Pediatric Holt-Oram Syndrome Clinical Presentation

  • Author: Poothirikovil Venugopalan, MBBS, MD, FRCP(Glasg), FRCPCH; Chief Editor: Steven R Neish, MD, SM   more...
 
Updated: Jun 23, 2010
 

History

  • Clinical features of Holt-Oram syndrome (HOS) vary depending on the severity of the cardiac and limb malformation.
  • Individuals with more severe congenital heart defects may present in the neonatal period. Abnormalities may also be detected in utero using fetal ultrasonography and fetal echocardiography.
  • Cardiac symptoms depend on the type of congenital heart defect. Atrial septal defect (ASD), the most common heart defect in HOS, causes no symptoms in the vast majority of affected individuals.
  • Severity of cardiac and limb malformations appears to be positively correlated in some studies; however, this has not been replicated in other studies.
  • In any sporadic case of ASD, the patient and parents should be examined for limb malformations, and the family history should be studied in detail.
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Physical

Physical findings may include the following:

  • Musculoskeletal defects
    • Upper limbs are usually affected, although the importance of isolated lower limb involvement associated with specific mutations has been reported.[6]
    • Although bilateral, the left side is often more significantly affected.
    • The most severe form is phocomelia with rudimentary limbs.
    • Mildest forms include clinodactyly, limited supination, and sloping shoulders.
    • The most common defects include radial thumb anomalies ranging from absent thumbs to displaced (distally placed), duplicated, or triphalangeal thumbs. Carpal and metacarpal anomalies (especially the fourth) may also be present. Refer to the following images. Photograph of the left hand of a 6-month-old infanPhotograph of the left hand of a 6-month-old infant with Holt-Oram syndrome showing total aplasia of the left thumb. Photograph showing hypoplastic right thumb of the Photograph showing hypoplastic right thumb of the right hand of a 6-month-old infant with Holt-Oram syndrome.
    • Hypoplasia of the radius manifests as short deformed forearm, although it may be so mild that it is detectable only on radiography of the forearm (see image below) Plain radiograph of the right forearm and hand of Plain radiograph of the right forearm and hand of a 5-month-old infant with Holt-Oram syndrome showing hypoplastic radius and ulna and only 4 metacarpals.
    • Sprengel deformity (upward displacement of the scapula) and hypoplasia of the shoulders, clavicles, and humerus have also been reported.
    • The number and location of hypoplastic muscles correlate with the severity of skeletal involvement. Accordingly, patients with hypoplasia of large and proximal muscles have phocomelia, and those with intrinsic hand muscle hypoplasia have only a triphalangeal thumb or no skeletal malformation.
    • Associated muscular hypoplasia that involves the hypothenar, wrist extensor, supinator, biceps brachii, triceps brachii, deltoid, pectoral, and trapezium muscles has also been reported.
    • Isolated (sporadic) patients have more severe involvement, which can include the ulnar ray.
  • Heart defects
    • The reported incidence ranges from 50-95%.
    • The most common lesion is a secundum ASD. Others include ventricular septal defect (VSD), atrioventricular (AV) block, pulmonic stenosis (including peripheral arterial), and mitral valve prolapse.
    • Approximately 17% of patients have more complex cardiac malformations, such as tetralogy of Fallot, hypoplastic left heart, endocardial cushion defects, and truncus arteriosus. Cardiac arrhythmias include paroxysmal tachycardia, prolonged PR interval, wandering atrial pacemaker, atrial ectopics, AV block, and sinus bradycardia. Syncope and sinus arrest have been reported. Multiple VSDs have also been reported.
    • According to Mglinets, "a specific feature of the syndrome is a change in the main palmar lines and their termination on the radial border of the hand not only in the absence of the thumb but also in the case of formation of the abortive xT-line, its radiants, and the axial triradius."[7]
    • Pulmonary hypoplasia has occasionally been reported and can present with neonatal respiratory distress.[8, 9] No other associated visceral anomaly has been reported.
  • Intelligence: Intelligence is normal.

A scoring system to assess severity has been recommended by Gall et al and modified by Gladstone and Sybert, as follows:

  • Scoring system to assess skeletal abnormalities in HOS
    • 0 - No abnormality on physical or radiological examination
    • 1 - Minor abnormalities, including reduced thenar eminence, clinodactyly, or hypoplasia of the thumb
    • 3 - Present arms and forearms, with one or more bones missing
    • 4 – Phocomelia
  • Scoring system to assess cardiac abnormalities in HOS
    • 0 - Asymptomatic, with no abnormal physical findings
    • 1 - Conduction defect
    • 2 - Structural heart abnormality that does not require surgery
    • 3 - Structural heart abnormality that requires surgery but is not life threatening
    • 4 - Potentially lethal malformation
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Contributor Information and Disclosures
Author

Poothirikovil Venugopalan, MBBS, MD, FRCP(Glasg), FRCPCH,  Consulting Staff, Department of Child Health, University Hospital of North Tees and Hartlepool, UK

Poothirikovil Venugopalan, MBBS, MD, FRCP(Glasg), FRCPCH, is a member of the following medical societies: British Cardiac Society, Paediatrician with Cardiology Expertise Special Interest Group, Royal College of Paediatrics and Child Health, and Royal College of Physicians and Surgeons of Glasgow

Disclosure: Nothing to disclose.

Specialty Editor Board

Ira H Gessner, MD  Professor Emeritus, Pediatric Cardiology

Ira H Gessner, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Heart Association, American Pediatric Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

John W Moore, MD, MPH  Professor of Clinical Pediatrics, Section of Pediatric Cardiology, Department of Pediatrics, University of California San Diego School of Medicine; Director of Cardiology, Rady Children's Hospital

John W Moore, MD, MPH is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, and Society for Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Gilbert Z Herzberg, MD  Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; Consulting Staff, Department of Pediatrics, Sound Shore Medical Center

Gilbert Z Herzberg, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Chief Editor

Steven R Neish, MD, SM  Director of Pediatric Cardiology Fellowship Program, Associate Professor, Department of Pediatrics, Baylor College of Medicine

Steven R Neish, MD, SM is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, and American Heart Association

Disclosure: Nothing to disclose.

References

  1. Garavelli L, De Brasi D, Verri R, Guareschi E, Cariola F, Melis D, et al. Holt-Oram syndrome associated with anomalies of the feet. Am J Med Genet A. May 1 2008;146A(9):1185-9. [Medline].

  2. Postma AV, van de Meerakker JB, Mathijssen IB, et al. A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res. Jun 6 2008;102(11):1433-42. [Medline].

  3. Böhm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, et al. Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Med Genet. Oct 1 2008;9:88. [Medline]. [Full Text].

  4. Ogur G, Gul D, Lenk MK, Imirzalioglu N, Alpay F, Ogur E. Variable clinical expression of Holt-Oram syndrome in three generations. Turk J Pediatr. Oct-Dec 1998;40(4):613-8. [Medline].

  5. Goldfarb CA, Wall L, Manske PR, et al. Radial longitudinal deficiency: the incidence of associated medical and musculoskeletal conditions. J Hand Surg [Am]. Sep 2006;31(7):1176-82. [Medline].

  6. Garavelli L, De Brasi D, Verri R, Guareschi E, Cariola F, Melis D, et al. Holt-Oram syndrome associated with anomalies of the feet. Am J Med Genet A. May 1 2008;146A(9):1185-9. [Medline].

  7. Mglinets VA. [Hand dermatoglyphics in patients with isolated triphalangia and Holt-Oram syndrome]. Genetika. Aug 1995;31(8):1147-53. [Medline].

  8. Tseng YR, Su YN, Lu FL, et al. Holt-Oram syndrome with right lung agenesis caused by a de novo mutation in the TBX5 gene. Am J Med Genet A. May 1 2007;143A(9):1012-4. [Medline].

  9. Smets K, Mortier G, Zecic A. Perinatal/neonatal case presentation: unexpected severe respiratory insufficiency in a newborn with Holt-Oram Syndrome. J Perinatol. Nov 2005;25(11):745-6. [Medline].

  10. 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]. [Full Text].

  11. Postma AV, van de Meerakker JB, Mathijssen IB, Barnett P, Christoffels VM, Ilgun A, et al. A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res. Jun 6 2008;102(11):1433-42. [Medline].

  12. Allanson JE, Newbury-Ecob RA. Holt-Oram syndrome: is there a "face"?. Am J Med Genet A. May 1 2003;118(4):314-8. [Medline].

  13. 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]. [Full Text].

  14. Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, 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]. [Full Text].

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

  16. Benson DW, Basson CT, MacRae CA. New understandings in the genetics of congenital heart disease. Curr Opin Pediatr. Oct 1996;8(5):505-11. [Medline].

  17. Bohm M. Holt-Oram syndrome. Circulation. Dec 8 1998;98(23):2636-7. [Medline]. [Full Text].

  18. Borozdin W, Bravo Ferrer Acosta AM, Bamshad MJ, et al. Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations. Hum Mutat. Sep 2006;27(9):975-6. [Medline].

  19. Borozdin W, Bravo-Ferrer Acosta AM, Seemanova E, et al. Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt-Oram and ulnar-mammary syndromes. Am J Med Genet A. Sep 1 2006;140(17):1880-6. [Medline].

  20. Bossert T, Walther T, Gummert J, et al. Cardiac malformations associated with the Holt-Oram syndrome--report on a family and review of the literature. Thorac Cardiovasc Surg. Oct 2002;50(5):312-4. [Medline].

  21. Brassington AM, Sung SS, Toydemir RM, Le T, Roeder AD, Rutherford AE, et al. Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet. Jul 2003;73(1):74-85. [Medline]. [Full Text].

  22. Brockhoff CJ, Kober H, Tsilimingas N, et al. Holt-Oram syndrome. Circulation. Mar 16 1999;99(10):1395-6. [Medline]. [Full Text].

  23. Bruneau BG, Logan M, Davis N, et al. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol. Jul 1 1999;211(1):100-8. [Medline].

  24. Cachat F, Rapatsalahy A, Sekarski N, Hurni M, von Segesser L, Payot M. [Three different types of atrial septal defects in the same family]. Arch Mal Coeur Vaiss. May 1999;92(5):667-9. [Medline].

  25. Cheng TO. Persistent left superior vena cava in Holt-Oram syndrome. Int J Cardiol. Oct 2000;76(1):83, 81-2. [Medline].

  26. DuPre CT, Fincher RM. Holt-Oram syndrome associated with hypoplastic peripheral vasculature and midsystolic click. South Med J. Apr 1993;86(4):453-6. [Medline].

  27. Ekure EN, Okoromah CN, Briggs E, Ajenifuja OA. Holt-Oram syndrome with hypoplastic left heart syndrome in an African child. Niger Postgrad Med J. Sep 2004;11(3):190-2. [Medline].

  28. Fan C, Liu M, Wang Q. Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. J Biol Chem. Mar 7 2003;278(10):8780-5. [Medline]. [Full Text].

  29. Gruenauer-Kloevekorn C, Reichel MB, Duncker GI, Froster UG. Molecular genetic and ocular findings in patients with holt-oram syndrome. Ophthalmic Genet. Mar 2005;26(1):1-8. [Medline].

  30. Hatcher CJ, Kim MS, Mah CS, et al. TBX5 transcription factor regulates cell proliferation during cardiogenesis. Dev Biol. Feb 15 2001;230(2):177-88. [Medline].

  31. He J, McDermott DA, Song Y, et al. Preimplantation genetic diagnosis of human congenital heart malformation and Holt-Oram syndrome. Am J Med Genet A. Apr 1 2004;126(1):93-8.

  32. Heinritz W, Moschik A, Kujat A, et al. Identification of new mutations in the TBX5 gene in patients with Holt-Oram syndrome. Heart. Mar 2005;91(3):383-4. [Medline]. [Full Text].

  33. Heinritz W, Shou L, Moschik A, Froster UG. The human TBX5 gene mutation database. Hum Mutat. Oct 2005;26(4):397. [Medline].

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

  35. Horb ME, Thomsen GH. Tbx5 is essential for heart development. Development. Apr 1999;126(8):1739-51. [Medline]. [Full Text].

  36. Hurst JA, Hall CM, Baraitser M. The Holt-Oram syndrome. J Med Genet. Jun 1991;28(6):406-10. [Medline].

  37. Keller BB. Developmental structure-function insights from Tbx5(del/+) mouse model of Holt-Oram syndrome. Am J Physiol Heart Circ Physiol. Sep 2005;289(3):H975-6. [Medline]. [Full Text].

  38. Kohlhase J, Chitayat D, Kotzot D, et al. SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders. Hum Mutat. Sep 2005;26(3):176-83. [Medline].

  39. Koishizawa T, Hayashi N, Tadokoro M, et al. [A case report of the radical correction of a truncus arteriosus and peripheral pulmonary stenosis in association with Holt-Oram syndrome]. Kyobu Geka. Feb 1995;48(2):133-6. [Medline].

  40. Koutlas ED, Papageorgiou AA, Athyros VG. Holt-Oram syndrome with malformations of renal and cerebral arteries. Acta Cardiol. 1996;51(4):373-6. [Medline].

  41. Le Meur N, Goldenberg A, Michel-Adde C, et al. Molecular characterization of a 14q deletion in a boy with features of Holt-Oram syndrome. Am J Med Genet A. May 1 2005;134(4):439-42. [Medline].

  42. Lee ML, Tsao LY, Wang YM. Interventional cardiac catheterization for the coarctation of the aortic arch and patent ductus arteriosus in a 3-day-old neonate with the Holt-Oram syndrome. Int J Cardiol. Jun 8 2005;101(3):503-5. [Medline].

  43. Lehner R, Goharkhay N, Tringler B, et al. Pedigree analysis and descriptive investigation of three classic phenotypes associated with Holt-Oram syndrome. J Reprod Med. Mar 2003;48(3):153-9. [Medline].

  44. McDermott DA, Bressan MC, He J, et al. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res. Nov 2005;58(5):981-6. [Full Text].

  45. McDermott DA, He J, Song YS, et al. Update: PGD and Holt-Oram syndrome. Am J Med Genet A. Jul 15 2005;136(2):223. [Medline].

  46. Moskowitz IP, Pizard A, Patel VV, et al. The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system. Development. Aug 2004;131(16):4107-16. [Medline]. [Full Text].

  47. Murakami M, Nakagawa M, Olson EN, Nakagawa O. A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc Natl Acad Sci U S A. Dec 13 2005;102(50):18034-9. [Medline]. [Full Text].

  48. Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet. Apr 1996;33(4):300-7. [Medline].

  49. Pizard A, Burgon PG, Paul DL, et al. Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum. Mol Cell Biol. Jun 2005;25(12):5073-83. [Medline]. [Full Text].

  50. Plageman TF, Yutzey KE. Microarray analysis of Tbx5-induced genes expressed in the developing heart. Dev Dyn. Oct 2006;235(10):2868-80. [Medline].

  51. Porsch M, Hofmeyer K, Bausenwein BS, et al. Isolation of a Drosophila T-box gene closely related to human TBX1. Gene. Jun 8 1998;212(2):237-48. [Medline].

  52. Schneider MD, Schwartz RJ. Heart or hand? Unmasking the basis for specific Holt-Oram phenotypes. Proc Natl Acad Sci U S A. Mar 16 1999;96(6):2577-8. [Medline]. [Full Text].

  53. Shono S, Higa K, Kumano K, Dan K. Holt-Oram syndrome. Br J Anaesth. Jun 1998;80(6):856-7. [Medline]. [Full Text].

  54. Sinkovec M, Petrovic D, Volk M, Peterlin B. Familial progressive sinoatrial and atrioventricular conduction disease of adult onset with sudden death, dilated cardiomyopathy, and brachydactyly. A new type of heart-hand syndrome?. Clin Genet. Aug 2005;68(2):155-60. [Medline].

  55. Smets K, Mortier G, Zecic A. Perinatal/neonatal case presentation: unexpected severe respiratory insufficiency in a newborn with Holt-Oram Syndrome. J Perinatol. Nov 2005;25(11):745-6. [Medline].

  56. Terrett JA, Newbury-Ecob R, Smith NM, Li QY, Garrett C, Cox P, et al. A translocation at 12q2 refines the interval containing the Holt-Oram syndrome 1 gene. Am J Hum Genet. Dec 1996;59(6):1337-41. [Medline]. [Full Text].

  57. Tucker KJ, Murphy J, Conti JB, Curtis AB. Syncope and sinus arrest associated with the upper limb-cardiovascular (Holt-Oram) syndrome. Pacing Clin Electrophysiol. Oct 1994;17(10):1678-80. [Medline].

  58. Weber M, Wenz W, van Riel A, et al. [The Holt-Oram syndrome. Review of the literature and current orthopedic treatment concepts]. Z Orthop Ihre Grenzgeb. Jul-Aug 1997;135(4):368-75. [Medline].

  59. Wilson GN. Correlated heart/limb anomalies in Mendelian syndromes provide evidence for a cardiomelic developmental field. Am J Med Genet. Apr 1 1998;76(4):297-305. [Medline].

  60. Yi CH, Terrett JA, Li QY, et al. Identification, mapping, and phylogenomic analysis of four new human members of the T-box gene family: EOMES, TBX6, TBX18, and TBX19. Genomics. Jan 1 1999;55(1):10-20. [Medline].

  61. Zaragoza MV, Lewis LE, Sun G, et al. Identification of the TBX5 transactivating domain and the nuclear localization signal. Gene. Apr 14 2004;330:9-18. [Medline].

  62. Zhou YQ, Zhu Y, Bishop J, et al. Abnormal cardiac inflow patterns during postnatal development in a mouse model of Holt-Oram syndrome. Am J Physiol Heart Circ Physiol. Sep 2005;289(3):H992-H1001. [Medline]. [Full Text].

 
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Photograph showing hypoplastic right thumb of the right hand of a 6-month-old infant with Holt-Oram syndrome.
Photograph of the left hand of a 6-month-old infant with Holt-Oram syndrome showing total aplasia of the left thumb.
Plain radiograph of the right forearm and hand of a 5-month-old infant with Holt-Oram syndrome showing hypoplastic radius and ulna and only 4 metacarpals.
A 2-dimensional echocardiographic picture taken from subxiphoid window showing a large secundum atrial septal defect (arrow) in a 7-year-old boy with Holt-Oram syndrome. ASD = Atrial septal defect; RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle.
Color Doppler echocardiographic picture taken from subxiphoid window showing the large left-to-right flow of blood (arrow) across the atrial septal defect. The red color pattern depicts flow direction from left atrium (LA) to right atrium (RA). ASD = Atrial septal defect; RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle.
 
 
 
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