Central Hypoventilation Syndrome, Congenital

Central Hypoventilation Syndrome, Congenital

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Central Hypoventilation Syndrome, Congenital is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • CCHS
  • Haddad syndrome
  • autonomic control, congenital failure of
  • Ondine curse, congenital
  • Ondine-Hirschsprung disease, included
  • OHD
  • CCHS with Hirschsprung disease, included

Disorder Subdivisions

  • None

General Discussion

Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory control with autonomic nervous system dysregulation (ANSD). The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, temperature regulation, breathing, bowel and bladder control, and more. Impaired breathing regulation (respiratory control) is the hallmark of CCHS. Individuals with CCHS typically present in the newborn period with inadequate shallow breathing (alveolar hypoventilation) during sleep and, in more severely affected individuals, during wakefulness and sleep. Breathing complications occur despite the lungs and airways being normal. A growing number of individuals are now being identified who present in later infancy, childhood, or even adulthood and are called Late Onset Congenital Central Hypoventilation Syndrome (LO-CCHS).



All individuals with CCHS have a mutation in the PHOX2B gene. The PHOX2B gene plays an important role in the development of the Autonomic Nervous System (ANS). The normal PHOX2B gene has a section with 20 repeats of a code for the amino acid, alanine. For those individuals with CCHS, the majority (~90%) have a mutation causing an increase in the number of these alanine repeats. This is called a polyalanine repeat expansion mutation (PARM). The remaining individuals with CCHS have a different type of abnormality in the PHOX2B gene. These other mutations in the PHOX2B gene are called a non-polyalanine repeat expansion mutation (NPARM).

Symptoms

The symptoms and severity of CCHS vary from one individual to another. The type of mutation in the PHOX2B gene and the repeat length are related to disease severity. A rapidly expanding understanding of the risks specific to the PHOX2B mutation is allowing physicians and parents to anticipate risks for continuous ventilation, pauses in the heart rhythm, and potentially neurocognitive outcome in individuals with CCHS.



The hallmark of CCHS is duskiness or a bluish discoloration of the skin and mucous membranes (cyanosis), resulting from very shallow breathing, and a general decrease in breathing (hypoventilation) during sleep (nap and night). These individuals will not increase his/her breathing or awaken to abnormal oxygen and carbon dioxide levels. This same lack of responsivity to low oxygen and elevated carbon dioxide occurs during wakefulness as well, even when awake breathing is adequate.



Some individuals with CCHS have anatomic/structural malformations including Hirschsprung disease. Overall, 16-20% of individuals with CCHS have Hirschsprung disease, but the risk is higher for those who have longer PARMs or who have NPARMs. Likewise, only individuals with large repeat expansion PARMs (specifically genotype 20/29 and 20/33 identified thus far; recall the normal genotype is 20/20 reflecting the number of alanines on each allele) and NPARMs have been identified with tumors of neural crest origin, including ganglioneuromas and ganglioneuroblastomas for the PARMs and neuroblastoma for the NPARMs.



Individuals with CCHS may also have a characteristic facies, heart rhythm abnormalities such as brief episodes when the heart stops beating (cardiac asystole), abnormalities affecting the normal contractions of the digestive system that pushes food through the digestive tract (altered gut motility) even in the absence of Hirschsprung disease, altered temperature regulation and pain perception, decreased anxiety and eye abnormalities.

Causes

PHOX2B, the disease-defining gene for CCHS, is located on chromosome 4 (specifically, 4p12). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 4p12" refers to band 12 on the short arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Genes contain the instructions for creating proteins which perform vital functions in the body.



The vast majority of individuals (90%) with CCHS are heterozygous for a polyalanine repeat expansion mutation (PARM) in exon 3 of the PHOX2B gene: the normal allele will have the normal 20 alanine repeats and the expanded allele will have anywhere from /ROHHAD24 all the way up to 33 repeats. So the PHOX2B genotype range for an individual with a PARM will be 20/24-20/33. The remaining individuals with CCHS have a non-polyalanine repeat expansion mutation (NPARM) typically between the end of exon 2 and into exon 3 of the PHOX2B gene. The altered DNA sequences resulting in the PARMs and NPARMs cause the protein resulting from the PHOX2B gene to function improperly.



The PHOX2B mutation results in malregulation of involuntary or automatic body functions (autonomic nervous system) primarily by abnormal development of early embryonic cells that form the neural crest. Individuals with the NPARMs will typically be more severely affected than individuals with the PARMs, and individuals with the greater number of repeats will typically be more severely affected than those with the fewer number of repeats.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. CCHS and the PHOX2B mutations are inherited in an autosomal dominant manner. Autosomal dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. Though 90-95% of the CCHS-related PHOX2B mutations are not inherited (new mutations or de novo), 5-10% of parents of children with CCHS are mosaic for the same mutation. That means that these mosaic parents have the PHOX2B mutation in some of the cells of their body, but presumably not in their brains as they are to breathe normally and do not appear to have CCHS.



The risk of passing the abnormal gene from an affected parent to his/her offspring is 50% for each pregnancy regardless of the sex of the resulting child or affected parent. The risk of passing the abnormal gene from mosaic parent to offspring is up to 50% for each pregnancy regardless of the sex of the resulting child. An individual with CCHS can have either a totally healthy normal child or a child with CCHS. Likewise, a mosaic parent can have either a totally healthy normal child or a child with CCHS. A mosaic parent can not have a mosaic child. When inherited, the PHOX2B mutation (repeat number in the PARMs or the specific NPARM) will be identical in the parent and the child.



Some individuals affected with CCHS have been found to have mutations in other genes, but these mutations do not cause CCHS.

Affected Populations

Congenital central hypoventilation syndrome (CCHS) is a rare disorder that affects males and females in equal numbers. Though the mutation is already present at birth, in milder cases the diagnosis may be missed. Some affected individuals will not be identified until after receiving sedation, anesthesia, or anti-seizure medications. As of 2010, approximately 1,000 cases are known worldwide with the vast majority diagnosed in the U.S. by the Chicago laboratories (PHOX2B Testing Without Walls at Children's Memorial Hospital/Northwestern University and Rush University Medical Center). The birth prevalence of CCHS 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.

Standard Therapies

Diagnosis

The diagnosis of CCHS is based on the clinical presentation, the related clinical features, documentation of an absence of other potentially confounding diagnoses, and confirmation with clinically available PHOX2B testing. The new American Thoracic Society (ATS) Statement on CCHS (published in 2010) advises that the PHOX2B Screening Test be the first step in making the genetic diagnosis of CCHS. This test will diagnose all of the polyalanine repeat expansion mutations (PARMs), mosaicism, polyalanine repeat contraction mutations, and the large deletion non-polyalanine expansion mutations (NPARMs). Another name for the PHOX2B Screening Test is fragment analysis (see www.genetests.org). If the PHOX2B Screening Test is normal and the subject has the clinical presentation of CCHS then the sequel PHOX2B Sequencing Test should be performed. The PHOX2B Sequencing Test will detect the PARMs, the contractions, and the NPARMs but it will not detect mosaicism, so this test is rarely useful in parents of children with CCHS. Because the PHOX2B Screening Test is less expensive with a more rapid turnaround time than the PHOX2B Sequencing Test, and it will detect the vast majority of the cases of CCHS, the two-step testing process is least costly, most expeditious, and most efficient for nearly all patients in whom CCHS is considered.



As recommended in the new ATS Statement on CCHS, physiologic evaluation should include annual comprehensive physiologic assessment during spontaneous breathing awake (in varying levels of concentration and activity) and during sleep in a pediatric respiratory physiology laboratory with extensive expertise in CCHS. Responses to endogenous and exogenous hypercarbia, hypoxemia, and hyperoxia should be assessed, ideally awake and asleep. 72 hour Holter recording should be performed annually to evaluate for asystoles (prolonged sinus pause) that might require a cardiac pacemaker. A tilt test should be performed annually to better understand the ANS response. An echocardiogram should be performed annually to rule out cor pulmonale or right ventricular hypertrophy. Neurocognitive testing should be performed annually to determine the effectiveness of the ventilatory management. In infants under the age of three years, the above-described testing should be performed every 6 months. Gastrointestinal motility studies and, if indicated, a rectal biopsy should be performed in the event of severe constipation. All of the above described tests are part of routine standard of care. Efforts are underway to create a comprehensive testing profile for autonomic regulation in children which will also be considered standard of care for children with CCHS.



Treatment

Most importantly, infants with CCHS will require artificial respiratory support. The safest way to deliver this is with a mechanical ventilatory via a tracheostomy. The tracheostomy requires a surgical procedure in which an opening is surgically created in the throat (tracheostomy) into which a small tube (cannula) is inserted. The baby requires a mechanical ventilator at home (with a back-up ventilator, pulse oximeter, end tidal carbon dioxide monitor, generator and preferably ventilatory batteries) as well as experienced registered nursing (R.N.) care 24 hours/day. In select cases, other assistive breathing apparatus and/or techniques may be used such as diaphragm pacing. In older children and adults, non-invasive (mask) ventilation may be considered. This technique is discouraged in infants and young children because of the risk of facial deformation from the mask and inadequate stability of mask ventilation at a time of rapidly progressing neurodevelopment. The goal is to optimize oxygenation and ventilation in order to optimize neurocognitive outcome. CCHS is a life-long disease and children with CCHS will always require artificial ventilation during sleep. Ventilatory needs will vary with the specific PHOX2B mutation. For example, individuals with small repeat expansions will typically require ventilator support during sleep only, whereas individuals with large repeat expansions and those with an NPARM will typically require artificial ventilation 24 hours/day. Supplemental oxygen alone is not adequate for treating the child with CCHS.



Some individuals with CCHS develop prolonged sinus pauses (asystoles) which require a cardiac pacemaker to correct the heart rhythm. The risk for asystoles varies with the specific PHOX2B mutation. Among children with the most common PARMs (20/25, 20/26, 20/27), those with the PHOX2B 20/27 genotype are at greatest risk.



Treatment of Hirschsprung disease usually consists of surgery to remove the non-functional segment of bowel and relieve obstruction. First, a temporary bowel opening of the colon in the abdominal wall (colostomy) is usually performed. The second operation consists of removing the diseased parts of the colon and rectum and connecting the normal bowel to the anus. In some centers with extensive expertise in Hirschsprung disease, the above-described procedures can be performed in one surgery.



Neuroblastomas are removed surgically, followed by chemotherapy in some cases. Treatment for other tumors originating from the neural crest depends on the type and location of the tumor. These other neural crest tumors are often detected anecdotally, but per the 2010 ATS Statement on CCHS should be screened for in children with the 20/28-20/33 PARM genotypes and the NPARMs.



Multidisciplinary care from a Center of Excellence with long-term comprehensive experience in the care of children and adults with CCHS is key to the successful management of these patients. This team may include pediatricians, med-peds physicians, pulmonologists, cardiologists, intensivists, ENT physicians, surgeons, gastroenterologists, neurologists, ophthalmologists, psychologists, psychiatrists, respiratory therapists, nurses, social workers, speech and language therapists, special education teachers, and more.



A high index of suspicion, early detection, and aggressive conservative intervention are critical to optimizing neurocognitive outcome and quality of life for individuals with CCHS. If inadequately treated, the affected individuals will likely suffer neurocognitive compromise and potentially sudden death. If treated conservatively and followed comprehensively, individuals with CCHS can have a good quality of life and an anticipated normal life span.

Investigational Therapies

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:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



For more information on Congenital Central Hypoventilation Syndrome and/or PHOX2B Testing, please contact:



Debra E. Weese-Mayer, M.D.

Professor of Pediatrics at Northwestern University Feinberg School of Medicine

Director, Center for Autonomic Medicine in Pediatrics (C.A.M.P.)

Children's Memorial Hospital

2300 Children's Plaza--Mailstop #165

Chicago, IL 60614

phone: 773-880-8188

fax: 773-880-8100

e-mail: DWeese-Mayer@ChildrensMemorial.org

http://www.childrensmemorial.org/depts/autonomic-medicine/overview.aspx http://www.childrensmemorial.org/findadoc/bios.aspx?ID=1775

References

JOURNAL ARTICLES

Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, and Trang H: American Thoracic Society Statement. Congenital central hypoventilation syndrome: Genetic basis, diagnosis, and management. Am J Respir Crit Care Med 181:626-644, 2010.



Carroll MS, Pallavi PP, and Weese-Mayer DE: Carbon dioxide chemoreception and hypoventilation syndromes with autonomic dysregulation. J Appl Physiol 108: 979 - 988, 2010.



Pallavi PP, Carroll MS, Rand CM, Kumar R, Harper R, and Weese-Mayer DE: CCHS and central chemoreception. Respir Physiol & Neurobiol, in press, 2010.



Weese-Mayer DE, Rand CM, Berry-Kravis EM, Jennings LJ, Loghmanee DA, Patwari PP, and Ceccherini I: Congenital central hypoventilation syndrome from past to future: Model for translational and transitional autonomic medicine. Pediatr Pulmonol 44(6):521-535, 2009.



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 33:459-61, 2003.



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 174:923-927, 2006.



Axelrod FB, Chelimsky GG, and Weese-Mayer DE: Pediatric autonomic disorders: State of the Art. Pediatrics 118:309-321, 2006.



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 174:1139-1144, 2006.



Carroll MS, Pallavi PP, and Weese-Mayer DE: Carbon dioxide chemoreception and hypoventilation syndromes with autonomic dysregulation. J Appl Physiol 108: 979 - 988, 2010.



Diedrich A, Malow BA, Antic NA, Sato K, Robertson D, Berry-Kravis EM, and Weese-Mayer DE: Vagal and sympathetic heart rate and blood pressure control in adult-onset PHOX2B mutation-confirmed congenital central hypoventilation syndrome. Clin Auton Med 17(3):177-185, 2007.



Goldberg DS, Ludwig IH. Congenital central hypoventilation syndrome: Ocular findings in 37 children. J Pediatr Ophthalmol Strabismus. 33-176-181, 1996.



Gronli JO, Santucci BA, Leurgans SE, and Weese-Mayer DE: Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol 43:77-86, 2008.



Ize-Ludlow D, Gray J, Sperling MA, et al. Rapid onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation presenting in childhood. Pediatrics 120:e179-e188, 2007.



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 100:229-236, 2001.



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 41, 373-380, 2004.



Pallavi 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, in press, 2010.



Pine DS, Weese-Mayer DE, Silvestri JM, Davies M, and Klein DF: Anxiety and congenital central hypoventilation syndrome. Am J Psychiatry 151:864-870, 1994.



Repetto GM, Corrales RJ, Abara SG, Zhou L, Berry-Kravis EM, Rand CM, and Weese-Mayer DE: Later-onset Congenital Central Hypoventilation Syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene. Acta Paediatr, published on-line October 2008; 98:190-192-195, 2009.



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 29:351-358, 2000.



Silvestri, JM, Weese-Mayer DE, and Flanagan EA: Congenital central hypoventilation syndrome: Cardiorespiratory responses to moderate exercise, simulating daily activity. Pediatr Pulmonol 20:89-93, 1995.



Todd ES, Weinberg SM, Berry-Kravis EM, Silvestri JM, Kenny AS, Rand CM, Zhou L, Maher BS, Marazita ML, Weese-Mayer DE. Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology. Pediatr Res 59:39-45, 2006.



Todd, ES, Scott NM, Weese-Mayer DE, Weinberg SM, Berry-Kravis EM, Silvestri JM, Kenny AS, Hauptman SA, Zhou L, Marazita ML. Characterization of dermatoglyphics in PHOX2B-confirmed congenital central hypoventilation syndrome. Pediatrics 118(2):e408-414, 2006



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 14:3697-3708, 2005.



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 10:1043-1044, 2007.



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 177:906-911, 2008.



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 76:421-426, 2005.



Vanderlaan M, Holbrook CR, Wang M, et al. Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome. Pediatr Pulmonol.37:217-229, 2004.



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, published on-line 24 September 2003, 123A:267-278, 2003.



Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, and Trang H: American Thoracic Society Statement. Congenital central hypoventilation syndrome: Genetic basis, diagnosis, and management. Am J Respir Crit Care Med 181:626-644, 2010.



Weese-Mayer DE, Silvestri JM, Marazita ML, and Hoo JJ: Congenital central hypoventilation syndrome: Inheritance and relation to SIDS. Am J Medical Genet 47(3):360-367, 1993.



Weese-Mayer DE, Silvestri JM, Huffman AD, Smok-Pearsall SM, Kowal MH, Maher BS, Cooper ME, and Marazita ML: Case/Control family study of ANS dysfunction in idiopathic congenital central hypoventilation syndrome. Am J Med Genet 100:237-245, 2001.



Zelko FA, Nelson MN, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE: Congenital central hypoventilation syndrome: Neurocognitive functioning in school age children. Pediatric Pulmonology 45(1):92-98, 2010.



FROM THE INTERNET

Weese-Mayer DE, Marazita ML, and Berry-Kravis EM: Congenital central hypoventilation syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource [database online], updated August 2008. Copyright University of Washington, Seattle, 1997-2007. Available at http://www.genetests.org.



McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 209880; Last Update: 2/11/2009.



Weese-Mayer DE, Marazita ML, Berry-Kravis EM, (Updated 7-24-08). Congenital Central Hypoventilation Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2010. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene?=ondine



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;181: 626?644. Available at: http://www.thoracic.org/newsroom/press-releases/resources/cchs-statement.pdf

Resources

CCHS Family Network (Congenital Central Hypoventilation Syndrome)

71 Maple Street

Oneonta, NY 13820

USA

Tel: (607)432-8872

Fax: (607)431-4351

Email: vanderlaanm@hartwick.edu

Internet: http://www.CCHSNetwork.org



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



International Foundation for Functional Gastrointestinal Disorders

700 W. Virginia St., 201

Milwaukee, WI 53217

USA

Tel: (414)964-1799

Fax: (414)964-7176

Tel: (888)964-2001

Email: iffgd@iffgd.org

Internet: http://www.iffgd.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



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