Timothy syndrome

Jump to: navigation, search

WikiDoc Resources for Timothy syndrome

Articles

Most recent articles on Timothy syndrome

Most cited articles on Timothy syndrome

Review articles on Timothy syndrome

Articles on Timothy syndrome in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Timothy syndrome

Images of Timothy syndrome

Photos of Timothy syndrome

Podcasts & MP3s on Timothy syndrome

Videos on Timothy syndrome

Evidence Based Medicine

Cochrane Collaboration on Timothy syndrome

Bandolier on Timothy syndrome

TRIP on Timothy syndrome

Clinical Trials

Ongoing Trials on Timothy syndrome at Clinical Trials.gov

Trial results on Timothy syndrome

Clinical Trials on Timothy syndrome at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Timothy syndrome

NICE Guidance on Timothy syndrome

NHS PRODIGY Guidance

FDA on Timothy syndrome

CDC on Timothy syndrome

Books

Books on Timothy syndrome

News

Timothy syndrome in the news

Be alerted to news on Timothy syndrome

News trends on Timothy syndrome

Commentary

Blogs on Timothy syndrome

Definitions

Definitions of Timothy syndrome

Patient Resources / Community

Patient resources on Timothy syndrome

Discussion groups on Timothy syndrome

Patient Handouts on Timothy syndrome

Directions to Hospitals Treating Timothy syndrome

Risk calculators and risk factors for Timothy syndrome

Healthcare Provider Resources

Symptoms of Timothy syndrome

Causes & Risk Factors for Timothy syndrome

Diagnostic studies for Timothy syndrome

Treatment of Timothy syndrome

Continuing Medical Education (CME)

CME Programs on Timothy syndrome

International

Timothy syndrome en Espanol

Timothy syndrome en Francais

Business

Timothy syndrome in the Marketplace

Patents on Timothy syndrome

Experimental / Informatics

List of terms related to Timothy syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S[2]

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][7]
Type Gene Protein involved Location Mutations Inheritance pattern Symptoms
Classic Timothy syndrome CACNA1C Voltage-dependent L-type calcium channel subunit alpha-1C 12p13.33 Exon 8 a Autosomal dominant Long QT syndrome with syndactyly
Atypical Timothy syndrome CACNA1C Voltage-dependent L-type calcium channel subunit alpha-1C 12p13.33 Exon 8 Autosomal dominant A very severe form of long QT syndrome without syndactyly

Pathophysiology

  • 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.

Causes

Genetic Causes

Differentiating Timothy syndrome from other Diseases

Epidemiology and Demographics

Incidence

  • 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

Screening

  • There is insufficient evidence to recommend routine screening for Timothy syndrome.

Natural History, Complications, Prognosis

Natural History

Complications

Prognosis

  • The prognosis for patients diagnosed with Timothy syndrome is grim.
  • The average age of death is 2.5 years in patients with Timothy syndrome.[28] [29]

Diagnosis

Diagnostic study of choice

Symptoms

Common Symptoms

Common symptoms of Timothy syndrome include:[31][32]

Less Common Symptoms

Less common symptoms of Timothy syndrome include:[33][34]

Electrocardiogram

Physical Examination

Characteristic phenotypic features of Timothy syndrome: bald head and lower–set ears, webbing of fingers and toes. Case courtesy by U. Krause Et Al[42]

HEENT

Heart

Neurodevelopmental

Extremities

Laboratory Findings

  • There are no diagnostic laboratory findings associated with Timothy syndrome.

Ultrasound

  • Ultrasound may be helpful in the diagnosis of syndactyly during pregnancy with Timothy syndrome patients.

X Ray, CT scan and MRI scan

Medical Therapy

Interventions

  • The feasibility of interventions depends on the severity of Timothy syndrome patients at the time of diagnosis which include:[57][58]

Implantable cardioverter-defibrillators (ICDs)

  • ICDs are good alternative choice of treatment for the patients who are resistant to beta blockers.

Left cardiac sympathetic denervation (LCSD)

Pacemaker

Surgery

  • Surgery is not the first-line treatment option for patients with Timothy syndrome. Surgery is usually reserved for patients with either:

Primary Prevention

Secondary Prevention

References

  1. 1.0 1.1 Reichenbach H, Meister EM, Theile H (1992). "[The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet]". Kinderarztl Prax. 60 (2): 54–6. PMID 1318983.
  2. Marks ML, Trippel DL, Keating MT (1995). "Long QT syndrome associated with syndactyly identified in females". Am J Cardiol. 76 (10): 744–5. doi:10.1016/s0002-9149(99)80216-1. PMID 7572644.
  3. Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L; et al. (2012). "Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome". Am J Med Genet A. 158A (1): 182–7. doi:10.1002/ajmg.a.34355. PMC 3319791. PMID 22106044.
  4. Schultz D, Mikala G, Yatani A, Engle DB, Iles DE, Segers B; et al. (1993). "Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart". Proc Natl Acad Sci U S A. 90 (13): 6228–32. doi:10.1073/pnas.90.13.6228. PMC 46901. PMID 8392192.
  5. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP (2015). "Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development". Am J Med Genet A. 167A (3): 629–34. doi:10.1002/ajmg.a.36924. PMID 25691416.
  6. Soldatov NM, Bouron A, Reuter H (1995). "Different voltage-dependent inhibition by dihydropyridines of human Ca2+ channel splice variants". J Biol Chem. 270 (18): 10540–3. doi:10.1074/jbc.270.18.10540. PMID 7737988.
  7. Lyford GL, Strege PR, Shepard A, Ou Y, Ermilov L, Miller SM; et al. (2002). "alpha(1C) (Ca(V)1.2) L-type calcium channel mediates mechanosensitive calcium regulation". Am J Physiol Cell Physiol. 283 (3): C1001–8. doi:10.1152/ajpcell.00140.2002. PMID 12176756.
  8. Walsh MA, Turner C, Timothy KW, Seller N, Hares DL, James AF; et al. (2018). "A multicentre study of patients with Timothy syndrome". Europace. 20 (2): 377–385. doi:10.1093/europace/euw433. PMID 28371864.
  9. Baurand A, Falcon-Eicher S, Laurent G, Villain E, Bonnet C, Thauvin-Robinet C; et al. (2017). "Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing". Am J Med Genet A. 173 (2): 531–536. doi:10.1002/ajmg.a.38045. PMID 27868338.
  10. Cheng EP, Yuan C, Navedo MF, Dixon RE, Nieves-Cintrón M, Scott JD; et al. (2011). "Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein". Circ Res. 109 (3): 255–61. doi:10.1161/CIRCRESAHA.111.248252. PMC 3151468. PMID 21700933.
  11. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R; et al. (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078.
  12. Dixon RE, Cheng EP, Mercado JL, Santana LF (2012). "L-type Ca2+ channel function during Timothy syndrome". Trends Cardiovasc Med. 22 (3): 72–6. doi:10.1016/j.tcm.2012.06.015. PMC 3640256. PMID 22999068.
  13. Dick IE, Joshi-Mukherjee R, Yang W, Yue DT (2016). "Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation". Nat Commun. 7: 10370. doi:10.1038/ncomms10370. PMC 4740114. PMID 26822303.
  14. Sepp R, Hategan L, Bácsi A, Cseklye J, Környei L, Borbás J; et al. (2017). "Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations". Am J Med Genet A. 173 (3): 784–789. doi:10.1002/ajmg.a.38084. PMID 28211989.
  15. De Oliveira CC, Figueiredo EA, Gazzinelli G, Howells RE, Pellegrino J (1975). "Biochemical changes in the transformation of Schistosoma mansoni cercariae to schistosomules". Comp Biochem Physiol B. 51 (4): 417–20. doi:10.1016/0305-0491(75)90031-0. PMID 1149428.
  16. Betzenhauser MJ, Pitt GS, Antzelevitch C (2015). "Calcium Channel Mutations in Cardiac Arrhythmia Syndromes". Curr Mol Pharmacol. 8 (2): 133–42. doi:10.2174/1874467208666150518114857. PMC 4762596. PMID 25981977.
  17. Corona-Rivera JR, Barrios-Prieto E, Nieto-García R, Bloise R, Priori S, Napolitano C; et al. (2015). "Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1". Eur J Med Genet. 58 (6–7): 332–5. doi:10.1016/j.ejmg.2015.04.001. PMID 25882468.
  18. Boczek NJ, Miller EM, Ye D, Nesterenko VV, Tester DJ, Antzelevitch C; et al. (2015). "Novel Timothy syndrome mutation leading to increase in CACNA1C window current". Heart Rhythm. 12 (1): 211–9. doi:10.1016/j.hrthm.2014.09.051. PMC 4907369. PMID 25260352.
  19. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
  20. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC; et al. (2001). "Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome". JAMA. 286 (18): 2264–9. doi:10.1001/jama.286.18.2264. PMID 11710892.
  21. Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C; et al. (2007). "Prevalence of long-QT syndrome gene variants in sudden infant death syndrome". Circulation. 115 (3): 361–7. doi:10.1161/CIRCULATIONAHA.106.658021. PMID 17210839.
  22. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C; et al. (2001). "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias". Circulation. 103 (1): 89–95. doi:10.1161/01.cir.103.1.89. PMID 11136691.
  23. Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C; et al. (2006). "Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study". Int J Legal Med. 120 (3): 129–37. doi:10.1007/s00414-005-0019-0. PMID 16012827.
  24. Juang JJ, Horie M (2016). "Genetics of Brugada syndrome". J Arrhythm. 32 (5): 418–425. doi:10.1016/j.joa.2016.07.012. PMC 5063259. PMID 27761167.
  25. Thomas D, Wimmer AB, Karle CA, Licka M, Alter M, Khalil M; et al. (2005). "Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome". Cardiovasc Res. 67 (3): 487–97. doi:10.1016/j.cardiores.2005.05.003. PMID 15950200.
  26. Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L; et al. (2012). "Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome". Am J Med Genet A. 158A (1): 182–7. doi:10.1002/ajmg.a.34355. PMC 3319791. PMID 22106044.
  27. Sepp R, Hategan L, Bácsi A, Cseklye J, Környei L, Borbás J; et al. (2017). "Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations". Am J Med Genet A. 173 (3): 784–789. doi:10.1002/ajmg.a.38084. PMID 28211989.
  28. 28.0 28.1 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 (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. PMID 15454078.
  29. 29.0 29.1 Splawski 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.
  30. Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L; et al. (2012). "Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome". Am J Med Genet A. 158A (1): 182–7. doi:10.1002/ajmg.a.34355. PMC 3319791. PMID 22106044.
  31. Tester DJ, Ackerman MJ (2014). "Genetics of long QT syndrome". Methodist Debakey Cardiovasc J. 10 (1): 29–33. doi:10.14797/mdcj-10-1-29. PMC 4051331. PMID 24932360.
  32. Sepp R, Hategan L, Bácsi A, Cseklye J, Környei L, Borbás J; et al. (2017). "Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations". Am J Med Genet A. 173 (3): 784–789. doi:10.1002/ajmg.a.38084. PMID 28211989.
  33. Tester DJ, Ackerman MJ (2014). "Genetics of long QT syndrome". Methodist Debakey Cardiovasc J. 10 (1): 29–33. doi:10.14797/mdcj-10-1-29. PMC 4051331. PMID 24932360.
  34. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP (2015). "Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development". Am J Med Genet A. 167A (3): 629–34. doi:10.1002/ajmg.a.36924. PMID 25691416.
  35. "A rare association of long QT syndrome and syndactyly: Timothy Syndrome (LQT 8)".
  36. Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S; et al. (2011). "Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals". J Am Coll Cardiol. 57 (1): 51–9. doi:10.1016/j.jacc.2010.07.038. PMC 3332533. PMID 21185501.
  37. Marks ML, Whisler SL, Clericuzio C, Keating M (1995). "A new form of long QT syndrome associated with syndactyly". J Am Coll Cardiol. 25 (1): 59–64. doi:10.1016/0735-1097(94)00318-k. PMID 7798527.
  38. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH; et al. (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. doi:10.1073/pnas.0502506102. PMC 1149428. PMID 15863612.
  39. "TRPM4 non-selective cation channel variants in long QT syndrome" Check |url= value (help).
  40. Tester DJ, Ackerman MJ (2014). "Genetics of long QT syndrome". Methodist Debakey Cardiovasc J. 10 (1): 29–33. doi:10.14797/mdcj-10-1-29. PMC 4051331. PMID 24932360.
  41. "Sudden Cardiac Arrest during Anesthesia in a 30-Month-Old Boy with Syndactyly: A Case of Genetically Proven Timothy Syndrome".
  42. "A rare association of long QT syndrome and syndactyly: Timothy Syndrome (LQT 8)".
  43. Sepp R, Hategan L, Bácsi A, Cseklye J, Környei L, Borbás J; et al. (2017). "Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations". Am J Med Genet A. 173 (3): 784–789. doi:10.1002/ajmg.a.38084. PMID 28211989.
  44. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301577.
  45. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R; et al. (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078.
  46. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R; et al. (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078.
  47. Sepp R, Hategan L, Bácsi A, Cseklye J, Környei L, Borbás J; et al. (2017). "Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations". Am J Med Genet A. 173 (3): 784–789. doi:10.1002/ajmg.a.38084. PMID 28211989.
  48. An HS, Choi EY, Kwon BS, Kim GB, Bae EJ, Noh CI; et al. (2013). "Sudden cardiac arrest during anesthesia in a 30-month-old boy with syndactyly: a case of genetically proven Timothy syndrome". J Korean Med Sci. 28 (5): 788–91. doi:10.3346/jkms.2013.28.5.788. PMC 3653096. PMID 23678275.
  49. 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.
  50. 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.
  51. Jacobs, Avrum; Knight, Bradley P.; McDonald, Karen T.; Burke, Martin C. (2006). "Verapamil decreases ventricular tachyarrhythmias in a patient with Timothy syndrome (LQT8)". Heart Rhythm. 3 (8): 967–970. doi:10.1016/j.hrthm.2006.04.024. ISSN 1547-5271.
  52. Shah DP, Baez-Escudero JL, Weisberg IL, Beshai JF, Burke MC (2012). "Ranolazine safely decreases ventricular and atrial fibrillation in Timothy syndrome (LQT8)". Pacing Clin Electrophysiol. 35 (3): e62–4. doi:10.1111/j.1540-8159.2010.02913.x. PMID 20883512.
  53. Gao Y, Xue X, Hu D, Liu W, Yuan Y, Sun H; et al. (2013). "Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome". Circ Arrhythm Electrophysiol. 6 (3): 614–22. doi:10.1161/CIRCEP.113.000092. PMID 23580742.
  54. Sepp R, Hategan L, Bácsi A, Cseklye J, Környei L, Borbás J; et al. (2017). "Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations". Am J Med Genet A. 173 (3): 784–789. doi:10.1002/ajmg.a.38084. PMID 28211989.
  55. Gao Y, Xue X, Hu D, Liu W, Yuan Y, Sun H; et al. (2013). "Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome". Circ Arrhythm Electrophysiol. 6 (3): 614–22. doi:10.1161/CIRCEP.113.000092. PMID 23580742.
  56. Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C; et al. (2009). "High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment "failures"". Circulation. 119 (2): 215–21. doi:10.1161/CIRCULATIONAHA.108.772533. PMID 19118258.
  57. Alexander ME, Cecchin F, Walsh EP, Triedman JK, Bevilacqua LM, Berul CI (2004). "Implications of implantable cardioverter defibrillator therapy in congenital heart disease and pediatrics". J Cardiovasc Electrophysiol. 15 (1): 72–6. doi:10.1046/j.1540-8167.2004.03388.x. PMID 15028076.
  58. Jons C, Moss AJ, Goldenberg I, Liu J, McNitt S, Zareba W; et al. (2010). "Risk of fatal arrhythmic events in long QT syndrome patients after syncope". J Am Coll Cardiol. 55 (8): 783–8. doi:10.1016/j.jacc.2009.11.042. PMID 20170817.
  59. Corona-Rivera JR, Barrios-Prieto E, Nieto-García R, Bloise R, Priori S, Napolitano C; et al. (2015). "Unusual retrospective prenatal findings in a male newborn with Timothy syndrome type 1". Eur J Med Genet. 58 (6–7): 332–5. doi:10.1016/j.ejmg.2015.04.001. PMID 25882468.
  60. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP (2015). "Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development". Am J Med Genet A. 167A (3): 629–34. doi:10.1002/ajmg.a.36924. PMID 25691416.
  61. Braun TL, Trost JG, Pederson WC (2016). "Syndactyly Release". Semin Plast Surg. 30 (4): 162–170. doi:10.1055/s-0036-1593478. PMC 5115922. PMID 27895538.
  62. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301579.



Linked-in.jpg