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Congenital central hypoventilation(CCHS)

MedGen UID:
220902
Concept ID:
C1275808
Disease or Syndrome
Synonyms: CCHS; Congenital Central Hypoventilation Syndrome; Congenital failure of autonomic control; Congenital Ondine curse; Idiopathic congenital central alveolar hypoventilation; Ondine curse (formerly); Ondine's curse (formerly); Primary alveolar hypoventilation
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
not inherited
MedGen UID:
832438
Concept ID:
CN227390
Intellectual Product
Source: Orphanet
Describes a disorder that is not inherited.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
not inherited (Orphanet)
SNOMED CT: CCHS - Congenital central hypoventilation (399040002); Congenital pulmonary hypoventilation (399040002); Primary alveolar hypoventilation (399040002); Congenital central hypoventilation (399040002)
 
Genes (locations): ASCL1 (12q23.2); BDNF (11p14.1); EDN3 (20q13.32); GDNF (5p13.2); PHOX2B (4p13); RET (10q11.21)
OMIM®: 209880
Orphanet: ORPHA661

Disease characteristics

Excerpted from the GeneReview: Congenital Central Hypoventilation Syndrome
Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory and autonomic regulation. It is typically characterized by a classic presentation in newborns and, rarely, a milder later-onset (LO-CCHS) presentation in toddlers, children, and adults. Classic CCHS presents in newborns as: Apparent hypoventilation with monotonous respiratory rates and shallow breathing either during sleep only or while awake as well as asleep; Autonomic nervous system dysregulation (ANSD); and In some individuals, altered development of neural crest-derived structures (i.e., Hirschsprung disease) and/or tumors of neural crest origin (neuroblastoma, ganglioneuroma, and ganglioneuroblastoma). Individuals with CCHS who have been diagnosed as newborns and ventilated conservatively and consistently throughout childhood have now reached the age of 20 to 30 years; they are highly functional and live independently. LO-CCHS manifests as nocturnal alveolar hypoventilation and mild ANSD. Individuals with LO-CCHS who were not identified until age 20 years or older have now reached the age of 30 to 55 years. [from GeneReviews]
Authors:
Debra E Weese-Mayer  |  Mary L Marazita  |  Casey M Rand, et. al.   view full author information

Additional descriptions

From OMIM
Idiopathic congenital central hypoventilation syndrome, also known as 'Ondine's curse' (Deonna et al., 1974), is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular, lung or cardiac disease, or an identifiable brainstem lesion. Patients breathe normally while awake, but hypoventilate with normal respiratory rates and shallow breathing during sleep; more severely affected patients hypoventilate both awake and asleep. These patients typically present in the first hours of life with cyanosis and increased carbon dioxide during sleep. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia (reviewed by Weese-Mayer et al., 1999). Congenital central hypoventilation syndrome has been associated with several disorders classified as neurocristopathies, that is, aberrant phenotypes arising from a defect of migration or differentiation of neural crest cells. These include neuroblastoma (Haddad et al., 1978), ganglioneuroma (Swaminathan et al., 1989), and most frequently Hirschsprung disease (HSCR) which appears in 16% of CCHS patients. The association of CCHS and HSCR is referred to as Haddad syndrome. Congenital central hypoventilation can be a feature of other developmental disorders, such as those caused by mutation in the MECP2 gene (300005).  http://www.omim.org/entry/209880
From GHR
Congenital central hypoventilation syndrome (CCHS) is a disorder that affects breathing. People with this disorder take shallow breaths (hypoventilate), especially during sleep, resulting in a shortage of oxygen and a buildup of carbon dioxide in the blood. Ordinarily, the part of the nervous system that controls involuntary body processes (autonomic nervous system) would react to such an imbalance by stimulating the individual to breathe more deeply or wake up. This reaction is impaired in people with CCHS, and they must be supported with a machine to help them breathe (mechanical ventilation) or a device that stimulates a normal breathing pattern (diaphragm pacemaker). Some affected individuals need this support 24 hours a day, while others need it only at night.Symptoms of CCHS usually become apparent shortly after birth. Affected infants hypoventilate upon falling asleep and exhibit a bluish appearance of the skin or lips (cyanosis). Cyanosis is caused by lack of oxygen in the blood. In some milder cases, CCHS may be diagnosed later in life. In addition to the breathing problem, people with this disorder may have difficulty regulating their heart rate and blood pressure, for example in response to exercise or changes in body position. They may have abnormalities in the nerves that control the digestive tract (Hirschsprung disease), resulting in severe constipation, intestinal blockage, and enlargement of the colon. They are also at increased risk of developing certain tumors of the nervous system called neuroblastomas, ganglioneuromas, and ganglioneuroblastomas. Some affected individuals develop learning difficulties or other neurological problems, which may be worsened by oxygen deprivation if treatment to support their breathing is not completely effective.Individuals with CCHS usually have eye abnormalities, including a decreased response of the pupils to light. They also have decreased perception of pain, low body temperature, and occasional episodes of profuse sweating.People with CCHS, especially children, may have a characteristic appearance with a short, wide, somewhat flattened face often described as "box-shaped." Life expectancy and the extent of any cognitive disabilities depend on the severity of the disorder, timing of the diagnosis, and the success of treatment.  https://ghr.nlm.nih.gov/condition/congenital-central-hypoventilation-syndrome

Clinical features

Ganglioneuroma
MedGen UID:
6545
Concept ID:
C0017075
Neoplastic Process
A benign neoplasm that usually arises from the sympathetic trunk in the mediastinum, representing a tumor of the sympathetic nerve fibers arising from neural crest cells.
Ganglioneuroblastoma
MedGen UID:
60218
Concept ID:
C0206718
Neoplastic Process
A malignant neoplasm characterized by the presence of neuroblastic and ganglion cells and a stroma with Schwannian differentiation.
Cardiovascular Abnormalities
MedGen UID:
116727
Concept ID:
C0243050
Disease or Syndrome
Any abnormality of the cardiovascular system.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Constipation means that a person has three or fewer bowel movements in a week. The stool can be hard and dry. Sometimes it is painful to pass. At one time or another, almost everyone gets constipated. In most cases, it lasts a short time and is not serious. . There are many things you can do to prevent constipation. They include - Eating more fruits, vegetables and grains, which are high in fiber. - Drinking plenty of water and other liquids. - Getting enough exercise. - Taking time to have a bowel movement when you need to. - Using laxatives only if your doctor says you should. - Asking your doctor if medicines you take may cause constipation. . It's not important that you have a bowel movement every day. If your bowel habits change, however, check with your doctor. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Aganglionic megacolon
MedGen UID:
6285
Concept ID:
C0025160
Pathologic Function
An abnormality resulting from a lack of intestinal ganglion cells (i.e., an aganglionic section of bowel) that results in bowel obstruction with enlargement of the colon.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Ganglioneuroma
MedGen UID:
6545
Concept ID:
C0017075
Neoplastic Process
A benign neoplasm that usually arises from the sympathetic trunk in the mediastinum, representing a tumor of the sympathetic nerve fibers arising from neural crest cells.
Aganglionic megacolon
MedGen UID:
6285
Concept ID:
C0025160
Pathologic Function
An abnormality resulting from a lack of intestinal ganglion cells (i.e., an aganglionic section of bowel) that results in bowel obstruction with enlargement of the colon.
Ganglioneuroblastoma
MedGen UID:
60218
Concept ID:
C0206718
Neoplastic Process
A malignant neoplasm characterized by the presence of neuroblastic and ganglion cells and a stroma with Schwannian differentiation.
Central hypoventilation
MedGen UID:
812169
Concept ID:
C3805839
Finding
Abnormality of temperature regulation
MedGen UID:
626
Concept ID:
C0005904
Sign or Symptom
An abnormality of temperature homeostasis.
Abnormality of the mouth
MedGen UID:
6447
Concept ID:
C0026633
Congenital Abnormality
An abnormality of the mouth.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Hyperhidrosis
MedGen UID:
11680
Concept ID:
C0038990
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCongenital central hypoventilation
Follow this link to review classifications for Congenital central hypoventilation in Orphanet.

Professional guidelines

PubMed

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. doi: 10.1164/rccm.200807-1069ST. PMID: 20208042

Recent clinical studies

Etiology

Charnay AJ, Antisdel-Lomaglio JE, Zelko FA, Rand CM, Le M, Gordon SC, Vitez SF, Tse JW, Brogadir CD, Nelson MN, Berry-Kravis EM, Weese-Mayer DE
Chest 2016 Mar;149(3):809-15. Epub 2016 Jan 12 doi: 10.1378/chest.15-0402. PMID: 26378991
Armstrong AE, Weese-Mayer DE, Mian A, Maris JM, Batra V, Gosiengfiao Y, Reichek J, Madonna MB, Bush JW, Shore RM, Walterhouse DO
Pediatr Blood Cancer 2015 Nov;62(11):2007-10. Epub 2015 May 22 doi: 10.1002/pbc.25572. PMID: 26011159
Paddeu EM, Giganti F, Piumelli R, De Masi S, Filippi L, Viggiano MP, Donzelli G
Sleep Breath 2015 Sep;19(3):1057-64. Epub 2014 Nov 25 doi: 10.1007/s11325-014-1080-z. PMID: 25631640
Nicholson KJ, Nosanov LB, Bowen KA, Kun SS, Perez IA, Keens TG, Shin CE
J Pediatr Surg 2015 Jan;50(1):78-81. Epub 2014 Dec 23 doi: 10.1016/j.jpedsurg.2014.10.002. PMID: 25598098
Carroll MS, Patwari PP, Kenny AS, Brogadir CD, Stewart TM, Weese-Mayer DE
J Appl Physiol (1985) 2014 Feb 15;116(4):439-50. Epub 2013 Dec 31 doi: 10.1152/japplphysiol.01310.2013. PMID: 24381123

Diagnosis

Preutthipan A, Kuptanon T, Kamalaporn H, Leejakpai A, Nugboon M, Wattanasirichaigoon D
J Med Case Rep 2015 Jun 25;9:149. doi: 10.1186/s13256-015-0631-7. PMID: 26109383Free PMC Article
Shimokaze T, Sasaki A, Meguro T, Hasegawa H, Hiraku Y, Yoshikawa T, Kishikawa Y, Hayasaka K
J Hum Genet 2015 Sep;60(9):473-7. Epub 2015 Jun 11 doi: 10.1038/jhg.2015.65. PMID: 26063465
Amimoto Y, Okada K, Nakano H, Sasaki A, Hayasaka K, Odajima H
J Clin Sleep Med 2014 Mar 15;10(3):327-9. doi: 10.5664/jcsm.3542. PMID: 24634632Free PMC Article
Wang TC, Su YN, Lai MC
Pediatr Neonatol 2014 Feb;55(1):68-70. Epub 2013 Jan 20 doi: 10.1016/j.pedneo.2012.12.003. PMID: 23597545
Kaymakçi A, Narter F, Yazar AS, Yilmaz MS
Turk J Pediatr 2012 Sep-Oct;54(5):519-22. PMID: 23427517

Therapy

Morélot-Panzini C, Gonzalez-Bermejo J, Straus C, Similowski T
Int J Artif Organs 2013 Jun 25;36(6):434-8. Epub 2013 May 8 doi: 10.5301/ijao.5000197. PMID: 23653299
Marics G, Amiel J, Vatai B, Lódi C, Mikos B, Tóth-Heyn P
Acta Paediatr 2013 Apr;102(4):e178-80. Epub 2012 Dec 29 doi: 10.1111/apa.12125. PMID: 23231723
Mahfouz AK, Rashid M, Khan MS, Reddy P
Can J Anaesth 2011 Dec;58(12):1105-9. Epub 2011 Oct 12 doi: 10.1007/s12630-011-9590-7. PMID: 21989548
Straus C, Similowski T
Respir Physiol Neurobiol 2011 Sep 15;178(2):357-8. Epub 2011 Jul 23 doi: 10.1016/j.resp.2011.07.007. PMID: 21801857
Duty BD, Wozniak SE, Selden NR
J Neurosurg Pediatr 2011 Apr;7(4):413-5. doi: 10.3171/2011.1.PEDS10520. PMID: 21456915

Prognosis

Massie J, Gillam L
Pediatr Pulmonol 2015 May;50(5):503-10. Epub 2014 Sep 5 doi: 10.1002/ppul.23097. PMID: 25195933
Magalhães J, Madureira N, Medeiros R, Fernandes PC, Oufadem M, Amiel J, Estêvão MH, Reis MG
Sleep Breath 2015 Mar;19(1):55-60. Epub 2014 May 4 doi: 10.1007/s11325-014-0996-7. PMID: 24792884
Reverdin AK, Mosquera R, Colasurdo GN, Jon CK, Clements RM
BMJ Case Rep 2014 May 19;2014 doi: 10.1136/bcr-2013-200911. PMID: 24842348Free PMC Article
Kaymakçi A, Narter F, Yazar AS, Yilmaz MS
Turk J Pediatr 2012 Sep-Oct;54(5):519-22. PMID: 23427517
Marsh K, Ehrhardt E
Neonatal Netw 2012 May-Jun;31(3):157-61. doi: 10.1891/0730-0832.31.3.157. PMID: 22564311

Clinical prediction guides

Charnay AJ, Antisdel-Lomaglio JE, Zelko FA, Rand CM, Le M, Gordon SC, Vitez SF, Tse JW, Brogadir CD, Nelson MN, Berry-Kravis EM, Weese-Mayer DE
Chest 2016 Mar;149(3):809-15. Epub 2016 Jan 12 doi: 10.1378/chest.15-0402. PMID: 26378991
Shimokaze T, Sasaki A, Meguro T, Hasegawa H, Hiraku Y, Yoshikawa T, Kishikawa Y, Hayasaka K
J Hum Genet 2015 Sep;60(9):473-7. Epub 2015 Jun 11 doi: 10.1038/jhg.2015.65. PMID: 26063465
Paddeu EM, Giganti F, Piumelli R, De Masi S, Filippi L, Viggiano MP, Donzelli G
Sleep Breath 2015 Sep;19(3):1057-64. Epub 2014 Nov 25 doi: 10.1007/s11325-014-1080-z. PMID: 25631640
Nicholson KJ, Nosanov LB, Bowen KA, Kun SS, Perez IA, Keens TG, Shin CE
J Pediatr Surg 2015 Jan;50(1):78-81. Epub 2014 Dec 23 doi: 10.1016/j.jpedsurg.2014.10.002. PMID: 25598098
Kaymakçi A, Narter F, Yazar AS, Yilmaz MS
Turk J Pediatr 2012 Sep-Oct;54(5):519-22. PMID: 23427517

Recent systematic reviews

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. doi: 10.1164/rccm.200807-1069ST. PMID: 20208042
Am J Respir Crit Care Med 1999 Jul;160(1):368-73. doi: 10.1164/ajrccm.160.1.16010. PMID: 10390427

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