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Timothy syndrome(TS)

MedGen UID:
331395
Concept ID:
C1832916
Disease or Syndrome
Synonyms: Long QT syndrome 8; Long QT syndrome with syndactyly; Timothy Syndrome Type 1; Timothy Syndrome Type 2; TS
SNOMED CT: Long QT syndrome with syndactyly (699256006); Timothy syndrome classic type (699256006); Timothy syndrome type 1 (699256006)
 
Gene (location): CACNA1C (12p13.33)
OMIM®: 601005

Definition

Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 ms, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis of Timothy syndrome is generally made within the first few days of life although it may be suspected prenatally due to 2:1 AV block or bradycardia in the fetus. Hand/foot findings are unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three. Facial findings include depressed nasal bridge, low-set ears, thin vermilion border of the upper lip, and round face. Neuropsychiatric involvement includes global developmental delays and autism spectrum disorders. Ventricular tachyarrhythmia is the leading cause of death, followed by infection and complications of intractable hypoglycemia. Average age of death is 2.5 years. [from GeneReviews]

Additional descriptions

From OMIM
Timothy syndrome is characterized by multiorgan dysfunction, including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism (Splawski et al., 2004).  http://www.omim.org/entry/601005
From GHR
Timothy syndrome is a rare disorder that affects many parts of the body including the heart, digits (fingers and toes), and the nervous system.Timothy syndrome is characterized by a heart condition called long QT syndrome, which causes the heart (cardiac) muscle to take longer than usual to recharge between beats. This abnormality in the heart's electrical system can cause irregular heartbeats (arrhythmia), which can lead to sudden death. Many people with Timothy syndrome are also born with structural heart defects that affect the heart's ability to pump blood effectively. As a result of these serious heart problems, many people with Timothy syndrome live only into childhood. The most common cause of death is a form of arrhythmia called ventricular tachyarrhythmia, in which the lower chambers of the heart (the ventricles) beat abnormally fast and lead to cardiac arrest.Timothy syndrome is also characterized by webbing or fusion of the skin between some fingers or toes (cutaneous syndactyly). About half of affected people have distinctive facial features such as a flattened nasal bridge, low-set ears, a small upper jaw, and a thin upper lip. Children with this condition have small, misplaced teeth and frequent cavities (dental caries). Additional signs and symptoms of Timothy syndrome can include baldness at birth, frequent infections, episodes of low blood sugar (hypoglycemia), and an abnormally low body temperature (hypothermia).Researchers have found that many children with Timothy syndrome have the characteristic features of autism or similar conditions known as autistic spectrum disorders. Affected children tend to have impaired communication and socialization skills, as well as delayed development of speech and language. Other nervous system abnormalities, including intellectual disability and seizures, can also occur in children with Timothy syndrome.Researchers have identified two forms of Timothy syndrome. Type 1, which is also known as the classic type, includes all of the characteristic features described above. Type 2, or the atypical type, causes a more severe form of long QT syndrome and a greater risk of arrhythmia and sudden death. Unlike the classic type, the atypical type does not appear to cause webbing of the fingers or toes.  https://ghr.nlm.nih.gov/condition/timothy-syndrome

Clinical features

Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are revered to as \
Prolonged QT interval
MedGen UID:
57494
Concept ID:
C0151878
Finding
Increased time between the start of the Q wave and the end of the T wave as measured by the electrocardiogram (EKG).
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are revered to as \

Recent clinical studies

Etiology

Nuzzi LC, Pike CM, Lewine EB, Cerrato FE, Alexander ME, Ferrari LR, Bae DS, Taghinia A, Waters PM, Labow BI
J Hand Surg Am 2015 Mar;40(3):452-5. Epub 2014 Dec 24 doi: 10.1016/j.jhsa.2014.10.053. PMID: 25542431
Gao Y, Xue X, Hu D, Liu W, Yuan Y, Sun H, Li L, Timothy KW, Zhang L, Li C, Yan GX
Circ Arrhythm Electrophysiol 2013 Jun;6(3):614-22. Epub 2013 Apr 11 doi: 10.1161/CIRCEP.113.000092. PMID: 23580742
Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L, Babul-Hirji R, Chitayat D
Am J Med Genet A 2012 Jan;158A(1):182-7. Epub 2011 Nov 21 doi: 10.1002/ajmg.a.34355. PMID: 22106044Free PMC Article
Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE
Nature 2011 Mar 10;471(7337):230-4. Epub 2011 Feb 9 doi: 10.1038/nature09855. PMID: 21307850Free PMC Article
Yates D, Yates A, Collyer T
Paediatr Anaesth 2007 May;17(5):492-5. doi: 10.1111/j.1460-9592.2006.02160.x. PMID: 17474959

Diagnosis

Kawaida M, Abe T, Nakanishi T, Miyahara Y, Yamagishi H, Sakamoto M, Yamada T
Pathol Int 2016 Oct;66(10):587-592. Epub 2016 Sep 4 doi: 10.1111/pin.12456. PMID: 27593853
Diep V, Seaver LH
Am J Med Genet A 2015 Nov;167A(11):2780-5. Epub 2015 Jul 31 doi: 10.1002/ajmg.a.37258. PMID: 26227324
Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP
Am J Med Genet A 2015 Mar;167A(3):629-34. doi: 10.1002/ajmg.a.36924. PMID: 25691416
Boczek NJ, Miller EM, Ye D, Nesterenko VV, Tester DJ, Antzelevitch C, Czosek RJ, Ackerman MJ, Ware SM
Heart Rhythm 2015 Jan;12(1):211-9. Epub 2014 Sep 28 doi: 10.1016/j.hrthm.2014.09.051. PMID: 25260352Free PMC Article
Papineau SD, Wilson S
Pediatr Dent 2014 May-Jun;36(3):245-9. PMID: 24960393

Therapy

Corona-Rivera JR, Barrios-Prieto E, Nieto-García R, Bloise R, Priori S, Napolitano C, Bobadilla-Morales L, Corona-Rivera A, Zapata-Aldana E, Peña-Padilla C, Rivera-Vargas J, Chavana-Naranjo E
Eur J Med Genet 2015 Jun-Jul;58(6-7):332-5. Epub 2015 Apr 13 doi: 10.1016/j.ejmg.2015.04.001. PMID: 25882468
An HS, Choi EY, Kwon BS, Kim GB, Bae EJ, Noh CI, Choi JY, Park SS
J Korean Med Sci 2013 May;28(5):788-91. Epub 2013 May 2 doi: 10.3346/jkms.2013.28.5.788. PMID: 23678275Free PMC Article
Gao Y, Xue X, Hu D, Liu W, Yuan Y, Sun H, Li L, Timothy KW, Zhang L, Li C, Yan GX
Circ Arrhythm Electrophysiol 2013 Jun;6(3):614-22. Epub 2013 Apr 11 doi: 10.1161/CIRCEP.113.000092. PMID: 23580742
Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L, Babul-Hirji R, Chitayat D
Am J Med Genet A 2012 Jan;158A(1):182-7. Epub 2011 Nov 21 doi: 10.1002/ajmg.a.34355. PMID: 22106044Free PMC Article
Shah DP, Baez-Escudero JL, Weisberg IL, Beshai JF, Burke MC
Pacing Clin Electrophysiol 2012 Mar;35(3):e62-4. Epub 2010 Sep 30 doi: 10.1111/j.1540-8159.2010.02913.x. PMID: 20883512

Prognosis

Nuzzi LC, Pike CM, Lewine EB, Cerrato FE, Alexander ME, Ferrari LR, Bae DS, Taghinia A, Waters PM, Labow BI
J Hand Surg Am 2015 Mar;40(3):452-5. Epub 2014 Dec 24 doi: 10.1016/j.jhsa.2014.10.053. PMID: 25542431
Boczek NJ, Miller EM, Ye D, Nesterenko VV, Tester DJ, Antzelevitch C, Czosek RJ, Ackerman MJ, Ware SM
Heart Rhythm 2015 Jan;12(1):211-9. Epub 2014 Sep 28 doi: 10.1016/j.hrthm.2014.09.051. PMID: 25260352Free PMC Article
Gao Y, Xue X, Hu D, Liu W, Yuan Y, Sun H, Li L, Timothy KW, Zhang L, Li C, Yan GX
Circ Arrhythm Electrophysiol 2013 Jun;6(3):614-22. Epub 2013 Apr 11 doi: 10.1161/CIRCEP.113.000092. PMID: 23580742
Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L, Babul-Hirji R, Chitayat D
Am J Med Genet A 2012 Jan;158A(1):182-7. Epub 2011 Nov 21 doi: 10.1002/ajmg.a.34355. PMID: 22106044Free PMC Article
Etheridge SP, Bowles NE, Arrington CB, Pilcher T, Rope A, Wilde AA, Alders M, Saarel EV, Tavernier R, Timothy KW, Tristani-Firouzi M
Am J Med Genet A 2011 Oct;155A(10):2578-83. Epub 2011 Sep 9 doi: 10.1002/ajmg.a.34223. PMID: 21910241

Clinical prediction guides

Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, Johnson AJ, Kanter R, Ackerman MJ
Circ Arrhythm Electrophysiol 2015 Oct;8(5):1122-32. Epub 2015 Aug 7 doi: 10.1161/CIRCEP.115.002745. PMID: 26253506Free PMC Article
Corona-Rivera JR, Barrios-Prieto E, Nieto-García R, Bloise R, Priori S, Napolitano C, Bobadilla-Morales L, Corona-Rivera A, Zapata-Aldana E, Peña-Padilla C, Rivera-Vargas J, Chavana-Naranjo E
Eur J Med Genet 2015 Jun-Jul;58(6-7):332-5. Epub 2015 Apr 13 doi: 10.1016/j.ejmg.2015.04.001. PMID: 25882468
Song L, Awari DW, Han EY, Uche-Anya E, Park SH, Yabe YA, Chung WK, Yazawa M
Stem Cells Transl Med 2015 May;4(5):468-75. Epub 2015 Mar 13 doi: 10.5966/sctm.2014-0245. PMID: 25769651Free PMC Article
Boczek NJ, Miller EM, Ye D, Nesterenko VV, Tester DJ, Antzelevitch C, Czosek RJ, Ackerman MJ, Ware SM
Heart Rhythm 2015 Jan;12(1):211-9. Epub 2014 Sep 28 doi: 10.1016/j.hrthm.2014.09.051. PMID: 25260352Free PMC Article
Barrett CF, Tsien RW
Proc Natl Acad Sci U S A 2008 Feb 12;105(6):2157-62. Epub 2008 Feb 4 doi: 10.1073/pnas.0710501105. PMID: 18250309Free PMC Article

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