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Holt-Oram syndrome, also called heart-hand syndrome, is an inherited disorder characterized by abnormalities of the upper limbs and heart. Holt and Oram first described this condition in 1960 in a 4-generation family with atrial septal defects and thumb abnormalities. [1]
Holt-Oram syndrome is inherited as an autosomal dominant trait that is completely penetrant. The disease is due to mutations in the transcription factorTBX5, which is important in the development of both the heart and upper limbs. [2,3]The pathophysiologic sequelae are a direct result of malformations of the heart and upper limbs. No contributory environmental factors are known. [4]
Although the clinical manifestations are variable, upper limb abnormalities are always present. Abnormalities may be unilateral or bilateral and asymmetric and may involve the radial, carpal, and thenar bones. Aplasia, hypoplasia, fusion, or anomalous development of these bones produces a spectrum of phenotypes, including triphalangeal or absent thumbs. [5]Occasionally, upper limb malformation can be sufficiently severe to produce phocomelia (a malformation in which the hands are attached close to the body); this has been termed pseudothalidomide syndrome. The most prevalent findings in persons with Holt-Oram syndrome are malformations or fusions of the carpal bones. Carpal bone abnormalities are the only findings present in every affected individual, although these anomalies may be evident only radiographically in some patients.
Approximately 75% of patients have some cardiac abnormality. In most patients, the abnormality is either anatrial septal defect (ASD) or aventricular septal defect (VSD), which varies in number, size, and location. ASDs are usually of the secundum variety, while VSDs tend to occur in the muscular trabeculated septum. Cardiac anomalies also may include cardiac conduction defects such as progressive atrioventricular block andatrial fibrillation. [6,7]These anomalies are frequently present even in the absence of septal defects.
Holt-Oram syndrome is a genetic disorder that is autosomal dominant and highly penetrant. Initial linkage studies demonstrate that the gene defect resides on the long arm of chromosome 12. [8,9]
Molecular genetic studies reveal that the disease is caused by mutations that inactivate the transcription factorTBX5. [10,11]Sporadic disease may represent a de novo germline mutation inTBX5.
Recognizing that individuals who present with sporadic disease may transmit the disease to offspring is important.
The identification of the role ofTBX5 in Holt-Oram syndrome suggests an important but as yet undefined role forTBX5 in human cardiac septation, isomerization, and upper limb development. [6]
Holt-Oram syndrome is the most common form of heart-hand syndrome, with prevalence estimated at 1 case per 100,000 total births. Most cases are attributed to new mutations. [12]
Holt-Oram syndrome has no sexual or racial predilection. [12]
A congenital disease, Holt-Oram syndrome is present at birth. Subtle limb involvement may not become clinically apparent until later in life when the cardiac symptoms of the disease manifest or when an individual has a child with a more severe presentation of the syndrome. [13]
Cardiac conduction disease is progressive with aging.
Middle-aged individuals often present with significant atrioventricular block or atrial fibrillation.
The prognosis of Holt-Oram syndrome is generally good, but it depends on the severity of the cardiac malformations. Significant intracardiac shunts can be associated with sudden death or the development of pulmonary hypertension and Eisenmenger syndrome.
Structural lesions are present at birth. The first clinical manifestation of the disease may be heart failure, cardiac arrhythmias (including heart block), or infective endocarditis.
Considerable physical and psychologic morbidity may be associated with limb abnormalities, particularly in severe cases.
Ensure that family members are aware that this is an autosomal dominant disorder and that the chance is 50% that offspring of an affected individual will also have the disorder.
Explain that the severity of a lesion in a parent is not an indication of the potential severity in offspring.
For patient education resources, see theHeart Health Center, as well asAtrial Fibrillation (A Fib) andVentricular Septal Defect.
Holt M, Oram S. Familial heart disease with skeletal malformations.Br Heart J. 1960 Apr. 22:236-42.[QxMD MEDLINE Link].[Full Text].
Varela D, Conceicao N, Cancela ML. Transcriptional regulation of human T-box 5 gene (TBX5) by bone- and cardiac-related transcription factors.Gene. 2021 Feb 5. 768:145322.[QxMD MEDLINE Link].
Azab B, Aburizeg D, Ji W, et al.TBX5 variant with the novel phenotype of mixed‑type total anomalous pulmonary venous return in Holt‑Oram Syndrome and variable intrafamilial heart defects.Mol Med Rep. 2022 Jun. 25(6):210.[QxMD MEDLINE Link].[Full Text].
Basson CT, Huang T, Lin RC, et al. Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations.Proc Natl Acad Sci U S A. 1999 Mar 16. 96(6):2919-24.[QxMD MEDLINE Link].[Full Text].
Nguyen JL, Ho CA. Congenital disorders of the pediatric thumb.JBJS Rev. 2022 Mar 1. 10(3):[QxMD MEDLINE Link].
McDermott DA, Hatcher CJ, Basson CT. Atrial fibrillation and other clinical manifestations of altered TBX5 dosage in typical Holt-Oram syndrome.Circ Res. 2008 Sep 26. 103(7):e96.[QxMD MEDLINE Link].[Full Text].
Cerbai E, Sartiani L. Holt-Oram syndrome and atrial fibrillation: opening the (T)-box.Circ Res. 2008 Jun 6. 102(11):1304-6.[QxMD MEDLINE Link].[Full Text].
Basson CT, Cowley GS, Solomon SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome).N Engl J Med. 1994 Mar 31. 330(13):885-91.[QxMD MEDLINE Link].[Full Text].
Basson CT, Solomon SD, Weissman B, et al. Genetic heterogeneity of heart-hand syndromes.Circulation. 1995 Mar 1. 91(5):1326-9.[QxMD MEDLINE Link].[Full Text].
McDermott DA, Bressan MC, He J, et al. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome.Pediatr Res. 2005 Nov. 58(5):981-6.[QxMD MEDLINE Link].[Full Text].
Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW. Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations.Cardiol Young. 2014 Sep 12. 1-6.[QxMD MEDLINE Link].
Krauser AF, Ponnarasu S, Schury MP. Holt Oram syndrome.StatPearls [Internet]. 2022 Jan.[QxMD MEDLINE Link].[Full Text].
Gupta M, Dosu A, Makan J. Holt-Oram syndrome: an incidental diagnosis.Cureus. 2022 May. 14(5):e24899.[QxMD MEDLINE Link].[Full Text].
Pete B, Harmath A, Szigeti Z, Papp C, Hajdu J. [Holt-Oram syndrome: genetic counseling and diagnosis with prenatal ultrasonography].Orv Hetil. 2007 Nov 18. 148(46):2173-6.[QxMD MEDLINE Link].
Sunagawa S, Kikuchi A, Sano Y, et al. Prenatal diagnosis of Holt-Oram syndrome: role of 3-D ultrasonography.Congenit Anom (Kyoto). 2009 Mar. 49(1):38-41.[QxMD MEDLINE Link].[Full Text].
[Guideline] Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Am Coll Cardiol. 2019 Apr 2. 73(12):e81-e192.[QxMD MEDLINE Link].[Full Text].
Paladini D, Tiesi M, Buffi D, Tuo G, Marasini M. Unexplained right atrial enlargement may be a sign of Holt-Oram syndrome in the fetus.Ultrasound Obstet Gynecol. 2014 Apr. 43(4):475-6.[QxMD MEDLINE Link].[Full Text].
Wall LB, Piper SL, Habenicht R, Oishi SN, Ezaki M, Goldfarb CA. Defining features of the upper extremity in Holt-Oram syndrome.J Hand Surg Am. 2015 Sep. 40(9):1764-8.[QxMD MEDLINE Link].[Full Text].
Al-Qattan MM, Abou Al-Shaar H. Molecular basis of the clinical features of Holt-Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications.Gene. 2015 Apr 15. 560(2):129-36.[QxMD MEDLINE Link].
He J, McDermott DA, Song Y, Gilbert F, Kligman I, Basson CT. Preimplantation genetic diagnosis of human congenital heart malformation and Holt-Oram syndrome.Am J Med Genet A. 2004 Apr 1. 126A(1):93-8.[QxMD MEDLINE Link].
[Guideline] Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the management of adults with congenital heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease).Circulation. 2008 Dec 2. 118(23):2395-451.[QxMD MEDLINE Link].[Full Text].
Craig T Basson, MD, PhD Translational Medicine Head – Cardiovascular, Translational Medicine Head - Diabetes and Metabolism, Novartis Institutes for BioMedical Research
Craig T Basson, MD, PhD is a member of the following medical societies:American College of Cardiology,American Heart Association
Disclosure: Nothing to disclose.
Carl J Vaughan, MD, MRCP Adjunct Assistant Professor, Department of Internal Medicine, Division of Cardiology, Weill Medical College of Cornell University; Consulting Cardiologist, Mercy University Hospital, Ireland
Carl J Vaughan, MD, MRCP is a member of the following medical societies:American College of Cardiology,American College of Physicians,American Heart Association
Disclosure: Nothing to disclose.
Luke K Kim, MD Assistant Professor of Medicine, Department of Internal Medicine, Division of Cardiology, New York Presbyterian Hospital, Weill Cornell Medical Center
Disclosure: Nothing to disclose.
Deborah A McDermott, MS, CGC Genetic Counselor/Research Associate, Department of Medicine, Division of Cardiology, Weill Medical College of Cornell University
Deborah A McDermott, MS, CGC is a member of the following medical societies:American Society of Human Genetics
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Yasmine S Ali, MD, MSCI, FACC, FACP Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine; President, LastSky Writing, LLC
Yasmine S Ali, MD, MSCI, FACC, FACP is a member of the following medical societies:American College of Cardiology,American College of Physicians,American Heart Association,American Medical Association,American Medical Writers Association,National Lipid Association,Tennessee Medical Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: LastSky Writing, LLC;Philips Healthcare;M Health; AKH, Inc.; PeerView Institute; LearnRoll, LLC; Kaplan; RxCe.com; M3 USA; ChesterPA511<br/>Serve(d) as a speaker or a member of a speakers bureau for: RxCe.com.
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