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Congenital central hypoventilation(CCHS)

MedGen UID:
347052
Concept ID:
C1859049
Disease or Syndrome
Synonyms: CCHS; Congenital Central Hypoventilation Syndrome; Congenital central hypoventilation syndrome; Congenital failure of autonomic control; Congenital Ondine curse; Haddad syndrome; Idiopathic congenital central alveolar hypoventilation; Ondine curse (formerly); Ondine Syndrome; Ondine's curse (formerly); Ondine-Hirschsprung disease; Primary alveolar hypoventilation
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
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).
 
Genes: PHOX2B; RET; GDNF; EDN3; BDNF; ASCL1
Cytogenetic locations: 10q11.21; 11p14.1; 12q23.2; 20q13.32; 4p13; 5p13.2
OMIM: 209880

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]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
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.  http://ghr.nlm.nih.gov/condition/congenital-central-hypoventilation-syndrome

Clinical features

Ganglioneuroma
MedGen UID:
505431
Concept ID:
CN002716
Finding
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.
Neuroblastoma
MedGen UID:
505432
Concept ID:
CN002717
Finding
Neuroblastoma is a solid tumor that originate in neural crest cells of the sympathetic nervous system. Most neuroblastomas originate in the abdomen, and most abdominal neuroblastomas originate in the adrenal gland. Neuroblastomas can also originate in the thorax, usually in the posterior mediastinum.
Abnormality of the mouth
MedGen UID:
424981
Concept ID:
CN000149
Finding
An abnormality of the `mouth` (FMA:49184).
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
Misalignment of the visual axes of the eyes. In comitant strabismus the degree of ocular misalignment does not vary with the direction of gaze. In noncomitant strabismus the degree of misalignment varies depending on direction of gaze or which eye is fixating on the target. (Miller, Walsh & Hoyt's Clinical Neuro-Ophthalmology, 4th ed, p641)
Low-set ears
MedGen UID:
504425
Concept ID:
CN000345
Finding
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.
Sensorineural hearing impairment
MedGen UID:
504436
Concept ID:
CN000380
Finding
A type of `hearing impairment` (HP:0000365) in one or both ears related to an `abnormal` (PATO:0000460) `functionality` (PATO:0001509) of the `cochlear nerve` (FMA:53431).
Aganglionic megacolon
MedGen UID:
505171
Concept ID:
CN002042
Finding
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.
Ganglioneuroma
MedGen UID:
505431
Concept ID:
CN002716
Finding
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.
Neuroblastoma
MedGen UID:
505432
Concept ID:
CN002717
Finding
Neuroblastoma is a solid tumor that originate in neural crest cells of the sympathetic nervous system. Most neuroblastomas originate in the abdomen, and most abdominal neuroblastomas originate in the adrenal gland. Neuroblastomas can also originate in the thorax, usually in the posterior mediastinum.
Polyhydramnios
MedGen UID:
504854
Concept ID:
CN001423
Finding
The presence of excess amniotic fluid in the uterus during pregnancy.
Aganglionic megacolon
MedGen UID:
505171
Concept ID:
CN002042
Finding
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.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Excessive sweating. In the localized type, the most frequent sites are the palms, soles, axillae, inguinal folds, and the perineal area. Its chief cause is thought to be emotional. Generalized hyperhidrosis may be induced by a hot, humid environment, by fever, or by vigorous exercise.
Abnormality of the cardiovascular system
MedGen UID:
427888
Concept ID:
CN001481
Finding
Any abnormality of the `cardiovascular system` (FMA:7161).
Abnormality of temperature regulation
MedGen UID:
425258
Concept ID:
CN003869
Finding
An abnormality of `temperature homeostasis` (GO:0001659).
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Pathologic Function
A disorder characterized by cessation of breathing.
Hypoventilation
MedGen UID:
505358
Concept ID:
CN002525
Finding
A reduction in the amount of air transported into the pulmonary alveoli by breathing, leading to hypercapnia (increase in the partial pressure of carbon dioxide).
Muscular hypotonia
MedGen UID:
504768
Concept ID:
CN001147
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.

Recent clinical studies

Etiology

Gelwane G, Trang H, Carel JC, Dauger S, Léger J
J Pediatr 2013 Jan;162(1):171-6.e2. Epub 2012 Aug 3 doi: 10.1016/j.jpeds.2012.06.036. [Epub ahead of print] PMID: 22863257
Gallego J
Compr Physiol 2012 Jul;2(3):2255-79. doi: 10.1002/cphy.c100037. PMID: 23723037
Jones KL, Pivnick EK, Hines-Dowell S, Weese-Mayer DE, Berry-Kravis EM, Santiago T, Nnorom C, Pourcyrous M
Pediatrics 2012 Nov;130(5):e1382-4. Epub 2012 Oct 8 doi: 10.1542/peds.2011-3844. [Epub ahead of print] PMID: 23045564
Bittencourt LR, Pedrazzoli M, Yagihara F, Luz GP, Garbuio S, Moreira GA, Perfeito JA, Tufik S
Sleep Breath 2012 Dec;16(4):951-5. Epub 2011 Nov 19 doi: 10.1007/s11325-011-0614-x. [Epub ahead of print] PMID: 22102181
Hasegawa H, Kawasaki K, Inoue H, Umehara M, Takase M; Japanese Society of Pediatric Pulmonology Working Group (JSPPWG)
Pediatr Int 2012 Feb;54(1):123-6. Epub 2011 Nov 29 doi: 10.1111/j.1442-200X.2011.03484.x. [Epub ahead of print] PMID: 21958325

Diagnosis

Szczapa T, Beck J, Migdal M, Gadzinowski J
J Perinatol 2013 Nov;33(11):905-7. doi: 10.1038/jp.2013.89. PMID: 24169930
Ramanantsoa N, Gallego J
Respir Physiol Neurobiol 2013 Nov 1;189(2):272-9. Epub 2013 May 18 doi: 10.1016/j.resp.2013.05.018. [Epub ahead of print] PMID: 23692929
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. [Epub ahead of print] PMID: 23653299
Nirupam N, Sharma R, Chhapola V, Kanwal SK, Berry-Kravis EM, Kumar V
Indian J Pediatr 2013 Aug;80(8):688-90. Epub 2012 Jul 25 doi: 10.1007/s12098-012-0837-2. [Epub ahead of print] PMID: 22829249
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. [Epub ahead of print] 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. [Epub ahead of print] 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. [Epub ahead of print] 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. [Epub ahead of print] 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

Perez IA, Keens TG
Respir Physiol Neurobiol 2013 Jan 1;185(1):186-93. Epub 2012 Oct 23 doi: 10.1016/j.resp.2012.10.008. [Epub ahead of print] PMID: 23099221
Nirupam N, Sharma R, Chhapola V, Kanwal SK, Berry-Kravis EM, Kumar V
Indian J Pediatr 2013 Aug;80(8):688-90. Epub 2012 Jul 25 doi: 10.1007/s12098-012-0837-2. [Epub ahead of print] PMID: 22829249
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
Bittencourt LR, Pedrazzoli M, Yagihara F, Luz GP, Garbuio S, Moreira GA, Perfeito JA, Tufik S
Sleep Breath 2012 Dec;16(4):951-5. Epub 2011 Nov 19 doi: 10.1007/s11325-011-0614-x. [Epub ahead of print] PMID: 22102181

Clinical prediction guides

Szczapa T, Beck J, Migdal M, Gadzinowski J
J Perinatol 2013 Nov;33(11):905-7. doi: 10.1038/jp.2013.89. PMID: 24169930
Perez IA, Keens TG
Respir Physiol Neurobiol 2013 Jan 1;185(1):186-93. Epub 2012 Oct 23 doi: 10.1016/j.resp.2012.10.008. [Epub ahead of print] PMID: 23099221
Gelwane G, Trang H, Carel JC, Dauger S, Léger J
J Pediatr 2013 Jan;162(1):171-6.e2. Epub 2012 Aug 3 doi: 10.1016/j.jpeds.2012.06.036. [Epub ahead of print] PMID: 22863257
Kaymakçi A, Narter F, Yazar AS, Yilmaz MS
Turk J Pediatr 2012 Sep-Oct;54(5):519-22. PMID: 23427517
Rand CM, Yu M, Jennings LJ, Panesar K, Berry-Kravis EM, Zhou L, Weese-Mayer DE
Am J Med Genet A 2012 Sep;158A(9):2297-301. Epub 2012 Jul 20 doi: 10.1002/ajmg.a.35499. [Epub ahead of print] PMID: 22821709

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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