the wide spectrum of severity in clinical manifestations dictates the age at which recognition of congenital central hypoventilation syndrome takes place. Increased awareness of this unusual clinical entity and a comprehensive evaluation of every patient are critical for early diagnosis and appropriate intervention.
Sleep-dependent hypoventilation in the absence of neuromuscular, heart, or lung disease is the hallmark of congenital central hypoventilation syndrome.
The severity of hypoventilation widely varies. In severe cases, hypoventilation is also present during wakefulness. Late-onset central hypoventilation syndrome has also been described.
Patients with congenital central hypoventilation syndrome have an absent or blunted ventilatory response to sustained hypercapnia. They also have a depressed ventilatory response to sustained hypoxia.
Patients with congenital central hypoventilation syndrome have disorders of autonomic nervous syndrome (ANS) control, with abnormalities in heart rate, blood pressure, and pupil diameter control. Although baseline heart rate in persons with congenital central hypoventilation syndrome does not differ from controls, the relative increase above the mean heart rate at rest and with exercise is attenuated and heart rate variability is decreased.8 Children with congenital central hypoventilation syndrome exhibit an increased frequency of arrhythmia, primarily sinus bradycardia, and transient asystole, with documented pauses as long as 6.5 seconds in congenital central hypoventilation syndrome compared with 1.4 seconds in controls. Children with congenital central hypoventilation syndrome exhibited lower blood pressure values during wakefulness and higher blood pressure values during sleep compared with controls, indicating attenuation of the normal sleep-related blood pressure decrement.
The enteric nervous system may also be abnormal; about 15-20% of patients with congenital central hypoventilation syndrome also have Hirschsprung disease.
Neural crest–derived tumors such as neuroblastoma are present in about 5% of patients with congenital central hypoventilation syndrome. The PHOX2B gene is speculated to be the first gene for which germline mutations can be shown to predispose to neuroblastoma.9 In 1978, the co-occurrence of Hirschsprung disease and central hypoventilation was named Haddad syndrome and was later expanded to include neuroblastoma, a triad currently known as the neurocristopathy syndrome.10
Physical
Unless Hirschsprung disease is present, no major diagnostic findings are present upon physical examination; in most cases, only subtle manifestations are present.
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.
Gastroesophageal reflux and decreased intestinal motility with constipation are often present in younger patients.
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 congenital central hypoventilation syndrome for a thorough ophthalmologic evaluation is important.
In congenital central ventilation syndrome, ventilation is most severely affected during quiet sleep, the state in which automatic neural control is predominant. Ventilatory patterns are also abnormal during active sleep and even during wakefulness, although to a milder degree. 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.
Other signs indicative of brainstem dysfunction, such as poor swallowing, may be present but are not essential to the diagnosis of congenital central hypoventilation syndrome.
Congenital central hypoventilation syndrome is diagnosed in individuals with the following:11
Hypoventilation with absent or negligible ventilatory sensitivity to hypercarbia and absent or variable ventilatory sensitivity to hypoxemia
Generally adequate ventilation while awake, but hypoventilation with normal respiratory rate and shallow breathing (diminished tidal volume) during sleep
Hypoventilation both while awake and asleep
Absent perception of asphyxia (ie, absent behavioral awareness of hypercarbia and hypoxemia) and absent arousal
No evidence of primary neuromuscular, lung, or cardiac disease or identifiable brain stem lesion that might account for the constellation of symptoms
Causes
PHOX2B is the main disease-causing gene for congenital central hypoventilation syndrome, an autosomal dominant disorder with incomplete penetrance. 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).
Correlations with genotype and phenotype have been described in patients with congenital central hypoventilation syndrome. An association with the number of PHOX2B repeats and the number of ANS dysfunction symptoms and the severity of respiratory disorders have been reported.
Patients with congenital central hypoventilation syndrome 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 congenital central hypoventilation syndrome who are at risk for developing malignant tumors may be identified.
More on Congenital Central Hypoventilation Syndrome
Overview: Congenital Central Hypoventilation Syndrome
Differential Diagnoses & Workup: Congenital Central Hypoventilation Syndrome
Treatment & Medication: Congenital Central Hypoventilation Syndrome
Follow-up: Congenital Central Hypoventilation Syndrome
References
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