Holt-Oram Syndrome Clinical Presentation

  • Author: Craig T Basson, MD, PhD; Chief Editor: Park W Willis IV, MD   more...
 
Updated: Jul 12, 2011
 

History

  • Patients may have a family history of cardiac and/or limb malformation.
  • Patients may present in infancy with obvious limb malformations and/or signs of cardiac failure secondary to ASD, VSD, or cardiac conduction disease.
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Physical

  • Upper limb deformity
    • Always present but may be unilateral or bilateral
    • Left-sided abnormalities often more severe than right arm or hand abnormalities
    • Unequal arm lengths due to aplasia, hypoplasia, fusion, or anomalous development of the radial, carpal, and thenar bones
    • Abnormal forearm pronation and supination
    • Triphalangeal or absent thumbs
    • Possible abnormal opposition of thumb
    • Possible sloping shoulders and restriction of shoulder joint movement
    • Phocomelia
  • Cardiac involvement
    • Bradycardia
    • Irregular pulse (ectopy)
    • Irregular pulse that occurs irregularly (atrial fibrillation)
    • Wide, fixed splitting of the second heart sound
    • Pulmonary systolic flow murmur
    • Holosystolic murmur (should raise consideration for a VSD)
  • Anomalies involving any of the following are indicators that a diagnosis of Holt-Oram syndrome can be excluded:
    • Ulnar bone
    • Lower limbs
    • Kidneys
    • Eyes
    • Auditory
    • Craniofacial
    • Vertebrae (may or may not occur in Holt-Oram syndrome)
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Causes

  • 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.[5, 6]
  • Molecular genetic studies reveal that the disease is caused by mutations that inactivate the transcription factor TBX5.[7]
  • Sporadic disease may represent a de novo germline mutation in TBX5.
  • Recognizing that individuals who present with sporadic disease may transmit the disease to offspring is important.
  • The identification of the role of TBX5 in Holt-Oram syndrome suggests an important but as yet undefined role for TBX5 in human cardiac septation, isomerization, and upper limb development.[3]
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Contributor Information and Disclosures
Author

Craig T Basson, MD, PhD  Gladys and Roland Harriman Professor of Medicine, Director of the Center for Molecular Cardiology, Director of Cardiovascular Research, Division of Cardiology, Department of Medicine, Weill Cornell Medical College; Attending Physician, New York Presbyterian Hospital

Craig T Basson, MD, PhD is a member of the following medical societies: American College of Cardiology and American Heart Association

Disclosure: Nothing to disclose.

Coauthor(s)

Carl J Vaughan, MD, MRCPI  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, MRCPI is a member of the following medical societies: American College of Cardiology, American College of Physicians, and American Heart Association

Disclosure: Nothing to disclose.

Luke K Kim, MD  Fellow, 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.

Specialty Editor Board

Russell F Kelly, MD  Program Director, Assistant Professor, Department of Internal Medicine, Division of Cardiology, Cook County Hospital, Rush Medical College

Russell F Kelly, MD is a member of the following medical societies: American College of Cardiology

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: Medscape Salary Employment

Frank M Sheridan, MD  Cardiology, Providence Everett Medical Center

Frank M Sheridan, MD is a member of the following medical societies: American College of Cardiology, American Heart Association, and Society for Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Amer Suleman, MD  Private Practice

Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Chief Editor

Park W Willis IV, MD  Sarah Graham Distinguished Professor of Medicine and Pediatrics, University of North Carolina at Chapel Hill School of Medicine

Park W Willis IV, MD is a member of the following medical societies: American Society of Echocardiography

Disclosure: Nothing to disclose.

References

  1. HOLT M, ORAM S. Familial heart disease with skeletal malformations. Br Heart J. Apr 1960;22:236-42. [Medline].

  2. 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. Mar 16 1999;96(6):2919-24. [Medline].

  3. McDermott DA, Hatcher CJ, Basson CT. Atrial Fibrillation and Other Clinical Manifestations of Altered TBX5 Dosage in Typical Holt-Oram Syndrome. Circ Res. Sep 26 2008;103(7):e96. [Medline].

  4. Cerbai E, Sartiani L. Holt-oram syndrome and atrial fibrillation: opening the (T)-box. Circ Res. Jun 6 2008;102(11):1304-6. [Medline].

  5. 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. Mar 31 1994;330(13):885-91. [Medline].

  6. Basson CT, Solomon SD, Weissman B, et al. Genetic heterogeneity of heart-hand syndromes. Circulation. Mar 1 1995;91(5):1326-9. [Medline].

  7. McDermott DA, Bressan MC, He J, Lee JS, Aftimos S, Brueckner M. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res. Nov 2005;58(5):981-6. [Medline].

  8. Pete B, Harmath A, Szigeti Z, Papp C, Hajdú J. [Holt-Oram syndrome: genetic counseling and diagnosis with prenatal ultrasonography]. Orv Hetil. Nov 18 2007;148(46):2173-6. [Medline].

  9. Sunagawa S, Kikuchi A, Sano Y, Kita M, Ono K, Horikoshi T, et al. Prenatal diagnosis of Holt-Oram syndrome: role of 3-D ultrasonography. Congenit Anom (Kyoto). Mar 2009;49(1):38-41. [Medline].

  10. 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. Apr 1 2004;126A(1):93-8. [Medline].

  11. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, 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. Dec 2 2008;118(23):2395-451. [Medline].

  12. Caglayan AO, Koklu E, Saatci C, Gunes T, Ozkul Y, Narin N, et al. Holt-Oram syndrome in two generations with translocation t(9;15)(p12;q11.2). Ann Saudi Med. May-Jun 2008;28(3):209-12. [Medline].

  13. Saura D, Campos JV, Villegas M, Picó F, de la Morena G, Valdés-Chávarri M. Heart-hand syndrome. Int J Cardiol. Sep 16 2008;129(1):e7-9. [Medline].

 
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Posteroanterior radiograph of the hands of a patient with Holt-Oram syndrome. The distal phalanx of the left thumb is hypoplastic. The carpal bones of both hands are abnormal, but the abnormalities on the left side are greater than those on the right side. Left-sided upper limb radial ray abnormalities are often greater than those on the right side. The scaphoid and trapezium of the left hand are enlarged and misshapen, resulting in a distal displacement of the thumb. Note the marked abnormalities of the left capitate and hamate. The left radial stylus is flattened.
 
 
 
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