Clinical Diagnosis

The American Thoracic Society has issued an updated statement on the diagnosis and management of congenital central hypoventilation syndrome (CCHS) [Patwari et al 2010b, Weese-Mayer et al 2010]. (full text: ; healthcare consumer version: )

CCHS is diagnosed in individuals with the following:

• Hypoventilation with absent or attenuated ventilatory response to hypercarbia and/or hypoxemia
• Generally adequate ventilation while awake and at rest and apparent hypoventilation with monotonous respiratory rate and shallow breathing (diminished tidal volume) during sleep OR apparent hypoventilation while both awake and asleep
• Absent perception of asphyxia (i.e., absent behavioral awareness of hypercarbia and/or hypoxemia) and absent arousal from sleep with development of physiologic compromise secondary to hypercarbia and/or hypoxemia
• No evidence of primary neuromuscular, lung, or cardiac disease or identifiable brain stem lesion that could account for the full constellation of signs and symptoms including autonomic nervous system dysregulation (ANSD)
• Presence of a CCHS-related PHOX2B mutation
• Symptoms of ANSD including but not limited to severe breath-holding spells; lack of physiologic responsiveness to the challenges of exercise and environmental stressors; diminished pupillary light response; esophageal dysmotility; severe constipation even in the absence of Hirschsprung disease; profuse sweating; reduced basal body temperature; and altered perception of anxiety

Molecular Genetic Testing

Gene. PHOX2B is the only gene in which mutations are known to cause CCHS.

PHOX2B has two polyalanine repeat regions in exon 3, the second of which is the region of primary importance in CCHS. This polyalanine repeat comprises any one of four codon combinations — GCA, GCT, GCC, or GCG — as each one encodes the amino acid alanine. The term "GCN" has been used to designate these four codons. The normal number of GCN repeats is 20; benign variants of nine, 13, 14, and 15 repeats have been reported [Amiel et al 2003, Weese-Mayer et al 2003a, Toyota et al 2004].

The two major types of PHOX2B mutations observed in CCHS are:

• Polyalanine repeat expansion mutations (PARMs) of between 24 and 33 repeats [Weese-Mayer et al 2003a; Repetto et al 2009]; and
• Non-polyalanine repeat expansion mutations (NPARMs), mutations that are not specifically polyalanine expansions, including sequence alterations outside of the polyalanine repeat and frameshift mutations affecting the region encoding the polyalanine repeat, which are typically small out-of-frame deletions or duplications of approximately 1 to 38 nucleotides.
  Note: Details of these mutations from all published reports are summarized in Berry-Kravis et al [2006] and Weese-Mayer et al [2010].

Clinical testing

• Targeted mutation analysis (fragment length analysis). This test, referred to as the PHOX2B Screening Test [Weese-Mayer et al 2010], amplifies the region encoding the polyalanine repeat and determines the polyalanine repeat length. Specifically, it detects the polyalanine repeat expansion mutations (PARMs) observed in 92% (185/201) of individuals with CCHS as well as some of the small out-of-frame deletion or duplication non-polyalanine repeat mutations (NPARMs) discussed above [Berry-Kravis et al 2006]. Thus, the PHOX2B Screening Test identifies mutations in approximately 95% of individuals with CCHS. In addition, it is the only clinically available test to identify low-level somatic mosaicism [Jennings et al 2010].
  
  Note: Small out-of-frame small deletions or duplications change the expected length of the PCR fragment and, thus, can also be detected by fragment length analysis; however, the identification of the precise nucleotide changes and confirmation of a frameshift require sequence analysis.
• Sequence analysis. Approximately 8% (16/201) of individuals with CCHS have a PHOX2B missense, nonsense, frameshift, or stop codon mutation, including frameshifts in the polyalanine region described above. As noted above, a subset of these NPARMs are detected by the PHOX2B Screening Test.
• Deletion/duplication analysis. PHOX2B deletions ranging from 6,216 base pairs (involving only PHOX2B exon 3) to 2.6 megabases (involving all of PHOX2B and 12 other genes) have been observed in a small cohort of individuals with clinical findings that may include alveolar hypoventilation or Hirschsprung disease [Jennings et al 2011]. Further study is necessary to elucidate the relationship between PHOX2B haploinsufficiency and the CCHS phenotype [Jennings et al 2011].

Table 1. Summary of Molecular Genetic Testing Used in Congenital Central Hypoventilation Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
PHOX2B	Targeted mutation analysis (fragment analysis; Screening Test 2)	PARMs 3; other out-of-frame NPARMs 4; nucleotide deletions and duplications in the polyalanine repeat region; 35-38 bp deletions; low level mosaicism for PARMs and for NPARMs 5	~95%	Clinical
	Sequence analysis	PARMS detected with targeted mutation analysis	92%
		All NPARMS (i.e., sequence variants not within the polyalanine repeat region) 6	8%
	Deletion / duplication analysis 7	Deletion of exon 3 or whole gene deletion plus other nearby genes 5	<1% 8

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. In individuals with the confirmed CCHS phenotype [Berry-Kravis et al 2006]

2. “Screening Test” refers to the test first described by Weese-Mayer et al [2003a] and developed by Weese-Mayer et al [2010].

3. PARMs= polyalanine repeat expansion mutations

4. NPARMs= non-polyalanine repeat expansion mutations

5. Jennings et al [2011]

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Constitutional polyalanine expansions can be detected, but not low-level mosaicism.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

8. True prevalence of whole-gene deletion of PHOX2B is unknown. Based on Jennings et al [2011], prevalence is likely very low.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband, the American Thoracic Society Statement on CCHS [2010] suggests step-wise PHOX2B testing in persons meeting clinical diagnostic criteria (see for full text):

1.

Targeted mutation analysis (fragment analysis; Screening Test) should be performed to identify the following [Berry-Kravis et al 2006, Bachetti et al 2011, Jennings et al 2011]:

• All the polyalanine repeat expansion mutations (PARMs)
• The 35-bp and 38-bp NPARM deletions
• Low-level mosaicism for these mutations

2.

If no mutation is identified with the Screening Test, perform sequence analysis of the entire PHOX2B coding region and intron-exon boundaries.

3.

If no mutation is identified and if clinical suspicion is high, perform deletion/duplication analysis to determine if an exon 3 or whole-gene deletion is present.
Note: This third step of testing became available after the ATS 2010 Statement was published.

Testing at-risk relatives. The molecular genetic test method used to evaluate parents, children, and at-risk sibs of individuals with CCHS depends on the mutation identified in the proband.

• Targeted mutation analysis (fragment length analysis; Screening Test) is used to evaluate relatives if the proband has a PARM or one of the large NPARMs (35- and 38-bp deletions).
  Note: Use of methods (i.e., the Screening Test) to identify low-level mosaicism in a parent is appropriate.
• Sequence analysis is used to evaluate the relatives of a proband who has a mutation that does not involve the polyalanine expansion; however, low-level mosaicism may not be detected using sequence analysis.
• Deletion/duplication analysis is used when the proband has an exonic, multiexonic, or whole-gene deletion.
• Parents of a proband who has the 20/24 genotype or the 20/25 genotype (i.e., 20 CGN repeats on one allele and 25 CGN repeats on the other allele) should be tested for the PHOX2B mutation with the Screening Test to determine if they are at risk for later-onset CCHS (LO-CCHS).
• Note: Germline mosaicism in a parent of a proband is rare and cannot be identified with molecular genetic testing of leukocytes or tissues other than germ cells.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) disorders

No other phenotypes are known to be associated with CCHS-related mutations in PHOX2B.

Benign allelic PHOX2B variants in intron 2 and in exon 3 have been reported in sudden infant death syndrome (SIDS) [Rand et al 2006] and Hirschsprung disease (HSCR) [Garcia-Barcelo et al 2003]. The significance of these variants in causation of these diseases is unknown at this time, though they are clearly not disease-defining in terms of the CCHS phenotype.

Schizophrenia and strabismus have been associated with the polyalanine repeat contraction variants in the PHOX2B polyalanine repeat tract observed in control populations without CCHS [Toyota et al 2004].

PHOX2B mutations have been reported in sporadic neuroblastoma [van Limpt et al 2004].

Natural History

Congenital central hypoventilation syndrome (CCHS) represents the extreme manifestation of autonomic nervous system (ANS) dysregulation (ANSD), with a hallmark of disordered respiratory control [Weese-Mayer et al 2010].

Classic CCHS is characterized by adequate ventilation while the individual is awake and apparent hypoventilation with monotonous respiratory rates and shallow breathing (diminished tidal volume) during sleep. More severely affected children hypoventilate both when awake and when asleep [Weese-Mayer et al 2010]. Children who hypoventilate both when awake and when asleep typically present in the newborn period, as do the vast majority of children who hypoventilate only when asleep. The salient respiratory and cardiac findings of CCHS are summarized in Table 2.

Autonomic nervous system dysregulation (ANSD) [Marazita et al 2001, Weese-Mayer et al 2001]. As would be expected in consideration of the role of PHOX2B in development of the autonomic nervous system [Howard et al 2000], children with CCHS have manifestations of ANSD (Table 3 and Table 4).

Physiologic evidence for ANSD [Faure et al 2002, O'Brien et al 2005, Trang et al 2003, Trang et al 2005]. Cardiovascular symptoms of ANSD include disturbances of heart rate and blood pressure.

• Although baseline heart rate 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 [Silvestri et al 1995, Trang et al 2003, Trang et al 2005].
• The frequency of arrhythmia is increased, primarily sinus bradycardia and transient asystoles, with documented pauses as long as 6.5 seconds in CCHS vs 1.4 seconds in controls [Silvestri et al 2000]. (See also Genotype-Phenotype Correlations).
• Blood pressure values are lower during wakefulness and higher during sleep (vs controls), indicating attenuation of the normal sleep-related blood pressure decrement [Trang et al 2003].
• Capacity to elevate blood pressure on standing and head-up tilt positions is limited; the normal standing-related blood pressure overshoot is absent [Trang et al 2005].

Many successfully ventilated individuals with CCHS are now in their 20s, suggesting the potential for a normal life span. The cause of death in individuals with CCHS is usually related to suboptimal ventilatory support or involvement with substances that could affect judgment or ventilation [Chen et al 2006]. Development of asystoles is another potential cause of sudden death in CCHS [Gronli et al 2008] among individuals with a prolonged R-R interval who have not received a cardiac pacemaker [Antic et al 2006] or in individuals who are not rigorous about monthly cardiac pacemaker assessment (e.g., the battery life is depleted or the pacemaker malfunctions).

Neurocristopathy (i.e., altered development of neural crest-derived structures) including Hirschsprung disease, congenital absence of parasympathetic intrinsic ganglion cells of the hindgut, in 16%-20% of individuals with CCHS. Hirschsprung disease typically presents in the newborn period, although it has been diagnosed later in infancy and early childhood. (See also Genotype-Phenotype Correlations).

Tumors of neural crest origin including neuroblastoma, ganglioneuroma, and ganglioneuroblastoma, observed in 5%-6% of children with CCHS [Trochet et al 2005b, Berry-Kravis et al 2006]. The tumors can present at variable ages: neuroblastoma typically before age two years; ganglioneuromas later as incidental findings. Tumor-related deaths are uncommon. (See also Genotype-Phenotype Correlations).

Later-onset CCHS (LO-CCHS) with PHOX2B mutations is characterized by alveolar hypoventilation during sleep and symptoms of autonomic nervous system dysregulation (ANSD); however, onset is in later infancy, childhood, or adulthood.

LO-CCHS results from reduced penetrance of certain PHOX2B mutations: genotypes 20/24 (i.e., 20 CGN repeats on one allele and 24 CGN repeats on the other allele) and 20/25, and rarely an NPARM or homozygosity for an allele coding for 24 alanine repeats.

LO-CCHS needs to be considered in individuals who do not have the characteristic CCHS phenotype, including:

• Those with the following:
  • Apparent life-threatening events and cyanosis during sleep;
  • Recurrent severe pulmonic infections with related hypoventilation;
  • Unexplained seizures;
  • Respiratory depression after anti-seizure medication, sedation, or anesthesia;
  • Unexplained neurocognitive delay with any history of prior cyanosis;
  • Unexplained nocturnal hypercarbia and hypoxemia;
  • Unresolved central alveolar hypoventilation after treatment for obstructive sleep apnea;
  • Seeming unresponsiveness to conditions of apparent hypercarbia or hypoxemia (prolonged underwater swimming, pneumonia);
• Infants and children who die suddenly and unexpectedly (“SIDS” and “sudden unexplained death of childhood [SUDC]”).

See ATS Statement at for more details.

Individuals* reported with LO-CCHS and a confirmed PHOX2B PARM or NPARM include the following:

• Two children [Matera et al 2004]
• One child [Trang et al 2004]
• One 35-year-old (presenting with respiratory failure) and his two daughters [Weese-Mayer et al 2005b]
• Five children [Trochet et al 2005b]
• Five adults presenting after age 21 years [Antic et al 2006]
• One adult [Diedrich et al 2007]
• Five family members presenting from childhood to adulthood [Doherty 2007]
• One adult [Barratt 2007]
• One child
• One child [Little 2008]
• Seventeen patients presenting between ages six months and 55 years [Trochet et al 2008]
• Five patients presenting from childhood to adulthood [Parodi 2008]
• One child [Repetto et al 2009]
• One child [Fine-Goulden et al 2009]
• One family presenting from neonatal period to adulthood [Lee et al 2009]
• One family presenting from neonatal period to childhood [Trivedi et al 2010]
• One child [Onal & Ersen 2010]
• One adult [Lovell et al 2010]

* Some individuals appear in more than one report.

Genotype-Phenotype Correlations

Respiratory. A correlation between the PHOX2B polyalanine repeat expansion mutation (PARM) length and the severity of the respiratory phenotype and associated symptoms has been observed [Weese-Mayer et al 2003a, Matera et al 2004, Berry-Kravis et al 2006].

ANSD. Association between the PARM length and quantitative ANSD traits (i.e., number of ANSD symptoms and number of affected systems as described in Weese-Mayer et al [2001] and Marazita et al [2001]) has been investigated [Weese-Mayer et al 2003a].

A significant association was observed between:

• PARM length and number of ANSD symptoms (p=0.02), but not number of ANSD-affected systems (p=0.13);
• PARM length and daily duration of required ventilatory support (p=0.003).

The type of PHOX2B mutation and the length of PARMs determine severity of ANSD. Increasing PARM length is associated with increasing frequency of organ system-specific physiologic ANSD. In contrast, the non-polyalanine repeat expansion mutations (NPARMs) known to have structural ANSD have less physiologic ANSD than PARMS [Patwari et al 2009].

Hirschsprung disease. Individuals with the 20/27 genotype or longer PARMs are at greatest risk for Hirschsprung disease. Nearly all individuals with NPARMs have Hirschsprung disease [Trochet et al 2005b, Berry-Kravis et al 2006].

Tumors of neural crest origin. Individuals with NPARMs have a greater risk of developing a tumor of neural crest origin than those with PARMs. Likewise, individuals with the longest PARMs are at an increased risk (albeit lower than the risk of those with NPARMs) of developing a tumor of neural crest origin [Trochet et al 2005b, Berry-Kravis et al 2006]. Prevalence of tumors of neural crest origin varies by type of PHOX2B mutation with report in PARMs with genotypes 20/29 and 20/33 only and in NPARMs [Amiel et al 2003, Weese-Mayer et al 2003a, Trochet et al 2005b, Weese-Mayer et al 2010].

Cardiac arrhythmia. A positive correlation between longest R-R interval and PARM length was identified among the three most common PHOX2B genotypes (20/25, 20/26, and 20/27). Specifically, the risk for prolonged sinus pauses and the need for a cardiac pacemaker are increased in individuals with PARMs of 20/26 and 20/27 as compared to 20/25 [Gronli et al 2008]. Likewise, a positive correlation between number of children for whom a cardiac pacemaker was recommended and PARM length was identified [Gronli et al 2008].

Facial features. The significant negative correlation between PARM length and four anthropometric measures (mandible breadth, nasolabial angle, lateral lip height, and mandible-face width index) gets smaller as the PARM length increases [Todd et al 2006b].

Dermatoglyphic pattern. No significant association was found between the PARM length and dermatoglyphic patterns [Todd et al 2006a]. However, an increase in arches among girls and an increase in ulnar loops among boys were reported.

Penetrance

Penetrance for the PHOX2B polyalanine repeat expansion mutation appears to be high. Amiel et al [2003], Sasaki et al [2003], Weese-Mayer et al [2003a], Matera et al [2004], and Berry-Kravis et al [2006] found no controls with a PHOX2B polyalanine repeat expansion mutation.

However, the recent identification of CCHS in adults and young children (but not infants) with the 20/24 genotype and the 20/25 genotype indicates reduced penetrance in early childhood for this specific genotype. This also appears to be true for a small subset of the NPARMs [Berry-Kravis et al 2006].

Anticipation

Limited data suggest that the polyalanine expansion in PHOX2B is meiotically stable. Many reports have documented a stable number of repeats during parent to child transmission, including instances of parental mosaicism for the expansion [Weese-Mayer et al 2003a, Trochet et al 2005b, Weese-Mayer et al 2005b, Antic et al 2006]. In all instances in which the PHOX2B polyalanine repeat expansion mutation was transmitted from a parent with CCHS to a child with CCHS or from a mosaic parent to a child with CCHS, no change was observed in the number of repeats (i.e., parent and child had mutated alleles of the same size).

Nomenclature

The appropriate nomenclature for this disorder is congenital central hypoventilation syndrome (CCHS).

A literary misnomer, "Ondine's curse," has been used in the past. In the German folk epic [Sugar 1978], the nymph Ondine falls in love with a mortal. When the mortal is unfaithful to Ondine, the king of the nymphs places a curse on the mortal that makes him 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 was not the one who cursed the mortal, individuals with CCHS do not forget to breathe, and individuals with CCHS are not “cursed,” the term “Ondine's curse” is a misnomer and should be discouraged.

Haddad syndrome refers to the co-occurrence of CCHS and Hirschsprung disease; the term is not widely used.

Prevalence

With the introduction of clinically available molecular genetic testing for PHOX2B, it has become apparent that CCHS is no longer as rare as previously considered. Current estimates of at least 1,000 individuals worldwide [Weese-Mayer et al 2009, Weese-Mayer et al 2010] are likely an underestimate because of the variable severity observed in later-onset CCHS (LO-CCHS).

The only population study in the literature thus far was performed in Taiwan [Hung et al 2007]. To date no prospective study has ascertained the incidence of CCHS in an ethnically diverse cohort.

From 2005 to 2011, more than 160 additional individuals with a PHOX2B mutation were identified [Authors, personal experience] — an average of 25 new cases per year [Rand et al 2011]. Further, testing of children with atypical presentations (LO-CCHS) who are found to have the 20/24 genotype and the 20/25 genotype continues to be delayed beyond the neonatal period and first year of life [Rand et al 2011].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with congenital central hypoventilation syndrome (CCHS) or later-onset CCHS (LO-CCHS), the following evaluations are recommended:

• Assessment in a pediatric respiratory physiology laboratory, with:
  • Study of spontaneous breathing awake and asleep including (at a minimum) tidal volume, respiratory inductance plethysmography of the chest and abdomen, hemoglobin saturation with pulse waveform, end-tidal carbon dioxide level with visible waveform, and electrocardiogram; and
  • Evaluation of the awake and asleep responses to exogenous and endogenous challenges of hypercarbia and/or hypoxemia.
• Venous or arterial blood gas or serum bicarbonate level to look for elevated carbon dioxide content
• Hemoglobin, hematocrit, and reticulocyte count to assess for polycythemia
• 72-hour Holter recording to assess for abrupt, prolonged asystoles
• Echocardiogram to assess for changes consistent with cor pulmonale
• Ophthalmologic examination (i.e., evaluation of pupillary responses) to assess for evidence of autonomic dysregulation
• Neurocognitive assessment to determine baseline function
• Comprehensive autonomic testing of all organ systems regulated by the ANS

See Table 5 for additional details.

Treatment of Manifestations

Ventilatory support. The treatment goals for classic CCHS are to secure the airway and to use chronic ventilatory support at home to compensate for the altered/absent ventilatory responses to hypoxemia and hypercarbia. Of note, although oxygen administration without artificial ventilation improves the PaO₂ (partial pressure of oxygen in arterial blood) and relieves cyanosis, it is not an adequate treatment of hypoventilation.

Because persons with CCHS may experience complete respiratory arrest or severe hypoventilation and, thus, the sequelae of hypoxemia, they require monitoring of objective measures of oxygenation (i.e., pulse oximeter) and ventilation (i.e., P_ETco₂ monitor) continuously during sleep and periodically while awake. They also require observation and continuous care by an RN trained and experienced in ventilator management.

For each of the options listed below, the goal is to provide the affected individual with the technology optimal for her/his life style needs.

Typically, the infant needing ventilatory support 24 hours per day is most safely and effectively supported via tracheostomy and use of a home mechanical ventilator.

As children who require continuous ventilatory support become ambulatory, diaphragm pacing by phrenic nerve stimulation can be considered to allow for increased mobility and improved quality of life. Diaphragm pacing is not typically recommended for the young child who requires only nighttime ventilatory support because the benefits do not outweigh the risks; however, for older adolescents and young adults, this could be an appropriate consideration.

• Diaphragm pacers for the active child with CCHS should be implanted at each phrenic nerve in the chest, ideally by thoracoscopic technique [Weese-Mayer et al 1996, Shaul et al 2002, Chin et al 2012].
• Older infants and toddlers with diaphragm pacers may be assessed for use of a Passy-Muir one-way speaking valve while awake, allowing for vocalization and use of the upper airway on exhalation.
• Children with diaphragm pacers may be assessed for capping of the tracheostomy tube while awake and paced, thereby allowing for inspiration and exhalation via the upper airway; tracheostomy is typically still required for mechanical ventilation during sleep to avoid upper airway obstruction and physiologic compromise.
• Although not yet accomplished, the older child with an entirely normal airway may be able to eliminate the need for a tracheostomy by relying on diaphragm pacing while awake and on mask ventilation while asleep; however, such a child may require interim endotracheal intubation to allow for optimal oxygenation and ventilation during acute illness that requires more aggressive ventilatory management.

Cooperative older children with CCHS who consistently require ventilatory support only while sleeping may be candidates for non-invasive support with either mask ventilation or negative-pressure ventilation; however, this must be done with careful consideration of each child’s needs. If successful, tracheal decannulation can be considered (with the caveat that in the event of severe illness, interim endotracheal intubation may be required in a pediatric intensive care unit). The child who normally requires ventilatory support during sleep only may, during an intercurrent illness, also require artificial ventilation both awake and asleep.

Note: Strauss et al [2010] reported that the ventilatory response to hypercarbia seemed to improve with the use of birth control pills in two young women with the 20/25 (i.e., 20 CGN repeats on one allele and 25 CGN repeats on the other allele) and 20/26 genotypes.

Cardiac. Prolonged transient asystoles may present as syncope and/or staring spells, and may be of such significant duration (≥3.0 seconds) as to warrant placement of a cardiac pacemaker for management [Silvestri et al 2000, Gronli et al 2008].

Hirschsprung disease. See Hirschsprung Disease Overview.

Tumors of neural crest origin. Neuroblastomas are removed surgically and followed by chemotherapy if they have advanced beyond stage 1. Other tumors of neural crest origin are treated individually by location and type.

Prevention of Secondary Complications

Mask ventilation in the infant and young child is strongly discouraged. Mask ventilation is not adequately stable as a life-sustaining support, with risk for repeated hypoxemia and neurocognitive compromise in the infant and young child. If mask ventilation is used, an actual ventilator is needed as the traditional Bi-PAP machine is not approved for life-sustaining support. Also, close longitudinal follow up by specialists with craniofacial and dental expertise is essential as the potential for doing harm with facial deformation is an important consideration, which may necessitate midface advancement in the teen years.

Surveillance

Agents/Circumstances to Avoid

Ideally, the child with CCHS should not go swimming. If they do, they should be carefully supervised, regardless of the presence or absence of a tracheostomy. Children with CCHS should not compete in underwater swimming contests as they cannot perceive the asphyxia that occurs with drowning and breath-holding and, therefore, are likely to swim longer and farther than children without CCHS, thereby increasing the risk of drowning.

Alcohol (respiratory depression), recreational drugs (varied effects), and prescribed as well as non-prescribed medications/sedatives/anesthetics that could induce respiratory depression should be avoided [Chen et al 2006].

Evaluation of Relatives at Risk

The molecular genetic test method used to evaluate parents, children, and at-risk sibs of individuals with CCHS depends on the mutation identified in the proband (see Testing Strategy). Parents of children with a known PHOX2B mutation should be tested for the family-specific mutation to determine their risk for later-onset CCHS or mosaicism.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

CCHS is inherited in an autosomal dominant manner [Weese-Mayer et al 2003a].

Risk to Family Members

Parents of a proband

• Most individuals with CCHS are heterozygous for a de novo mutation in PHOX2B.
• Some individuals with CCHS have a parent with CCHS [Weese-Mayer et al 2003a, Trochet et al 2005b, Weese-Mayer & Berry-Kravis 2004, Antic et al 2006].
• Somatic and germline mosaicism for a PHOX2B mutation are present in about 5%-10% of asymptomatic parents of individuals with CCHS [Weese-Mayer et al 2003a, Trochet et al 2005b, Berry-Kravis et al 2006]. Parents with mosaicism should have comprehensive physiologic assessment to determine if features of the CCHS phenotype are present.
• Recommendations for the evaluation of parents of a proband with a presumed de novo mutation include testing of both parents for the PHOX2B mutation present in the proband including methods known to detect low-level mosaicism [Jennings et al 2011].

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• If a parent of the proband has mosaicism for the PHOX2B mutation observed in the proband, the recurrence risk to the sibs of the proband is 50% or lower.
• When the parents are clinically unaffected, the sibs of the proband may still be at risk, as mosaicism in asymptomatic parents has been reported and germline mosaicism only (i.e., mosaicism not detected in asymptomatic parents of a proband), although not yet reported, remains a possibility [Weese-Mayer et al 2003a].

Offspring of a proband. Each child of an individual with CCHS has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

PHOX2B polyalanine expansion. PHOX2B has two polyalanine repeat regions in exon 3. The second polyalanine repeat region in exon 3 is the region of primary importance in CCHS. The polyalanine repeat can comprise any one of four codon combinations — GCA, GCT, GCC, or GCG — as each one encodes the amino acid alanine. The term "GCN" has been used to designate these four codons.

Mutations that result in polyalanine expansion have been described as a cause of disease in a number of homeodomain- and non-homeodomain-containing transcription factors including:

• HOXD13 (synpolydactyly)
• HOXA13 (see Hand-Foot-Genital Syndrome)
• RUNX2 (see Cleidocranial Dysplasia)
• ZIC2 (see Holoprosencephaly Overview) [Goodman & Scambler 2001]

There is precedent for polyalanine repeat tract expansion in a homeobox gene as a cause of neurologic disease resulting from presumed failure of specification and/or migration of a specific neuronal cell type. ARX, (the aristaless-related homeobox gene) has been associated with XLAG (X-linked lissencephaly and ambiguous genitalia) [Kitamura et al 2002], X-linked intellectual disability [Bienvenu et al 2002], X-linked and sporadic infantile spasms, and other developmental disorders with intellectual disability and epilepsy [Stromme et al 2002]. ARX contains a polyalanine tract that is expanded in some affected individuals, particularly those with infantile spasms or myoclonic epilepsy. Other affected individuals have missense or truncating mutations that likely result in loss of function.

Mice with mutations in Arx show aberrant differentiation and migration of GABA-ergic neurons in neocortex [Kitamura et al 2002]. Given the expression patterns of PHOX2B in central autonomic structures and peripheral neural crest derivatives and the wide range of ANS dysfunction seen in CCHS, it seems likely that a similar mechanism of aberrant differentiation and/or migration of central and peripheral noradrenergic sympathetic and parasympathetic neurons results from the polyalanine tract expansion in PHOX2B.

Role of PHOX2B in embryogenesis. PHOX2B has an early embryologic action as a transcriptional activator in:

• Promotion of neuronal differentiation including upregulation of expression of proneural genes (including MASH1); and
• Expression of motor neuron differentiation [Dubreuil et al 2002].

PHOX2B has a separate role via a different pathway, in which it represses expression of inhibitors of neurogenesis [Dubreuil et al 2002]. PHOX2B is required for expression of tyrosine hydroxylase (see GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia), dopamine beta hydroxylase (see Dopamine Beta-Hydroxylase Deficiency) [Lo et al 1999], and RET (see Multiple Endocrine Neoplasia Type 2 and Hirschsprung Disease Overview) and for maintenance of MASH1, suggesting that PHOX2B regulates the noradrenergic neuronal phenotype in vertebrates [Pattyn et al 1999]. The importance of PHOX2B early in the embryologic origin of the ANS – with a role in determining the fate of early neuronal cells and a role in disinhibition of neuron differentiation – could account for the seeming imbalance in the sympathetic and parasympathetic nervous system and dysfunction in the enteric nervous system seen in children with CCHS. Studies by Pattyn et al [1997] and Pattyn et al [1999] indicate an early expression pattern of PHOX2B in rhombencephalon, suggesting a link to early patterning events for later neurogenesis in the hindbrain.

In the mouse, Phox2b is expressed in the neonatal CNS, specifically in the area postrema, nucleus tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, ventral surface of medulla, locus coeruleus (until embryonic day 11.5), and cranial nerves III (oculomotor), IV (trochlear), Vll (facial), IX (glossopharyngeal), and X (vagus). Until mid-gestation in the mouse, Phox2b is expressed in the Vth (trigeminal) cranial nerve. In the mouse peripheral nervous system, Phox2b is expressed in the distal VIIth, IXth, and Xth cranial sensory ganglia from embryonic day 9.5 and in all autonomic nervous system ganglia from the time these are formed until at least mid-gestation. Finally, by embryonic day 9-9.5, the Phox2b protein is detected in enteric neuroblasts invading the foregut mesenchyme. It is expressed in the esophagus, small intestine, and large intestine [Pattyn et al 1997, Pattyn et al 1999] and in all undifferentiated neural crest-derived cells in the gut with a rostrocaudal gradient [Young et al 1999]. In the Phox2b knockout mouse, the gut has no enteric neurons and even the neural crest-derived cells that are found in the foregut at E10.5 do not survive or migrate further [Young et al 1999].

The phenotypic findings of CCHS (symptoms of ANSD in the respiratory control system, cardiovascular system, ophthalmologic system, neurologic system, and gastrointestinal system) follow logically from the embryologic distribution of PHOX2B. It remains unclear how the distribution and actions of PHOX2B account for involvement of other systems often included in the ANSD profile of the child with CCHS, including the sudomotor, psychological, and renal systems.

Mutations in other genes have been identified in persons with CCHS (Table 6); their significance is not known.

The PHOX2B repeat expansion mutation segregated with CCHS in families from which parental samples were analyzed, while the RET, GDNF, BDNF, and HASH1 mutations did not. It is unknown to the authors if all individuals with these mutations have been tested for PHOX2B mutations. Therefore, the role of mutations in genes other than PHOX2B in disease causation is unclear; they could be pathogenic or benign polymorphisms. See Weese-Mayer et al [2003a] for a complete discussion.

Normal allelic variants. PHOX2B has a "GCN" repeat in exon 3 that comprises any one of four codon combinations GCA, GCT, GCC, or GCG — each encoding the amino acid alanine. (The term "GCN" has been used to designate these four codons). A 20-repeat length is normal; benign variants of 7, 13, 14, and 15 repeats have been reported [Amiel et al 2003, Weese-Mayer et al 2003a, Toyota et al 2004]

Pathologic allelic variants. GCN tract of 25-33 repeats (For more information, see Table A.) Seventy-six individuals with a non-polyalanine repeat expansion mutation have been identified thus far [Amiel et al 2003, Sasaki et al 2003, Weese-Mayer et al 2003a, Matera et al 2004, Trochet et al 2005a, Berry-Kravis et al 2006, Weese-Mayer et al 2010].

Mutation information is summarized in the ATS statement [Weese-Mayer et al 2010]; click for full text.

Normal gene product. PHOX2B encodes a highly conserved homeobox domain transcription factor (314 amino acids), with two short and stable polyalanine repeats of nine and 20 residues encoded by the GCN repeat in exon 3 [Amiel et al 2003].

Abnormal gene product. Disorders caused by triplet repeat expansions can cause disease through either gain-of-function or loss-of-function mechanisms. There is no CCHS phenotype in mice haploinsufficient for Phox2b (although these mice have dilated pupils and atrophy of the ciliary ganglion) [Cross et al 2004] and nearly all individuals with CCHS have mutations that alter the protein downstream from the homeodomain [Amiel et al 2003, Sasaki et al 2003, Weese-Mayer et al 2003a, Matera et al 2004], suggesting that mutations causing CCHS result in a change in function as opposed to simply reducing the amount of the PHOX2B protein. Because paired-homeodomain proteins such as PHOX2B bind to their target sites on DNA as dimers, PHOX2B mutant proteins that have the binding site intact could potentially act in a dominant-negative manner by interfering with the function of the wild-type protein when it dimerizes with a mutant protein.

Several lines of evidence support a possible dominant-negative mechanism for PHOX2B mutations in CCHS:

• Other polyalanine repeat mutations in homeodomain proteins associated with human disease are thought to act in a dominant-negative fashion (syndactyly and HOXD13 [Goodman et al 1997]; hand-foot-genital syndrome and HOXA13 [Utsch et al 2002]).
• Transcriptional activity of PHOX2B deletion variants (deleted for 1- to 13-alanine residues), was decreased to roughly 50%-70% of wild-type activity, while a disease-associated five-repeat expansion reduced transcriptional activity to about 20% of wild type [Toyota et al 2004].
• Deletion variants and alleles with nine, 13, 14, and 15 alanine repeats as well as an expansion with 22 repeats appear to be population variants not associated with CCHS, while individuals with five repeat expansions may have CCHS and individuals with six or more repeat expansions uniformly have CCHS [Amiel et al 2003, Weese-Mayer et al 2003b, Toyota et al 2004].
• Weese-Mayer et al [2003a] and Matera et al [2004] have shown correlations between polyalanine repeat length in CCHS and severity of autonomic symptoms.

Both polyalanine repeat expansion mutations and non-polyalanine repeat expansion mutations in PHOX2B have been shown to impair transcriptional function; and transcriptional impairment increases with expansion length for polyalanine repeat expansion mutations [Matera et al 2004, Bachetti et al 2005]. For non-polyalanine repeat expansion mutations, the least impairment of transcriptional function, comparable to activity from the smallest (5-repeat) polyalanine expansion, was seen with the 618delC and the 577delG frameshift mutations [Bachetti et al 2005], both of which are -1 frameshifts occurring in the same area of the protein. This is consistent with incomplete penetrance for a small subset of non-polyalanine repeat expansion mutations and the 20/25 genotype (i.e., 20 CGN repeats on one allele and 25 CGN repeats on the other allele). Thus, specific types and locations of mutations may be more likely to present with variable expressivity and reduced penetrance, based on a relatively smaller effect on PHOX2B-mediated transcription than is seen for fully penetrant mutations.

Given the data available from mouse models and humans with CCHS, it is likely that a threshold effect for PHOX2B activity exists, below which the CCHS phenotype is manifest. Thus, loss of an allele is likely insufficient to cause disease in most cases, but activity is likely reduced below the disease threshold in individuals with all but the smallest polyalanine expansion mutations or distal truncating mutations because of a dominant-negative effect on function of the wild-type protein, reducing PHOX2B activity to less than 50%. As intranuclear and intracellular protein aggregates are also seen with certain mutations including longer polyalanine repeat mutations and many non-polyalanine repeat mutations, a gain of function mechanism may also play a role in the CCHS phenotype.

Published Guidelines/Consensus Statements

1. Patwari PP, Lareau S, Sockrider M, Weese-Mayer DE. Congenital central hypoventilation syndrome (CCHS). American Thoracic Society Patient Information Series. Available online. 2010. Accessed 7-6-12.
2. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H, on behalf of the ATS Congenital Central Hypoventilation Syndrome Subcommittee. An official ATS clinical policy statement: congenital central hypoventilation syndrome: Genetic basis, diagnosis, and management. Available online. 2010. Accessed 7-6-12. [PubMed: 20208042]

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Suggested Reading

1. Mellins RB, Balfour HH, Turino GM, Winters RW. Failure of automatic control of ventilation (Ondine's curse). Report of an infant born with this syndrome and review of the literature. Medicine (Baltimore). 1970;49:487–504. [PubMed: 5286083]

Author Notes

Children’s Memorial Hospital
Center for Autonomic Medicine in Pediatrics
Dr Weese-Mayer’s Web page

University of Pittsburgh
School of Dental Medicine

Rush University
Neurological Care Programs
Dr Berry-Kravis’s Web page

ATS Statement on CCHS for health care consumers

Revision History

• 10 November 2011 (me) Comprehensive update posted live
• 24 July 2008 (cd) Revision: Testing Strategy
• 23 February 2007 (me) Comprehensive update posted to live Web site
• 17 December 2004 (me) Comprehensive update posted to live Web site
• 28 January 2004 (me) Review posted to live Web site
• 12 August 2003 (mm) Original submission