Timothy Syndrome
Summary
Clinical characteristics.
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.
Diagnosis/testing.
Timothy syndrome is diagnosed by clinical features and by the presence of a pathogenic variant in CACNA1C, the gene encoding the CaV1.2 calcium channel.
Management.
Treatment of manifestations: Treatment includes use of beta-blockers and/or other antiarrhythmic drugs to maintain QT interval stability to prevent ventricular tachyarrhythmia. In some instances pacemakers can be placed during the first days of life to control 2:1 AV block and resultant bradycardia, but an implantable cardioverter defibrillator to prevent sudden cardiac death should be considered in all affected persons. Treatment for congenital heart defects follows usual protocols.
Prevention of secondary complications: Because anesthesia is a known trigger for cardiac arrhythmia, close cardiac monitoring is warranted during surgery.
Surveillance: Monitoring of serum glucose concentrations, especially in individuals treated with beta-blockers, which may mask hypoglycemic symptoms.
Agents/circumstances to avoid: Drugs reported to prolong QT interval; drugs and dietary practices that could lead to hypoglycemia.
Evaluation of relatives at risk: Although Timothy syndrome usually occurs as a result of a de novo pathogenic variant, in rare instances sibs could be affected because of parental germline mosaicism; thus, monitoring of fetal cardiac rate and function during at-risk pregnancies is warranted.
Genetic counseling.
Due to high mortality Timothy syndrome often results from a de novo pathogenic variant. The risk to sibs of a proband is small; however, because parental germline mosaicism occurs, the sibs of a proband may be at increased risk of inheriting a CACNA1C pathogenic variant. Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant has been identified.
Diagnosis
Timothy syndrome is a multisystem disorder characterized by cardiac, hand, facial, and neurodevelopmental features caused by pathogenic variants in the CaV1.2 L-type calcium channel gene, CACNA1C.
Suggestive Findings
Diagnosis of Timothy syndrome should be suspected in individuals with the following two features:
- A rate-corrected QT (QTc) interval >480 ms
- 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
Additional findings that may be present:
- Congenital heart defects (patent ductus arteriosus [PDA], patent foramen ovale [PFO], ventricular septal defect [VSD], tetralogy of Fallot [TOF], hypertrophic cardiomyopathy [HCM]) (in ~61% of individuals)
- Facial anomalies including depressed nasal bridge, low-set ears, thin vermilion of the upper lip, round face (in ~85% of individuals)
- Neurologic symptoms including autism, seizures, intellectual disability, hypotonia
Establishing the Diagnosis
The diagnosis of Timothy syndrome is established in a proband with the identification of a pathogenic variant in CACNA1C (see Table 1).
Molecular testing approaches may include the following:
- Targeted analysis for pathogenic variants of CACNA1C, followed by sequence analysis if no pathogenic variant is found
- Sequence analysis of CACNA1C, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found
- Use of a multigene panel that includes CACNA1C and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in Timothy Syndrome
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|---|---|
| CACNA1C | Targeted analysis for pathogenic variants | >95% 3 |
| Sequence analysis 4 | 100% 5 | |
| Gene-targeted deletion/duplication analysis 6 | Unknown; none reported 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
All 16 individuals with classic Timothy syndrome in whom molecular genetic testing was performed had the same pathogenic variant, p.Gly406Arg, in exon 8A of CACNA1C [Splawski et al 2004].
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gillis et al [2012] reported a pathogenic variant in exon 38.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No deletions or duplications of CACNA1C have been reported to cause Timothy syndrome. No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
Phenotypic features of Timothy syndrome are summarized in Table 2 and Table 3 [Reichenbach et al 1992; Marks et al 1995a; Marks et al 1995b; Splawski et al 2004; Lo-A-Njoe et al 2005; Timothy 2005, personal communication; Bloise 2006, personal communication].
Cardiac Manifestations
Long QT interval. In addition to QT interval prolongation, electrocardiographic manifestations that are common in individuals with Timothy syndrome and rare in other long QT syndromes (LQTSs) include:
- Atrioventricular (AV) block. The 2:1 AV block is likely caused by the extremely prolonged ventricular repolarization and refractory periods and not by AV node malfunction.
- Macroscopic T-wave alternans: Positive and negative T waves on a beat-to-beat basis. This ECG pattern may also be observed in individuals with LQTS type 3 (SCN5A pathogenic variant) and marked prolongation of the QT interval.
Age at diagnosis. In general, the diagnosis of Timothy syndrome is made within the first few days of life based on the markedly prolonged rate-corrected QT interval including bradycardia and 2:1 AV block [Reichenbach et al 1992, Marks et al 1995a, Lo-A-Njoe et al 2005]. Rarely, diagnosis may be delayed until age two to four years [Marks et al 1995b, Splawski et al 2005].
Occasionally, the diagnosis of Timothy syndrome is suspected prenatally because of fetal distress secondary to cardiac findings of 2:1 AV block or bradycardia with a heart rate that is usually 70-80. (Normal fetal heart rate is 120-150.) In one instance, biventricular hypertrophy and biventricular dysfunction were seen on fetal echocardiogram [Splawski et al 2005].
Congenital heart defects are present in approximately 70% of individuals and include PDA, PFO, VSD, TOF, and HCM.
Table 2.
Cardiac Phenotype of Classic Timothy Syndrome
| Cardiac Phenotype | Affected 1/Evaluated | % | Not Available |
|---|---|---|---|
| QTc prolongation | 25/25 | 100 | 0 |
| TWA | 7/10 | 70 | 15 |
| Functional 2:1 AV block | 17/21 | 81 | 4 |
| Tachyarrhythmias | 21/25 | 84 | 0 |
| Congenital heart disease (PDA, PFO, VSD, TOF, HCM) | 13/21 | 61 | 4 |
TWA = T-wave alternance
PDA = patent ductus arteriosus
PFO = patent foramen ovale
VSD = ventricular septal defect
TOF = tetralogy of Fallot
HCM = hypertrophic cardiomyopathy
- 1.
n = 25 (13 males, 12 females)
Extracardiac Manifestations
Cutaneous syndactyly may involve fingers two (index), three (middle), four (ring), and five (little), and bilateral cutaneous syndactyly of toes two and three. Syndactyly may be unilateral or bilateral and involve fingers four and five only, fingers three through five, or fingers two through five.
Craniofacial findings
- Low-set ears
- Depressed nasal bridge
- Premaxillary underdevelopment
- Baldness at birth and for the first two years of life, followed by thin scalp hair
- Small, widely spaced teeth and poor dental enamel with severe caries [Splawski et al 2004]
Neuropsychiatric involvement occurs in approximately 80% of individuals. Developmental delays observed include language, motor, and generalized cognitive impairment. Children were impaired in all areas of adaptive function, including communication, socialization, and daily living skills. Some children did not produce speech sounds (babbling) during infancy; others had significant problems in articulation and receptive and expressive language. Profound developmental delay, intractable seizures, stroke, cortical blindness, and myopathy were reported in one individual [Gillis et al 2012].
Five children were formally evaluated for autism [Splawski et al 2004]. Three met the diagnostic criteria, one met criteria for autism spectrum disorders, and one had severe delays in language development. Other children in this series were deceased or unavailable for evaluation. However, the association between autism spectrum disorders and Timothy syndrome was significant (p = 1.2x10-8). See Table 3.
Other findings
- Frequent infections (sinus, ear, respiratory) secondary to altered immune responses
- Intermittent hypoglycemia
- Joint contractures [Gillis et al 2012]
Table 3.
Extracardiac Phenotype of Timothy Syndrome
| Extracardiac Phenotype | Affected 1/Evaluated | % | Not Available |
|---|---|---|---|
| Cutaneous syndactyly | 25/25 | 100 | 0 |
| Craniofacial findings 2 | 18/21 | 85 | 4 |
| Sepsis or severe infections | 11/19 | 57 | 6 |
| Neuropsychiatric involvement | 15/19 | 78 | 6 |
| Autism 3 | 3/10 | 30 | 15 |
| Autism spectrum disorder 3 | 2/10 | 20 | 15 |
| Severe language delay 3 | 1/10 | 10 | 15 |
| Problems in social relationships + mild language delay 3 | 2/10 | 20 | 15 |
- 1.
n = 25: 13 males, 12 females
- 2.
Low-set ears, depressed nasal bridge, premaxillary underdevelopment, baldness at birth, thin scalp hair, small, widely spaced teeth
- 3.
Formal evaluation for autism was performed.
Cause of Death
Ventricular tachyarrhythmia (ventricular tachycardia and ventricular fibrillation), present in 80% of individuals, is the leading cause of death in Timothy syndrome. Average age at death in 14 of 25 children with classic Timothy syndrome was 2.5 years [Reichenbach et al 1992; Marks et al 1995a; Marks et al 1995b; Splawski et al 2004; Lo-A-Njoe et al 2005; Timothy 2005, personal communication; Bloise 2006, personal communication]. Two deaths reported were not related to tachyarrhythmi: one from severe infections (despite aggressive antibiotic therapy) and the other from complications of intractable hypoglycemia.
Genotype-Phenotype Correlations
The classic Timothy syndrome phenotype results from the p.Gly406Arg pathogenic variant in exon 8A, an exon contained in a specific splice variant of CACNA1C (see Molecular Genetics). Transcripts containing exon 8A are found in approximately 20% of all cardiac mRNAs. Compared to atypical Timothy syndrome (formerly referred to as type 2), classic Timothy syndrome has milder cardiac symptoms with an average QTc of 580 ms, rare multiple arrhythmias, and association of most arrhythmias with medications and/or anesthesia.
In contrast, the two individuals with atypical (type 2) Timothy syndrome had pathogenic variants (p.Gly402Ser and p.Gly406Arg) in exon 8 of an alternate splice form that represents 80% of all cardiac mRNAs, resulting in a more severe phenotype than classic Timothy syndrome with an average QTc of 640 ms and multiple episodes of unprovoked arrhythmia [Bloise et al 2007].
The milder phenotype of the second individual with atypical Timothy syndrome reported by Splawski et al [2005] is attributed to somatic mosaicism (in which the pathogenic variant is present in some, not all, cells).
Gillis et al [2012] reported a de novo (without confirmation of parental identity) novel CACNA1C pathogenic variant (p.Ala1473Gly) associated with a severe phenotype: profound developmental delay, intractable seizures, joint contractures, stroke, cortical blindness, and myopathy.
Penetrance
No study has specifically investigated the issue of the penetrance of TS. Of note, however, penetrance was 100% in the 18 affected individuals with Timothy syndrome reported to date [Splawski et al 2004, Lo-A-Njoe et al 2005, Splawski et al 2005] and it has remained very high (22 of 23 individuals with pathogenic variants had clearly abnormal electrocardiogram) in the two reports of gain-of-function CACN1C pathogenic variants in association with QT prolongation without extracardiac abnormalities [Fukuyama et al 2014, Wemhöner et al 2015].
Nomenclature
Timothy syndrome is named after Katherine Timothy, who followed children with the disorder for more than 14 years, identifying the non-cardiac manifestations and collecting samples that led to the discovery of the gene in which pathogenic variants are causative.
Prevalence
The prevalence of TS in not known. Its high mortality and severe manifestations point to a very low prevalence in the general population. Milder phenotypes of "isolated" QT prolongation associated with pathogenic variants in CACNA1C may have higher prevalence, although it has never been quantified.
Differential Diagnosis
Long QT syndrome (LQTS) is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes (TdP) ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death. LQTS is typically inherited in an autosomal dominant manner.
- Nonsyndromic autosomal dominant LQTS is characterized by QT interval prolongation. The most common symptom is TdP, which causes a syncopal event and is usually self-terminating. Syncope typically occurs without warning. In some instances, TdP degenerates to ventricular fibrillation, cardiac arrest, and sudden death if the individual is not defibrillated. Approximately 50%-70% of individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms; cardiac events may occur from infancy through middle age but are most common from the pre-teen years through the 20s.The clinical phenotype of an individual with a CACNA1C pathogenic variant but no extracardiac findings (i.e., LQTS type 8) can be indistinguishable from other forms of LQTS.
- Andersen-Tawil syndrome (long QT syndrome type 7) is characterized by a triad of features: periodic paralysis (episodic flaccid muscle weakness); prolonged QT interval and ventricular arrhythmias; and dysmorphic features including low-set ears, wide-spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. In the first or second decade, affected individuals present with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion.Approximately 60% of individuals with Andersen-Tawil syndrome have a detectable pathogenic variant in KCNJ2, which encodes the inward rectifier potassium channel protein, Kir2.1. KCNJ2 pathogenic variants may also cause a purely cardiac phenotype.Andersen-Tawil syndrome is inherited in an autosomal dominant manner. At least 50% of diagnosed individuals have an affected parent; the remaining cases are caused by de novo pathogenic variants.
- Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and LQTc usually greater than 500 msec. The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. More than half of untreated children with JLNS die prior to age 15 years.The genes in which pathogenic variants cause JLNS are KCNQ1 and KCNE1; mutation of these genes can also cause a purely cardiac phenotype.JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are typically heterozygous for a pathogenic variant in KCNQ1 or KCNE1. Rarely, only one parent may be a carrier; and the other pathogenic variant may arise de novo. Parents may or may not have the LQTS phenotype.
Acquired causes of QT prolongation due to electrolyte imbalance (e.g., hypokalemia) or QT-prolonging drugs (e.g., macrolide antibiotics) should be excluded before considering Timothy syndrome diagnosis. In such cases the removal of the offending agent should lead to ECG normalization. However, some cases of drug-induced QT prolongation may also have a genetic predisposition (including pathogenic variants in long QT syndrome genes).
Syndactyly. Cutaneous syndactyly of the fingers and cutaneous syndactyly of toes two and three can both be seen in numerous disorders. The latter is seen in Bardet-Biedl syndrome and Smith-Lemli-Opitz syndrome, in which it can be a significant clue to diagnosis.
Autism. See OMIM PS209850.
See Long QT syndrome: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Timothy syndrome, the following evaluations are recommended:
- Electrocardiogram
- Echocardiogram
- Developmental and neurologic assessment
- Orthopedist consultation for skeletal abnormalities
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Note: All medical procedures requiring anesthesia should be performed with caution (see Prevention of Secondary Complications).
Long QT interval
- Beta-blockers. While most individuals with Timothy syndrome are treated with beta-blockers to maintain QT interval stability and thereby prevent ventricular tachyarrhythmia, no data concerning the effectiveness of beta-blockers are available. Verapamil and ranolazine have been reported effective in case reports. However, no cohort-based analysis of the efficacy of pharmacologic therapy is available.
- Pacemaker. To control 2:1 AV block and resultant bradycardia, a pacemaker can be placed with general success within the first days of life.
- Implants. The implantable cardioverter defibrillator is most important in preventing sudden cardiac death in individuals with Timothy syndrome. An implant should be considered in every individual with confirmed diagnosis as soon as body weight allows the procedure (as determined by the treating clinician).
Congenital heart defects. Standard treatment is indicated.
Respiratory infections. Standard treatment (antibiotic therapy, steroids) is indicated. The possibility of reduced immune response should be considered.
Surgical release of syndactyly. Standard treatment is indicated.
Prevention of Primary Manifestations
Arrhythmias in Timothy syndrome must be prevented with the standard therapy described in Treatment of Manifestations.
Prevention of Secondary Complications
Anesthesia is a known trigger for cardiac arrhythmia in individuals with Timothy syndrome. Therefore, any surgical intervention must be performed under close cardiac monitoring. Because clinical experience with Timothy syndrome is scarce, all compounds used for general anesthesia should be regarded as potentially dangerous.
Prevention of extracardiac complications (including use of appropriate antibiotic prophylaxis/therapy before surgical intervention) must always be considered.
Surveillance
Surveillance includes the following:
- Monitoring of serum glucose concentrations, especially in individuals treated with beta-blockers, which may mask hypoglycemic symptoms
- A complete cardiac evaluation based on the status of the individual patient
Agents/Circumstances to Avoid
The following should be avoided:
- All drugs reported to prolong QT interval (CredibleMeds®)
- Drugs and dietary practices that could lead to hypoglycemia
Evaluation of Relatives at Risk
Using molecular genetic testing for the CACNA1C pathogenic variants found in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Pharmacologic therapies under investigation to shorten ventricular repolarization, restore one-to-one conduction, and reduce the risk of arrhythmias include sodium channel blockers and calcium channel blockers. Although verapamil has been used in one case [Jacobs et al 2006] and the partial effectiveness of sodium channel blockers mexiletine and ranolazine has been reported for two patients [Shah et al 2012, Gao et al 2013], no data are available to support their routine use in Timothy syndrome.
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.