* Extremities examination of patients with Timothy syndrome shows webbed fingers(syndactyly) and toes.<ref name="pmid23678275">{{cite journal| author=An HS, Choi EY, Kwon BS, Kim GB, Bae EJ, Noh CI et al.| title=Sudden cardiac arrest during anesthesia in a 30-month-old boy with syndactyly: a case of genetically proven Timothy syndrome. | journal=J Korean Med Sci | year= 2013 | volume= 28 | issue= 5 | pages= 788-91 | pmid=23678275 | doi=10.3346/jkms.2013.28.5.788 | pmc=3653096 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23678275 }}</ref>
* Extremities examination of patients with Timothy syndrome shows webbed fingers(syndactyly) and toes.<ref name="pmid23678275">{{cite journal| author=An HS, Choi EY, Kwon BS, Kim GB, Bae EJ, Noh CI et al.| title=Sudden cardiac arrest during anesthesia in a 30-month-old boy with syndactyly: a case of genetically proven Timothy syndrome. | journal=J Korean Med Sci | year= 2013 | volume= 28 | issue= 5 | pages= 788-91 | pmid=23678275 | doi=10.3346/jkms.2013.28.5.788 | pmc=3653096 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23678275 }}</ref>
OR
Signs and symptoms
* [[Clubbing]]
.<ref name="Marks_1995a">{{cite journal | author = Marks M, Whisler S, Clericuzio C, Keating M | title = A new form of long QT syndrome associated with syndactyly. | journal = J Am Coll Cardiol | volume = 25 | issue = 1 | pages = 59-64 | year = 1995 | id = PMID 7798527}}</ref><ref name="Marks_1995b">{{cite journal | author = Marks M, Trippel D, Keating M | title = Long QT syndrome associated with syndactyly identified in females. | journal = Am J Cardiol | volume = 76 | issue = 10 | pages = 744-5 | year = 1995 | id = PMID 7572644}}</ref><ref name="Splawski_2004">{{cite journal | author = Splawski I, Timothy K, Sharpe L, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz P, Joseph R, Condouris K, Tager-Flusberg H, Priori S, Sanguinetti M, Keating M | title = Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. | journal = Cell | volume = 119 | issue = 1 | pages = 19-31 | year = 2004 | id = PMID 15454078}}</ref>
* [[Cyanosis]]
* Pitting/non-pitting [[edema]] of the upper/lower extremities
* Muscle atrophy
* Fasciculations in the upper/lower extremity
**
===Signs and symptoms===
The most striking sign of Timothy syndrome is the co-occurrence of both [[syndactyly]] (~0.03% of births) and [[long QT syndrome]] (1% per year) in a single patient. Other common symptoms of Timothy syndrome are cardiac [[arrhythmia]] (94%), heart malformations (59%), [[autism]] or an autism spectrum disorder (80% who survive long enough for evaluation). Facial dysmorphologies such as flattened noses also occur in approximately half of patients. Children with this disorder have small teeth which, due to poor [[Tooth enamel|enamel]] coating, are prone to [[dental cavities]] and often require removal. The average age of death due to complications of these symptoms is 2.5 years.<ref name="Marks_1995a">{{cite journal | author = Marks M, Whisler S, Clericuzio C, Keating M | title = A new form of long QT syndrome associated with syndactyly. | journal = J Am Coll Cardiol | volume = 25 | issue = 1 | pages = 59-64 | year = 1995 | id = PMID 7798527}}</ref><ref name="Marks_1995b">{{cite journal | author = Marks M, Trippel D, Keating M | title = Long QT syndrome associated with syndactyly identified in females. | journal = Am J Cardiol | volume = 76 | issue = 10 | pages = 744-5 | year = 1995 | id = PMID 7572644}}</ref><ref name="Splawski_2004">{{cite journal | author = Splawski I, Timothy K, Sharpe L, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz P, Joseph R, Condouris K, Tager-Flusberg H, Priori S, Sanguinetti M, Keating M | title = Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. | journal = Cell | volume = 119 | issue = 1 | pages = 19-31 | year = 2004 | id = PMID 15454078}}</ref>
Atypical Timothy syndrome has largely the same symptoms as the classical form. Differences in the atypical form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and [[atrial fibrillation]]s. Patients with atypical Timothy syndrome also have more facial deformities, including protruding foreheads and tongues. Finally, one patient with atypical Timothy syndrome had body development discrepancy wherein her upper body was normally developed (that of a 6-year-old) while her lower half resembled a 2 or 3-year-old.<ref name="Splawski_2005">{{cite journal | author = Splawski I, Timothy K, Decher N, Kumar P, Sachse F, Beggs A, Sanguinetti M, Keating M | title = Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. | journal = Proc Natl Acad Sci U S A | volume = 102 | issue = 23 | pages = 8089-96; discussion 8086-8 | year = 2005 | id = PMID 15863612}}</ref>
Atypical Timothy syndrome has largely the same symptoms as the classical form. Differences in the atypical form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and [[atrial fibrillation]]s. Patients with atypical Timothy syndrome also have more facial deformities, including protruding foreheads and tongues. Finally, one patient with atypical Timothy syndrome had body development discrepancy wherein her upper body was normally developed (that of a 6-year-old) while her lower half resembled a 2 or 3-year-old.<ref name="Splawski_2005">{{cite journal | author = Splawski I, Timothy K, Decher N, Kumar P, Sachse F, Beggs A, Sanguinetti M, Keating M | title = Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. | journal = Proc Natl Acad Sci U S A | volume = 102 | issue = 23 | pages = 8089-96; discussion 8086-8 | year = 2005 | id = PMID 15863612}}</ref>
Synonyms and keywords: Long QT syndrome 8; LQT8; Long QT syndrome with syndactyly; TS
Overview
Timothy syndrome is a rare syndrome that follows autosomal dominant inheritance pattern. Timothy syndrome is a multisystem disorder characterized by physiological and developmental defects which include long QT-prolongation, arrhythmias, structural heart defects, syndactyly and autism spectrum disorders. Timothy syndrome may be classified into 2 groups, classical form(type-1) and atypical form(type-2). Timothy syndrome caused by mutations in CACNA1C, which encodes for calcium channel α subunit. Timothy syndrome often ends in early death. The United States of America in order to categorize a condition as a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed in 1983 by congress for the rare diseases. Today an average of 25-30 million Americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number.
Historical Perspective
Timothy syndrome was first discovered by Reichenbach and Marks, in 1992.[1][2]
In 1995, Splawski, Reichenbach, and Marks were the first to give the name Timothy syndrome in the honor of Dr. Katherine W. Timothy who did the phenotypic analysis.[3]
Classification
Timothy syndrome may be classified into 2 groups as follows:[4][5][6]
There is one more mutation in G406R that is associated with the timothy syndrome.[12]
The location of G406R is in domain one segment six (D1S6) which holds glycine at this position and plays a very important role in voltage-dependent inactivation
Due to the fact that exon 8(atypical Timothy syndrome) is more expressed in heart muscles than that of exon 8a(classic Timothy syndrome) patients with exon 8 mutation have a severe form of long QT interval.
The incidence of timothy syndrome is unknown worldwide.
Only 20 cases were reported worldwide.
Prevalence
The prevalence of timothy syndrome is less than 1 per 100,000 individuals worldwide.
Mortality rate
In patients with timothy syndrome the average age of death is 2.5 years
Age
Timothy syndrome commonly affects individuals of younger age group, the median age of diagnosis is usally within the first few days after birth.
Race
There is no racial predilection to Timothy syndrome.
Gender
Timothy syndrome affects men and women equally.
Risk Factors
There are no established risk factors for Timothy syndrome.
Screening
There is insufficient evidence to recommend routine screening for Timothy syndrome.
Natural History, Complications, Prognosis
Natural History
The symptoms of Timothy syndrome usually develop in the first decade of life, and start with symptoms such as cardiac, hand/foot, facial, and neurodevelopmental symptoms.
Bilateral cutaneous syndactyly of the third, fourth, and fifth fingers. Case courtesy by Hyo Soon An Et Al[28]Ventricular fibrillation
Physical Examination
Physical examination of patients with [disease name] is usually normal. OR Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3]. OR The presence of [finding(s)] on physical examination is diagnostic of [disease name]. OR The presence of [finding(s)] on physical examination is highly suggestive of [disease name].
Appearance of the Patient
Patients with [disease name] usually appear [general appearance].
Pupils non-reactive to light / non-reactive to accommodation / non-reactive to neither light nor accommodation
Ophthalmoscopic exam may be abnormal with findings of ___
Hearing acuity may be reduced
Weber test may be abnormal (Note: A positive Weber test is considered a normal finding / A negative Weber test is considered an abnormal finding. To avoid confusion, you may write "abnormal Weber test".)
Rinne test may be positive (Note: A positive Rinne test is considered a normal finding / A negative Rinne test is considered an abnormal finding. To avoid confusion, you may write "abnormal Rinne test".)
A high/low grade early/late systolic murmur / diastolic murmur best heard at the base/apex/(specific valve region) may be heard using the bell/diaphgram of the stethoscope
Abdomen
Abdominal examination of patients with [disease name] is usually normal.
Atypical Timothy syndrome has largely the same symptoms as the classical form. Differences in the atypical form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and atrial fibrillations. Patients with atypical Timothy syndrome also have more facial deformities, including protruding foreheads and tongues. Finally, one patient with atypical Timothy syndrome had body development discrepancy wherein her upper body was normally developed (that of a 6-year-old) while her lower half resembled a 2 or 3-year-old.[23]
Interestingly, children with Timothy syndrome tend to be born via cesarean section due to fetal distress.
Physical Examination
Extremities
Syndactyly and other deformities are typically observed and diagnosed at birth.
Electrocardiogram
Long QT syndrome sometimes presents itself as a complication due to surgery to correct syndactyly. Other times, children collapse spontaneously while playing. In all cases, it is confirmed with ECG measurements. The sequencing of the CACNA1C gene further confirms the diagnosis.
Treatment
Surgery is typically used to correct structural heart defects and syndactyly. Propanolol or beta-adrenergic blockers are often prescribed as well as insertion of a pacemaker to maintain proper heart rhythm. With the characterization of Timothy syndrome mutations indicating that they cause defects in calcium currents, it has been suggested that calcium channel blockers may be effective as a therapeutic agent.[23]
↑ 22.022.1Splawski I, Timothy K, Sharpe L, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz P, Joseph R, Condouris K, Tager-Flusberg H, Priori S, Sanguinetti M, Keating M (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. PMID 15454078.CS1 maint: Multiple names: authors list (link)
↑ 23.023.123.2Splawski I, Timothy K, Decher N, Kumar P, Sachse F, Beggs A, Sanguinetti M, Keating M (2005). "Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations". Proc Natl Acad Sci U S A. 102 (23): 8089–96, discussion 8086-8. PMID 15863612.CS1 maint: Multiple names: authors list (link)
↑Marks M, Whisler S, Clericuzio C, Keating M (1995). "A new form of long QT syndrome associated with syndactyly". J Am Coll Cardiol. 25 (1): 59–64. PMID 7798527.CS1 maint: Multiple names: authors list (link)
↑Marks M, Trippel D, Keating M (1995). "Long QT syndrome associated with syndactyly identified in females". Am J Cardiol. 76 (10): 744–5. PMID 7572644.CS1 maint: Multiple names: authors list (link)