DiagnosisClinical DiagnosisThe 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 hypoxemiaGenerally 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 hypoxemiaNo 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 mutationSymptoms 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 anxietyMolecular Genetic TestingGene. 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]; andNon-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 testingTargeted 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency ^{1Test AvailabilityPHOX2BTargeted 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%ClinicalSequence analysis PARMS detected with targeted mutation analysis92%All NPARMS (i.e., sequence variants not within the polyalanine repeat region) 68%Deletion / duplication analysis 7Deletion of exon 3 or whole gene deletion plus other nearby genes 5<1% 81. 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 mutations4. NPARMs= non-polyalanine repeat expansion mutations5. 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.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 StrategyTo confirm/establish the diagnosis in a proband, the American Thoracic Society Statement on CCHS suggests step-wise PHOX2B testing in persons meeting clinical diagnostic criteria [Weese-Mayer et al 2010; 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 deletionsLow-level mosaicism for these mutations2.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.Genetically Related (Allelic) disordersNo 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 HistoryCongenital 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.Table 2. Published Clinical Features of Congenital Central Hypoventilation Syndrome (CCHS)View in own windowClinical FeatureReferencesRespiratory Alveolar hypoventilationWeese-Mayer et al [2010]Lack of normal ventilatory and arousal responses to hypercarbia and hypoxemia Weese-Mayer et al [2010]
Carroll et al [2010]
Patwari et al [2010a]
Carroll et al [2011]Limited breath-to-breath variabilityWeese-Mayer et al [2010]
Weese-Mayer et al [2003b]Cardiac Decreased heart rate beat-to-beat variabilityWoo et al [1992]
Ogawa et al [1993]
Silvestri et al [2000]
Trang et al [2005] Increased ratios of low frequency-band to high frequency-band spectral power and transient asystolesWoo et al [1992]
Ogawa et al [1993]
Silvestri et al [2000] Attenuated heart rate response to exerciseSilvestri et al [1995] Attenuated pulse arterial tonometry signal magnitude following sigh and with cold hand pressor testO'Brien et al [2005] Length of polyalanine repeat expansion mutation (PARM) associated with risk of prolonged sinus pauses and cardiac pacemaker placementGronli et al [2008] FaciesSee footnote 1Todd et al [2006b]DermatoglyphicsSee footnote 2 Todd et al [2006a]1. A characteristic facial phenotype has been described in CCHS [Todd et al 2006b]. The facies are generally shorter and flatter (evidenced by significantly decreased upper-face height, increased nasal tip protrusion, decreased nasolabial angle, decreased upper-lip height) and typically show an inferior inflection of the lateral segment of vermillion border on the upper lip. The significantly decreased facial index and decreased upper facial index (such that the face is short relative to its width) results in the characteristic box-shaped face. The results also suggest that males with CCHS are more significantly affected than females. Using five variables to characterize facies (upper-lip height, biocular width, upper facial height, nasal tip protrusion, and the lip trait), 85.7% of individuals with CCHS and 82.2% of controls were correctly predicted. 2. Dermatoglyphic pattern type frequencies are altered in individuals with CCHS compared to controls. In particular, an increase of arches was observed in females, and an increase of ulnar loops in males. The largest differences were noted for the left hand and for individuals with both CCHS and Hirschsprung disease [Todd et al 2006a].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].Table 3. Physiologic Regulation of the Autonomic Nervous SystemView in own windowFeatures of ANS DysregulationReferencesClinicalSevere constipation even in absence of Hirschsprung diseaseWeese-Mayer et al [1993]
Weese-Mayer et al [2001]Esophageal dysmotility/dysphagia, decreased perception of discomfort, sporadic profuse sweating, decreased basal body temperatureWeese-Mayer et al [1999]
Weese-Mayer et al [2001]
Faure et al [2002] Pupillary abnormalitiesWeese-Mayer et al [1992]
Goldberg & Ludwig [1996]
Patwari et al [2011] Decreased perception of anxietyPine et al [1994]Decreased body temperatureSaiyed et al [2011]AnatomicHirschsprung disease (~16%-20% of individuals) Berry-Kravis et al [2006]
de Pontual et al [2006]
Trochet et al [2005b] Tumors of neural crest origin (e.g., neuroblastoma, ganglioneuroblastoma, and ganglioneuroma)Trochet et al [2005b]
Berry-Kravis et al [2006] Including gastrointestinal, ophthalmologic, psychological, and sudomotor systemsTable 4. Neuropathologic and Neuroimaging FindingsView in own windowFindingReferencesNeuronal loss of reticular nuclei and nearby cranial nerve nuclei (one case)Liu et al [1978] Absent arcuate nucleus (one case)Folgering et al [1979] Hypoxia-induced posterior thalamic, cerebellar, midbrain, and limbic deficitsMacey et al [2005b] Multiple areas of white matter abnormality on brain MRIKumar et al [2005] Abnormal functional MRI (fMRI) brain responses to cold pressor challenge, hypoxia, and hyperoxiaMacey et al [2005a]
Macey et al [2005b]
Woo et al [2005] MRI changes ¹ in:
 • Hypothalamus (responsible for thermal drive to breathing)
 • Posterior thalamus and midbrain (mediating O₂ and oscillatory motor patterns)
 • Caudal raphé and locus coeruleus (regulating serotonergic and noradrenergic systems)
 • Lateral medulla, parabrachial pons, and cerebellum (coordinating chemoreceptor and somatic afferent activity with breathing)
 • Insular and cingulate cortices (mediating shortness of breath perception) Patwari et al [2010a]1. Structural and functional alterations in these sites may be caused by PHOX2B mutations or result from hypoxia/perfusion alterations related to suboptimal management/compliance [Patwari et al [2010a].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 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 childOne 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 CorrelationsRespiratory. 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.

Differential DiagnosisChildren with congenital central hypoventilation syndrome (CCHS) typically present in the newborn period. Studies should be performed to rule out primary neuromuscular, lung, or cardiac disease or an identifiable brain stem lesion that could account for the full constellation of symptoms characteristic of CCHS, including the ANSD. PHOX2B genetic testing (which became available in 2003) allows for distinction between CCHS and other disorders in the differential diagnosis including severe prematurity [Bajaj et al 2005], identifiable brain stem findings that could (but do not) account for the hypoventilation [Bachetti et al 2006], asphyxia, infection, trauma, tumor, and infarction. Because it is anticipated that a growing number of children and adults with a mild CCHS phenotype will be heterozygous for a PHOX2B mutation, the differential diagnosis for unexplained childhood and adult alveolar hypoventilation or adverse event (cyanosis or seizures) secondary to sedation, severe pulmonary infection, or treated obstructive sleep apnea must include CCHS. ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) is distinct from CCHS. ROHHAD was first described more than 45 years ago as “late-onset central hypoventilation syndrome with hypothalamic dysfunction” [Fishman et al 1965]; Katz et al [2000] suggested that it was distinct from CCHS. ROHHAD is a rare disorder characterized by dramatic weight gain over a six- to 12-month period between ages 1.5 and 10 years, which is typically followed by: Hypothalamic dysfunction (altered water balance, hyperprolactinemia, hypothyroidism, altered onset of puberty, growth hormone deficiency, and ACTH insufficiency) [Ize-Ludlow et al 2007, Bougnères et al 2008]; Central alveolar hypoventilation (sometimes preceded by obstructive sleep apnea); and ANSD (altered thermoregulation, diaphoresis, pupillary response, and vasomotor function). The acronym was developed in 2007 by Dr. Ize-Ludlow and colleagues to reflect these findings. Affected children can also have mild to severe behavioral problems; a subset has sympathetic tumors such as ganglioneuroblastomas. Although ROHHAD is suspected to be genetic in origin, candidate gene investigations have not identified a genetic association with any of the following genes: PHOX2B, TRKB, BDNF [Ize-ludlow et al 2007], ASCL1, NECDIN [DePontual et al 2006], HTR1A, OTP, or PACAP [Rand et al 2011]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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; andEvaluation 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 contentHemoglobin, hematocrit, and reticulocyte count to assess for polycythemia72-hour Holter recording to assess for abrupt, prolonged asystolesEchocardiogram to assess for changes consistent with cor pulmonaleOphthalmologic examination (i.e., evaluation of pupillary responses) to assess for evidence of autonomic dysregulationNeurocognitive assessment to determine baseline functionComprehensive autonomic testing of all organ systems regulated by the ANSSee Table 5 for additional details.Treatment of ManifestationsVentilatory 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 ComplicationsMask 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.SurveillanceTable 5. Clinical Evaluations to Characterize CCHS Phenotype Based on PHOX2B MutationView in own windowPHOX2B Mutation Annual In-Hospital Comprehensive Testing ^{1Annual Neurocognitive Assessment Annual 72-hr Holter Recording and ECG Hirschsprung Disease AssessmentTumors of Neural Crest Origin AssessmentPARM: 20/24, 20/25XXXPARM: 20/26, 20/27XXXXPARM: 20/28-20/33XXXXX 2NPARMXX XXX 3Deletion / duplication 4XX XXX 2Adapted from Weese-Mayer et al [2010]PARM = polyalanine repeat expansion mutation with number of repeats on each allele, e.g., 20/24NPARM = non-polyalanine repeat expansion mutation (i.e., missense, nonsense, frameshift, stop codon)1. Awake and asleep physiologic testing in varying levels of concentration and activity; exogenous and endogenous gas challenges; autonomic testing2. Annual chest and abdominal imaging to identify ganglioneuromas and ganglioneuroblastomas and potentially neuroblastomas3. Chest and abdominal imaging and urine cathecholamines every 3 months in the first 2 years, then every 6 months until age 7 years to identify neuroblastomas 4. Exonic or whole-gene deletion or duplicationNote: In infants and those newly diagnosed with LO-CCHS the recommendation is for above-described evaluation every 6 months until age 3 years (or 3 years from the LO-CCHS diagnosis)Agents/Circumstances to AvoidIdeally, 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 RiskThe 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 InvestigationSearch 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.}

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Congenital Central Hypoventilation Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPHOX2B4p13Paired mesoderm homeobox protein 2BPHOX2B homepage - Mendelian genesPHOX2BData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Congenital Central Hypoventilation Syndrome (View All in OMIM) View in own window 209880CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL; CCHS 603851PAIRED-LIKE HOMEOBOX 2B; PHOX2BMolecular Genetic PathogenesisPHOX2B 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.Table 6. Other Genes with Mutations Reported in Individuals with CCHS with or without a PHOX2B Polyalanine Expansion MutationView in own windowGene Symbol# Individuals Reported with a Mutation in the Gene# Individuals with Mutation in Specified Gene AND PHOX2B Polyalanine Expansion MutationReferenceRET 83Amiel et al [1998]
Sakai et al [1998]
Sakai et al [2001]
Fitze et al [2003]
Sasaki et al [2003]GDNF 1 1Amiel et al [1998] EDN3 11Bolk et al [1996] BDNF 1 1Weese-Mayer et al [2002] ASCL(HASH1)53de Pontual et al [2003]
Sasaki et al [2003] PHOX2A1-Sasaki et al [2003] GFRA1 1 1Sasaki et al [2003] BMP2 11Weese-Mayer et al [2003a] ECE1 1 1Weese-Mayer et al [2003a]
Berry-Kravis et al [2006]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.