December 13, 2019
Years published: 1986, 1989, 1990, 1992, 1994, 2004, 2005, 2009, 2010, 2013, 2016, 2019
NORD gratefully acknowledges the CCHS Family Network for assistance in the preparation of this report.
Congenital central hypoventilation syndrome (CCHS) is a rare lifelong and life-threatening disorder. CCHS affects the central and autonomic nervous system which controls many of the automatic functions in the body such as heart rate, blood pressure, sensing of oxygen and carbon dioxide levels in the blood, temperature, bowel and bladder control, and more. The most recognized symptom of CCHS is the inability to control breathing that varies in severity, resulting in the need for life-long ventilatory support during sleep in some patients or all the time in others. There are estimated to be 1000 – 1200 cases of CCHS world-wide. CCHS affects males and females equally. Currently, there is no cure for CCHS.
The underlying cause of CCHS is mutation in the PHOX2B gene. Most children with CCHS have mutations of the PHOX2B gene called poly-alanine repeat expansion mutations (PARMs). Some children with CCHS have different mutations in the PHOX2B gene not related to PARMs called non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein. See the Causes section for more information.
The hallmark of CCHS is reduced or shallow breathing due to dysregulation of the respiratory drive. In general, reduced and shallow breathing is most apparent in non–REM sleep, but breathing is also abnormal during REM sleep and wakefulness, although usually to a milder degree. Individuals with CCHS also cannot sense oxygen or carbon dioxide levels in their body, which results in discoloration of their skin and lips, indicating that oxygen levels in the body are low. Low oxygen levels can cause increased risk for organ damage, especially to the brain. Thus, it is important to optimize oxygenation and ventilation in these patients. Depending on the severity of CCHS, the degree of life-long ventilatory support can vary from sleep only to constant support.
Adequate ventilation is essential to ensure optimal growth and development of CCHS patients. Ventilation can be managed with a mechanical ventilator via tracheostomy or masks, or using phrenic pacemakers. Monitoring both oxygen saturations and CO2 using end-tidal capnography at home helps ensure adequate ventilation in all conditions (sleep, awake, during illness and growth spurts). The support of experienced at-home nursing care will help families continue functioning at home. Ventilatory needs vary greatly across mutations, and sometimes within the same mutation. Appropriate ventilation for each child is essential to ensure optimal developmental outcomes. Because of the CCHS patient’s inability to sense changes in CO2, as well as O2, supplemental oxygen alone is not adequate for treating the individual with CCHS, and can mask elevated CO2 levels when both are not monitored.
Cardiac asystoles (heart stops beating) have been noted in several PARM mutations, and should be monitored extensively and actively throughout CCHS patients’ lives. This can include, but not be limited to regular extended Holter monitoring, implantable loop recorders, etc. CCHS patients do not sense cardiac pauses and are often asymptomatic until a life-threatening event occurs (loss of consciousness, sudden death). Within the CCHS community, children across many PARM mutations have demonstrated need for cardiac pacemaker implantation, even at a young age.
Additional cardiovascular symptoms of CCHS include altered temperature regulation, altered heart rate variability, altered blood pressure regulation, and poor circulation that may only be apparent under stressors such as illness or surgery.
Both PARM and NPARM CCHS patients can present with alterations in their digestive system. Mild symptoms can be reflux and poor upper GI motility. Other patients can present with Hirschsprung’s disease (HD). HD is more often present in NPARMs or higher PARM expansions. Reflux is often treated via medication, while poor upper GI motility may often be managed with therapy and altered diets. Surgical treatment is required for HD.
Some children with CCHS have been identified with ophthalmological problems associated with CCHS. These include, strabismus, abnormal pupil dilation, the need to wear corrective lenses, as well as Marcus Gunn jaw-winking syndrome and absent or reduced depth perception. Management can range from corrective lenses, wearing sunglasses when outside to surgical procedures.
The endocrine system can be affected by mutations in the PHOX2B gene. The most commonly noted are growth hormone deficiency and congenital hyperinsulinemia.
Patients with CCHS can develop tumors of neural crest origin, such as ganglioneuromas, ganglioneurblastomas, and neuroblastomas. Treatment for these tumors involves surgery followed by chemotherapy, if needed.
The 2010 ATS Statement recommends that CCHS children with 20/29-20/33 PARM mutations as well as those with NPARMs should be screened at diagnosis of CCHS and with advancing age for neural crest tumors.
The underlying cause of CCHS is a change (mutation) in the PHOX2B gene, a key player in the prenatal development of the nervous system. The majority of individuals with CCHS (~90%) have mutations in exon 3 of the PHOX2B gene that normally has a repeat of 20 alanines. These mutations cause an increase in the number of these alanine repeats from the normal 20 alanines to a range of 24 to 33 alanines and are called poly-alanine repeat expansion mutations (PARMs). The remaining individuals with CCHS have different mutations in the PHOX2B gene not related to PARMs including missense, nonsense, frameshift, or stop codon mutations. These are non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein, and the variations in these mutations result in the broad range of symptoms and differing degrees of severity encountered among individuals with CCHS.
CCHS is a dominant genetic condition, meaning only one PHOX2B gene needs to contain a mutation to result in the phenotypic presentation of CCHS. Although most genetic diseases are inherited from parents, the majority of CCHS cases are spontaneous in nature. The rate of inheritance of CCHS from a parent who has CCHS is believed to be 50%. Mosaic parents have been identified within the CCHS population, but this is still extremely rare. Parents who wish to have additional children after having a child with CCHS are encouraged to seek genetic counseling. PHOX2B mutations are stable in transmission from one generation to the next, but penetrance and phenotype can still vary significantly.
CCHS is a rare disorder that affects females and males in equal numbers. Though the mutation is already present before birth, in milder cases the diagnosis may be missed until after the newborn period. Some affected individuals will not be identified until after receiving sedation, anesthesia, or anti-seizure medications, making it especially important to educate health care personnel about CCHS and to have a high index of suspicion for considering a diagnosis of CCHS. As of 2013, more than 1,000 cases are known worldwide. The birth prevalence of CCHS has been extrapolated from incidence figures and general birth rates, but the true prevalence is unknown as culturally diverse large population based studies have not been reported. Because the milder cases of CCHS may go unrecognized or misdiagnosed, it is difficult to estimate the true frequency of CCHS in the general population, though the anticipation is far greater than the current estimate.
Along with early recognition of the clinical features of CCHS, the gold standard test to diagnose CCHS is genetic testing to identify mutations in the PHOX2B gene, including PARMs, NPARMs, or deletions and duplications.
PHOX2B gene testing is appropriate for:
Please contact the CCHS Family Network for additional information about genetic testing:
A multidisciplinary team approach to the management of CCHS is essential to ensuring proper ventilation and development of children with CCHS. Local children’s hospitals may be sufficient in the management of CCHS. In complex cases, CCHS specialists (listed below) can be found throughout the world and can be consulted, or seen for management of CCHS. Primary team members who play an active role in patient management should include: the primary caregivers (parents or family members), pulmonologists, cardiologists, ENT physicians, gastroenterologists, endocrinologists, neurologists, ophthalmologists, social workers, and speech/language pathologists (SLPs).
Early detection and management of CCHS with adequate ventilation and appropriate therapies have helped CCHS patients live fulfilling lives. Proper management has allowed CCHS patients to seek higher education, enter the work force and have families of their own
Please refer to the Signs and Symptoms section for additional information.
Clinical Testing and Work-Up
The 2010 American Thoracic Society (ATS) statement on CCHS recommends that CCHS patients undergo annual assessment of spontaneous breathing awake, as well as during sleep in a pediatric respiratory physiology laboratory. At minimum, a 72-hour Holter study should also be performed annually to evaluate for cardiac pauses, pauses greater than 3.0 seconds should be assessed for cardiac pacemaker implantation by a cardiologist. An echocardiogram, hematocrits, and reticulocyte counts may also be needed to evaluate for signs of heart problems (cor pulmonale) that occur as a consequence of inadequate ventilation. Consultation with a gastroenterologist (and possibly rectal biopsy) may be needed for patients with constipation to evaluate for Hirschsprung’s disease. In patients with PARM mutations 20/29 and higher, and patients with NPARM mutations, routine serial chest and abdominal imaging is crucial for detecting emergence of a neural crest tumor, specifically neuroblastoma (NPARMs) and ganglioneuroblastoma/ganglioneuroma (PARMs). Ophthalmologic testing may also need to be done in some patients to assess for ophthalmologic dysfunction.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
NORD Natural History Registry
The CCHS Family Network participates in the NORD/FDA’s Natural History Registry. The goal of this registry is to expand the current knowledge of the syndrome, as well as to aid medical professionals and researchers in the identification of important aspects and treatment of CCHS. Please contact The CCHS Family Network at [email protected] or at http://www.cchsnetwork.org/
Contact information for physicians with expertise in CCHS is available at the CCHS Family Network: http://www.cchsnetwork.org/
JOURNAL ARTICLES and CHAPTERS
Chin AC, Shaul DB, Patwari PP, Keens TG, Kenny AS, and Weese-Mayer DE: Diaphragmatic pacing in infants and children with congenital central hypoventilation syndrome (CCHS). In: Sleep Disordered Breathing in Children: A Clinical Guide (Kheirandish-Gozal L and Gozal D, editors), Springer Press, New York, NY. 2012: 553-573.
Weese-Mayer DE, Patwari PP, Rand CM, Diedrich AM, Kuntz NL, and Berry-Kravis EM: Congenital Central Hypoventilation Syndrome (CCHS) and PHOX2B Mutations. In: Primer on the Autonomic Nervous System (Robertson D, Biaggioni I, Burnstock G, Low PA, and Paton, JFR, editors), Academic Press, Oxford, UK. 2012: 445-450.
Patwari PP, Carroll MS, Rand CM, Kumar R, Harper R, and Weese-Mayer DE: Congenital central hypoventilation syndrome and the PHOX2B gene: A model of respiratory and autonomic dysregulation. Respir Physiol & Neurobiol. 2010;173(3):322-335.
Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al. An official ATS clinical policy statement: Congenital central hypoventilation syndrome: Genetic basis, diagnosis, and management. Am J Respir Crit Care Med. 2010 Mar 15;181(6):626-44.
Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H; ATS Congenital Central Hypoventilation Syndrome Subcommittee.
Am J Respir Crit Care Med. 2010;Mar 15;181(6):626-44.
Zelko FA, Nelson MN, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE: Congenital central hypoventilation syndrome: Neurocognitive functioning in school age children. Pediatric Pulmonology 2010;45(1):92-98.
Weese-Mayer DE, Rand CM, Berry-Kravis EM, Jennings LJ, Patwari PP, and Ceccherini I: Congenital central hypoventilation syndrome from past to future: Model for translational and transitional autonomic medicine. Pediatr Pulmonol. 2009;44(6):521-535.
Goldberg DS, Ludwig IH. Congenital central hypoventilation syndrome: Ocular findings in 37 children. J Pediatr Ophthalmol Strabismus 1996;33-176-181.Gronli JO, Santucci BA, Leurgans SE, and Weese-Mayer DE: Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol. 2008;43:77-86
Trochet D, de Pontual L, Straus C, Gozal D, Trang H, Landrieu P, Munnich A, Lyonnet S, Gaultier C, Amiel J. PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome. Am J Respir Crit Care Med. 2008;177:906-911.
Trochet D, de Pontual L, Keren B, Munnich A, Vekemans M, Lyonnet S, Amiel J. Polyalanine expansions might not result from unequal crossing-over. Hum Mut. 2007;10:1043-1044.
Antic N, Malow BA, Lange N, McEvoy RD, Olson AL, Turkington P, Windisch W, Samuels M, Stevens CA, Berry-Kravis EM, and Weese-Mayer DE: PHOX2B mutation-confirmed congenital central hypoventilation syndrome: Presentation in adulthood. Am J Respir Crit Care Med. 2006;174:923-927.
Berry-Kravis EM, Zhou L, Rand CM, and Weese-Mayer DE: Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006;174:1139-1144.
Trochet D, Hong SJ, Lim JK, Brunet JF, Munnich A, Kim KS, Lyonnet S, Goridis C, Amiel J. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005:14:3697-3708.
Trochet D, O’Brien LM, Gozal D, Trang H, Nordenskjd A, Laudier B, Svensson P-J, Uhrig S, Cole T, Munnich A, Gaultier C, Lyonnet S, Amiel J. PHOX2B genotype allows for prediction of tumor risk in Congenital Central Hypoventilation Syndrome. Am J Hum Genet. 2005;76:421-426.
Matera I, Bachetti T, Puppo F, Di Duca M, Morandi F, Casiraghi GM, Cilio MR, Hennekam R, Hofstra R, Schober JG, Ravazzolo R, Ottonello G, Ceccherini I. PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset central hypoventilation syndrome. J Med Genet, 2004;41, 373-380.
Vanderlaan M1, Holbrook CR, Wang M, Tuell A, Gozal D.Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome. Pediatr Pulmonol. 2004;Mar;37(3):217-29.
Amiel J, Laudier B, Attie-Bitach T et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33:459-61.
Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, and Marazita ML: Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2B. Am J Med Genet. 2003;123A:267-278.
Marazita ML, Maher BS, Cooper ME, Silvestri JM, Huffman AD, Smok-Pearsall SM, Kowal MH, and Weese-Mayer DE: Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with congenital central hypoventilation syndrome. Am J Med Genet. 2001;100:229-236.
Silvestri JM, Hanna BD, Volgman AS, Jones JP, Barnes SD, and Weese-Mayer DE: Cardiac rhythm disturbances among children with idiopathic congenital central hypoventilation syndrome. Pediatr Pulmonol. 2000;29:351-358.
Silvestri, JM, Weese-Mayer DE, and Flanagan EA: Congenital central hypoventilation syndrome: Cardiorespiratory responses to moderate exercise, simulating daily activity. Pediatr Pulmonol. 1995;20:89-93.
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