AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The appropriate 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. Because Ondine did not actually curse the mortal (it was her king) and the approximately 300 children worldwide with CCHS do not 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 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 CCHS.

Although the cases described by Severinghaus and Mitchell were markedly different from the typical cases in infants with CCHS, the term Ondine curse gained wide acceptance to denote CCHS in infants and children. In recent years, the term has fallen out of favor. Children with CCHS have progressive hypercapnia and hypoxemia when asleep, particularly during light and deep sleep and, to a lesser extent, during rapid eye movement (REM) sleep. Unfortunately, patients with CCHS 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 the last couple of years in determining the genetic basis of CCHS 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 CCHS 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 CCHS 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 related to 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 CCHS. Although initial studies show mutation of PHOX2B in 62% of patients with CCHS in France and 40% in Japan, more recent studies have identified mutations of the PHOX2B gene in almost 93-100% of probands with CCHS (Trochet, 2005; Berry-Kravis, 2006). 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 exon 3 of PHOX2B.

Marazita et al reported on 20 individuals with unique protein-altering mutations in other genes, as follows:

• 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 CCHS. Parental samples from these families were analyzed. The ret, GDNF, BDNF, and HASH1 mutations were not associated with CCHS. Therefore, the role of mutations in genes other than PHOX2B in CCHS causation is unclear. These mutations could be benign or pathogenic polymorphisms. For a complete discussion, see Weese-Mayer DE, Berry-Kravis EM: Genetics of congenital central hypoventilation syndrome: Lessons from a seemingly orphan disease. Am J Resp Crit Care Med 2004; 170: 16-21.

Conflicting data exist about whether family members of people with CCHS are also affected. On one hand, family members of people with CCHS do not have evidence of respiratory control dysfunction. On the other hand, many family members have some derangement in ANS function.

Autonomic nervous system dysfunction

Some investigators believe that ANS dysfunction is universally present in varying degrees in patients with CCHS (O'Brien, 2005). 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 CCHS, lending further support to the notion that significant dysregulation of central ANS control is common in patients with CCHS. Research is now directed at correlating the gene defect with the complex phenotypic expression that indicates ANS imbalance.

Structural central nervous system abnormalities

Based on the initial premise that CCHS 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. More recently, 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 CCHS. Thus, more than one brain region is likely affected in CCHS, and accurate mapping of the several regions involved may provide some clues to the type and function of neurons affected by this condition.

Physiologic abnormalities of ventilatory control

Interestingly, despite absent rebreathing ventilatory responses to both hypercapnia and hypoxia, most patients with CCHS 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 CCHS 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 CCHS. 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 and/or rhythmic entrainment of respiration take over and play a significant role in the modulation of breathing during exercise in children with CCHS.

States of alertness exert profound influences on cardiorespiratory control. Respiratory output is primarily controlled by metabolic inputs during non-REM (NREM) sleep. In contrast, during REM sleep, the predominant control is not metabolic; rather, the control is some form of behavioral-like drive, especially during phasic REM sleep.

CCHS is characterized by dysfunction in the metabolic control of breathing; therefore, more severe gas-exchange disturbances occur during NREM sleep. This is clearly in contrast with other respiratory disorders associated with sleep-disordered breathing, such as obstructive and restrictive lung disease, in which gas-exchange abnormalities preferentially occur during REM sleep. These unique findings during NREM 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.

Because ventilatory and arousal responses to respiratory stimuli may at least partially involve separate neural pathways, if children with CCHS have a disorder of chemoreceptor input integration, they may still arouse to respiratory stimuli. To examine this issue, hypercapnic arousal responses were conducted in 8 children with CCHS. Six of the 8 children (75%) aroused to hypercapnia, and one additional child developed tachycardia (>200 bpm) during hypercapnia. Thus, most children with CCHS arouse to hypercapnia during sleep, suggesting that the most probable mechanism for CCHS is a brainstem lesion in the area where input from chemoreceptors is integrated.

Frequency

United States

CCHS is a very rare disorder with an estimated prevalence of 1 per 200,000 live births (Trang, 2005).

International

See In the US. Some speculate that about 300 children worldwide have CCHS (Weese-Mayer, 2006).

Mortality/Morbidity

The clinical outcome of children with CCHS 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.

Race

No differences in the occurrence of CCHS are evident based on race.

Sex

Both sexes appear to be equally affected.

Age

CCHS is present at birth, even though 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical presentation of patients with congenital central hypoventilation syndrome (CCHS) may be quite variable and dependent 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 CCHS 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.

Currently, the accepted school of thought states that this apparent improvement over the first few months of life results 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 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 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. 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 CCHS.
• • The severity of hypoventilation varies considerably. In severe cases, hypoventilation is also present during wakefulness. Late-onset central hypoventilation syndrome has also been described.
  • Patients with CCHS have an absent or blunted ventilatory response to sustained hypercapnia. They also have a depressed ventilatory response to sustained hypoxia.
• Patients with CCHS have disorders of ANS control, with abnormalities in heart rate, blood pressure, and pupil diameter control.
• The enteric nervous system may also be abnormal; about 15-20% of patients with CCHS also have Hirschsprung disease.
• Neural crest–derived tumors such as neuroblastoma are present in about 5% of patients with CCHS. The PHOX2B gene is speculated to be the first gene for which germline mutations can be shown to predispose to neuroblastoma (Gaultier, 2005). 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 (Haddad, 1978).

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 CCHS for a thorough ophthalmologic evaluation is important.
• In CCHS, 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 diagnose of CCHS.
• The proposed diagnostic criteria for CCHS include each of the following:
• • Persistent evidence of sleep hypoventilation (PaCO₂ >60 mm Hg) is present.
  • The onset of symptoms usually occurs during the first year of life.
  • Primary pulmonary disease or neuromuscular dysfunction is absent, which could explain the hypoventilation.
  • No evidence of primary cardiac disease exists.

Causes

PHOX2B is the main disease-causing gene for CCHS, 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 CCHS. 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 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Perform urine collection for amino acids and organic acids to evaluate for metabolic disorders that may occur as recurrent apparent life-threatening events or cyanotic spells.
• For PHOX2B testing, contact Rush University Genetics Laboratory at (312) 942-6298.

Imaging Studies

• Imaging studies of the CNS are strongly recommended. Computerized axial tomographic scans of the brain have been used in the past but have a low yield in the evaluation of brainstem regions because of bone-air interface reconstruction artifacts. Thus, when CCHS is suspected, T1 and T2 MRI testing is currently the recommended imaging approach for anatomic evaluation of the CNS. If Hirschsprung disease is present, consider extending the MRI study to include the spine to evaluate for the presence of ganglioneuromata in selected patients with suspected neurocristopathy.
• Perform cardiac evaluation, including chest radiography and echocardiography.
• Perform diaphragm fluoroscopy, ultrasonography, or both to rule out unilateral or bilateral diaphragmatic paralysis or paresis. On occasion, measuring maximal transdiaphragmatic pressures against an occluded airway when the patient is crying and breathing 100% oxygen or, preferentially, a mixture that contains 95% oxygen and 5% carbon dioxide may be useful.

Other Tests

• Although specific methods for establishing the diagnosis of congenital central hypoventilation syndrome (CCHS) vary among medical centers, the following guidelines for evaluation of a patient exemplify a typical approach in a tertiary center:
• • Administer a polysomnographic study in a well-equipped laboratory to carefully determine respiratory patterning and gas-exchange abnormalities during different behavioral 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. Periodically repeat these studies because significant developmental changes occur in sleep and respiratory patterns during the first year of life. A sleep study needs to 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 proposed diagnostic criteria, they are an essential 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, in a semiquantitative fashion, 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.
  • At a later stage, pursue more quantitative measurements with a mask and pneumotachograph if the patient is awake or by incorporating a pneumotachograph to the ventilator circuit if the patient is asleep. These studies must be conducted in each of the defined states (ie, waking, REM, NREM) so they can be incorporated into the polysomnographic evaluation described above.
• Obtain an electrocardiogram as part of the cardiac evaluation.
• If extensive hypotonia is present, nerve conduction studies and electromyography (EMG) may be required after extensive clinical neurologic assessment.

Procedures

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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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
  • Infants with CCHS may have significant hypotonia and temporary feeding difficulties. In addition, moderate-to-severe gastroesophageal reflux is frequently present. Initiate early administration of prokinetic agents and antireflux medications in patients with hypotonia, temporary feeding difficulties, and gastroesophageal reflux; furthermore, begin nasogastric feeding to provide adequate nutrition. More radical approaches (eg, 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. Although little attention has been given to the visual system of children with CCHS, 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.
• Respiratory stimulants: Attempts to enhance the respiratory stability and promote eucapnia in patients with CCHS failed when pharmacologic approaches were used. Trials with doxapram in 2 infants and with the carotid body stimulant almitrine bismesylate in 13 patients did not show consistent improvements in spontaneous ventilatory or gas-exchange parameters. Therefore, respiratory stimulants have no current role in the treatment of CCHS.
• 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 tracheotomy. The types of positive-pressure ventilators used in the home vary among centers and have gradually evolved, reflecting the dynamic needs of the population of patients with CCHS and the technical developments in the field.
  • Most of the ventilators are volume cycled and pressure limited and most are used in the spontaneous intermittent mandatory ventilation (SIMV) mode. They provide a set tidal volume; therefore, to compensate for air leaks around the tracheotomy tube, increasing volume and peak airway pressure is usually necessary.

    Pressure plateau ventilation is suggested to be a useful alternative in home mechanical ventilation of children with CCHS who are not receiving adequate ventilation with standard volume ventilation using demand compressor ventilators. The pressure-limited plateau ventilatory technique uses a volume ventilator but in a pressure-limit assist/control mode. Therefore, large volumes can be dialed as tidal volume into the ventilator. Because pressure is limited, the excess volume, which was not used to achieve the pressure plateau with each breath, is discarded via the pressure relief valve. This approach allows for breath-by-breath compensation of variable leaks. Pressure plateau ventilation is particularly useful in young patients and obviates the need for cuffed tubes or the use of ventilators that require continuous gas flow.

  • 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 usually recommended. Indeed, this type of mild nighttime hyperventilation in optimal conditions, such as the sleep laboratory, has been noted to improve daytime spontaneous ventilation and gas exchange in patients with CCHS who require only nighttime ventilatory support.
• Noninvasive ventilatory support
  • Experience with negative-pressure ventilation in patients with CCHS has been favorable; however, it is restricted to only a few centers in the United States and the world. This ventilatory modality is cumbersome and requires significant equipment adjustments over time. In addition, noninvasive ventilatory support may be associated with upper airway obstruction in younger children with CCHS, most probably elicited by absent pharyngeal dilator activation during non–centrally mediated inspiration.
  • More recently, transition from invasive mechanical ventilation to nasal mask ventilation has been reported in patients with CCHS who are older than 7-8 years and who were nocturnally dependent on the ventilator. This transition generally fails in patients younger than 5 years or in children who require daytime ventilatory support; however, recent reports of infants receiving adequate noninvasive ventilatory support for more than 2 years suggest that nasal mask ventilation may be a viable option in selected patients, even at younger ages.
• Diaphragm pacing
  • Daytime diaphragm pacing in children with CCHS provides greater mobility than mechanical ventilation (Shaul, 2002). 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.
• • Major disadvantages of diaphragm pacing include cost, discomfort associated with surgical implantation, and potential need for repeated surgical revisions because of pacer malfunction. Despite these potential limitations, most parental reports regarding diaphragm pacing are favorable. The recent development of a quadripolar electrode offers several advantages that primarily include greater durations of diaphragmatic pacer support at diminished risk of phrenic nerve damage, diaphragmatic fatigue, and optimization of pacing requirements during exercise.
  • Deciding on the most appropriate type of ventilatory support requires referral to specialized centers with personnel experienced in diaphragm pacing.

Surgical Care

Surgical interventions include traditional procedures.

• Tracheotomy 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.

Consultations

The diagnostic evaluation of patients with CCHS requires a multidisciplinary approach involving many specialists.

• Neurologist: Consultation with a pediatric neurologist is required in the evaluation of hypotonia, any central pathology associated with hypoventilation, or seizure activity (seizures can occur in some children with CCHS spontaneously or as a result of acute hypoxia). Nerve conduction studies, 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.
• 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 health care 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 CCHS can lead active lives and are not restricted from any of the usual activities engaged 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

As noted in Treatment, the use of medications is restricted to the treatment of associated diseases rather than the primary disorder, which requires some sort of ventilatory support. These patients frequently have problems with gastroesophageal reflux.

Drug Category: Prokinetic agents

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. In addition, adequacy of ventilatory support must be established based on an overnight sleep study in the laboratory.
• The CCHS family network provides community support.

Complications

• Major complications of CCHS relate to delay in diagnosis or to complications associated with procedures (eg, tracheostomy, gastrostomy tube, colostomy).
• Rarely, patients may develop neural crest–derived tumors (eg, ganglioneuroma, neuroblastoma, ganglioneuroblastoma).

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/or seizure disorders are frequent in older patients who may not have benefited from prompt recognition or intervention.

Patient Education

• For excellent patient education resources, visit eMedicine's Children's Health Center. Also, see eMedicine's patient education article Sudden Infant Death Syndrome (SIDS).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The major medicolegal situations that may develop primarily involve the delayed diagnosis of congenital central hypoventilation syndrome (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 known associations between exposure to chemicals during a particular phase of pregnancy and ultimate development of CCHS exist.
• 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 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.

Special Concerns

• CCHS is a diagnosis of exclusion. This means that cardiac, neurologic, pulmonary, and generalized disorders need to be excluded before the diagnosis of CCHS is established.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• American Thoracic Society. Idiopathic congenital central hypoventilation syndrome: diagnosis and management. Am J Respir Crit Care Med. Jul 1999;160(1):368-73. [Medline]. [Full Text].
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• Chiaretti A, Zorzi G, Di Rocco C, et al. Neurotrophic factor expression in three infants with Ondine's curse. Pediatr Neurol. Nov 2005;33(5):331-6. [Medline].
• Fleming PJ, Cade D, Bryan MH, Bryan AC. Congenital central hypoventilation and sleep state. Pediatrics. Sep 1980;66(3):425-8. [Medline].
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• Gaultier C, Trang-Pham H, Praud JP. Cardiorespiratory control during sleep in the congenital central hypoventilation syndrome. Pediatr Pulmonol. 1997;23:140-142.
• Gozal D. Congenital central hypoventilation syndrome: an update. Pediatr Pulmonol. Oct 1998;26(4):273-82. [Medline].
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• Marazita ML, Berry-Kravis EM, Weese-Mayer DE. Congenital Central Hypoventilation Syndrome. GeneReviews. 2004;2-3. [Full Text].
• O'Brien LM, Holbrook CR, Vanderlaan M, et al. Autonomic function in children with congenital central hypoventilation syndrome and their families. Chest. Oct 2005;128(4):2478-84. [Medline].
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Article Last Updated: Nov 27, 2006