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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; Haddad syndrome; 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
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
not genetically inherited
MedGen UID:
832438
Concept ID:
CN227390
Finding
Source: Orphanet
clinical entity without genetic inheritance.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: CCHS - Congenital central hypoventilation (399040002); Congenital pulmonary hypoventilation (399040002); Congenital central hypoventilation (399040002); Ondine curse (399040002)
 
Genes (locations): ASCL1 (12q23.2); 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 normal 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 nervous system reaction is impaired in people with CCHS. 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 when affected infants hypoventilate upon falling asleep. In these infants, a lack of oxygen in the blood often causes a bluish appearance of the skin or lips (cyanosis). In some milder cases, CCHS may not become apparent until later in life.In addition to the breathing problem, people with CCHS may have difficulty regulating their heart rate and blood pressure, for example, in response to exercise or changes in body position. They also have decreased perception of pain, low body temperature, and occasional episodes of heavy sweating.People with CCHS may have additional problems affecting the nervous system. About 20 percent of people with CCHS have abnormalities in the nerves that control the digestive tract (Hirschsprung disease), resulting in severe constipation, intestinal blockage, and enlargement of the colon. (Some researchers refer to the combination of CCHS and Hirschsprung disease as Haddad syndrome.) Some affected individuals develop learning difficulties or other neurological problems. People with CCHS are also at increased risk of developing certain tumors of the nervous system called neuroblastomas, ganglioneuromas, and ganglioneuroblastomas.Additionally, individuals with CCHS usually have eye abnormalities, including a decreased response of the pupils to light. People with CCHS, especially children, may have a characteristic appearance with a short, wide, somewhat flattened face often described as "box-shaped."In CCHS, life expectancy and the extent of any intellectual 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

From HPO
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 moderately malignant neoplasm composed of primitive neuroectodermal cells dispersed in myxomatous or fibrous stroma intermixed with mature ganglion cells. It may undergo transformation into a neuroblastoma. It arises from the sympathetic trunk or less frequently from the adrenal medulla, cerebral cortex, and other locations. Cervical ganglioneuroblastomas may be associated with HORNER SYNDROME and the tumor may occasionally secrete vasoactive intestinal peptide, resulting in chronic diarrhea.
Abnormality of the cardiovascular system
MedGen UID:
116727
Concept ID:
C0243050
Congenital Abnormality
Any abnormality of the cardiovascular system.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of FECES. These symptoms are associated with a variety of causes, including low DIETARY FIBER intake, emotional or nervous disturbances, systemic and structural disorders, drug-induced aggravation, and infections.
Aganglionic megacolon
MedGen UID:
6285
Concept ID:
C0025160
Pathologic Function
An abnormal dilation of the colon not due to obstruction.
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
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
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 abnormal dilation of the colon not due to obstruction.
Ganglioneuroblastoma
MedGen UID:
60218
Concept ID:
C0206718
Neoplastic Process
A moderately malignant neoplasm composed of primitive neuroectodermal cells dispersed in myxomatous or fibrous stroma intermixed with mature ganglion cells. It may undergo transformation into a neuroblastoma. It arises from the sympathetic trunk or less frequently from the adrenal medulla, cerebral cortex, and other locations. Cervical ganglioneuroblastomas may be associated with HORNER SYNDROME and the tumor may occasionally secrete vasoactive intestinal peptide, resulting in chronic diarrhea.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
A transient absence of spontaneous respiration.
Hypercapnia
MedGen UID:
9359
Concept ID:
C0020440
Sign or Symptom
A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood.
Hypoxemia
MedGen UID:
152145
Concept ID:
C0700292
Finding
A finding indicating decreased oxygen levels in the blood.
Hypoventilation
MedGen UID:
469022
Concept ID:
C3203358
Pathologic Function
A reduction in the amount of air entering the pulmonary alveoli.
Central hypoventilation
MedGen UID:
812169
Concept ID:
C3805839
Finding
Abnormality of temperature regulation
MedGen UID:
330395
Concept ID:
C1832160
Finding
An abnormality of temperature homeostasis.
Abnormality of the mouth
MedGen UID:
6447
Concept ID:
C0026633
Congenital Abnormality
Congenital absence of or defects in structures 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:
5690
Concept ID:
C0020458
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

Sasaki A, Kishikawa Y, Imaji R, Fukushima Y, Nakamura Y, Nishimura Y, Yamada M, Mino Y, Mitsui T, Hayasaka K
Pediatr Int 2019 Apr;61(4):393-396. Epub 2019 Apr 17 doi: 10.1111/ped.13812. PMID: 30786110
Ballard HA, Leavitt OS, Chin AC, Kabre R, Weese-Mayer DE, Hajduk J, Jagannathan N
Paediatr Anaesth 2018 Nov;28(11):963-973. Epub 2018 Sep 24 doi: 10.1111/pan.13475. PMID: 30251310
Wang A, Kun S, Diep B, Davidson Ward SL, Keens TG, Perez IA
J Clin Sleep Med 2018 Feb 15;14(2):261-264. doi: 10.5664/jcsm.6948. PMID: 29351818Free PMC Article
Esteso Orduña B, Seijas Gómez R, García Esparza E, Briceño EM, Melero Llorente J, Fournier Del Castillo MC
J Clin Exp Neuropsychol 2018 Feb;40(1):75-83. Epub 2017 Jul 14 doi: 10.1080/13803395.2017.1319913. PMID: 28708033
Khayat A, Medin D, Syed F, Moraes TJ, Bin-Hasan S, Narang I, Al-Saleh S, Amin R
Sleep Breath 2017 May;21(2):513-519. Epub 2017 Feb 11 doi: 10.1007/s11325-017-1478-5. PMID: 28190166

Diagnosis

Maloney MA, Kun SS, Keens TG, Perez IA
Expert Rev Respir Med 2018 Apr;12(4):283-292. Epub 2018 Feb 28 doi: 10.1080/17476348.2018.1445970. PMID: 29486608
Zaidi S, Gandhi J, Vatsia S, Smith NL, Khan SA
Auton Neurosci 2018 Mar;210:1-9. Epub 2017 Nov 13 doi: 10.1016/j.autneu.2017.11.003. PMID: 29249648
Khayat A, Medin D, Syed F, Moraes TJ, Bin-Hasan S, Narang I, Al-Saleh S, Amin R
Sleep Breath 2017 May;21(2):513-519. Epub 2017 Feb 11 doi: 10.1007/s11325-017-1478-5. PMID: 28190166
Sandoval RL, Zaconeta CM, Margotto PR, Cardoso MT, França EM, Medina CT, Canó TM, Faria AS
Rev Paul Pediatr 2016 Sep;34(3):374-8. Epub 2016 Jan 6 doi: 10.1016/j.rpped.2015.10.009. PMID: 26838603Free PMC Article
Kaymakçi A, Narter F, Yazar AS, Yilmaz MS
Turk J Pediatr 2012 Sep-Oct;54(5):519-22. PMID: 23427517

Therapy

Paglietti MG, Cherchi C, Porcaro F, Agolini E, Schiavino A, Petreschi F, Novelli A, Cutrera R
Ital J Pediatr 2019 Apr 18;45(1):49. doi: 10.1186/s13052-019-0636-8. PMID: 30999961Free PMC Article
Ballard HA, Leavitt OS, Chin AC, Kabre R, Weese-Mayer DE, Hajduk J, Jagannathan N
Paediatr Anaesth 2018 Nov;28(11):963-973. Epub 2018 Sep 24 doi: 10.1111/pan.13475. PMID: 30251310
Schirwani S, Pysden K, Chetcuti P, Blyth M
J Clin Sleep Med 2017 Nov 15;13(11):1359-1362. doi: 10.5664/jcsm.6818. PMID: 28992836Free PMC Article
Khayat A, Medin D, Syed F, Moraes TJ, Bin-Hasan S, Narang I, Al-Saleh S, Amin R
Sleep Breath 2017 May;21(2):513-519. Epub 2017 Feb 11 doi: 10.1007/s11325-017-1478-5. PMID: 28190166
Basu SM, Chung FF, AbdelHakim SF, Wong J
Anesth Analg 2017 Jan;124(1):169-178. doi: 10.1213/ANE.0000000000001470. PMID: 27918326

Prognosis

Maloney MA, Kun SS, Keens TG, Perez IA
Expert Rev Respir Med 2018 Apr;12(4):283-292. Epub 2018 Feb 28 doi: 10.1080/17476348.2018.1445970. PMID: 29486608
Esteso Orduña B, Seijas Gómez R, García Esparza E, Briceño EM, Melero Llorente J, Fournier Del Castillo MC
J Clin Exp Neuropsychol 2018 Feb;40(1):75-83. Epub 2017 Jul 14 doi: 10.1080/13803395.2017.1319913. PMID: 28708033
Boka V, Lefkelidou A, Athanasiadou E
Eur Arch Paediatr Dent 2016 Jun;17(3):211-4. Epub 2015 Dec 24 doi: 10.1007/s40368-015-0213-9. PMID: 26702938
Massie J, Gillam L
Pediatr Pulmonol 2015 May;50(5):503-10. Epub 2014 Sep 5 doi: 10.1002/ppul.23097. PMID: 25195933
Kaymakçi A, Narter F, Yazar AS, Yilmaz MS
Turk J Pediatr 2012 Sep-Oct;54(5):519-22. PMID: 23427517

Clinical prediction guides

Musthaffa YM, Goyal V, Harris MA, Kapur N, Leger J, Harris M
J Pediatr Endocrinol Metab 2018 Dec 19;31(12):1325-1333. doi: 10.1515/jpem-2018-0086. PMID: 30447143
Esteso Orduña B, Seijas Gómez R, García Esparza E, Briceño EM, Melero Llorente J, Fournier Del Castillo MC
J Clin Exp Neuropsychol 2018 Feb;40(1):75-83. Epub 2017 Jul 14 doi: 10.1080/13803395.2017.1319913. PMID: 28708033
Schirwani S, Pysden K, Chetcuti P, Blyth M
J Clin Sleep Med 2017 Nov 15;13(11):1359-1362. doi: 10.5664/jcsm.6818. PMID: 28992836Free PMC Article
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
Kaymakçi A, Narter F, Yazar AS, Yilmaz MS
Turk J Pediatr 2012 Sep-Oct;54(5):519-22. PMID: 23427517

Recent systematic reviews

Basu SM, Chung FF, AbdelHakim SF, Wong J
Anesth Analg 2017 Jan;124(1):169-178. doi: 10.1213/ANE.0000000000001470. PMID: 27918326

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