History

Clinical features of Holt-Oram syndrome (HOS) vary depending on the severity of the cardiac and limb malformation.^{[17, 18]}Note the following:

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.

Physical

Physical findings may include musculoskeletal and/or cardiac defects. Intelligence in patients with Holt-Oram syndrome (HOS) is normal.

Musculoskeletal defects

Note the following:

Upper limbs are usually affected, although the importance of isolated lower limb involvement associated with specific mutations has been reported.^[1]
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 infant with Holt-Oram syndrome showing total aplasia of the left thumb.
View Media Gallery

Photograph showing hypoplastic right thumb of the right hand of a 6-month-old infant with Holt-Oram syndrome.
View Media Gallery
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 a 5-month-old infant with Holt-Oram syndrome showing hypoplastic radius and ulna and only 4 metacarpals.
View Media Gallery
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

Note the following:

The reported incidence ranges from 50-95%.
The most common lesion is a secundum astrial septal defect (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 syndrome, endocardial cushion defects, and truncus arteriosus. Cardiac arrhythmias include paroxysmal atrial 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."^[19]
Pulmonary hypoplasia has occasionally been reported and can present with neonatal respiratory distress.^{[20, 21]}No other associated visceral anomaly has been reported.
Occasionally left ventricular non-compaction may be associated with Holt-Oram syndrome. ^[22]

Severity Scoring System

A scoring system to assess severity of Holt-Oram syndrome (HOS) anomalies has been recommended by Gall et al and modified by Gladstone and Sybert. These are outlined below.

Skeletal defects

A scoring system to assess skeletal abnormalities in HOS is as follows:

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

Cardiac defects

A scoring system to assess cardiac abnormalities in HOS is as follows:

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

Differential Diagnoses

Garavelli L, De Brasi D, Verri R, et al. Holt-Oram syndrome associated with anomalies of the feet. Am J Med Genet A. 2008 May 1. 146A(9):1185-9. [QxMD MEDLINE Link].
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].
Wang ZC, Ji WH, Ruan CW, et al. Prevalence and spectrum of TBX5 mutation in patients with lone atrial fibrillation. Int J Med Sci. 2016. 13(1):60-7. [QxMD MEDLINE Link]. [Full Text].
Guo DF, Li RG, Yuan F, et al. TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome. Mol Med Rep. 2016 May. 13(5):4349-56. [QxMD MEDLINE Link]. [Full Text].
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. 2008 Jun 6. 102(11):1433-42. [QxMD MEDLINE Link].
Darwich R, Li W, Yamak A, et al. KLF13 is a genetic modifier of the Holt-Oram syndrome gene TBX5. Hum Mol Genet. 2017 Mar 1. 26(5):942-54. [QxMD MEDLINE Link].
Li B, Chen S, Sun K, Xu R, Wu Y. Genetic analyses identified a SALL4 gene mutation associated with Holt-Oram syndrome. DNA Cell Biol. 2018 Apr. 37(4):398-404. [QxMD MEDLINE Link].
Bohm J, Heinritz W, Craig A, et al. Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Med Genet. 2008 Oct 1. 9:88. [QxMD MEDLINE Link]. [Full Text].
Steimle JD, Moskowitz IP. TBX5: A key regulator of heart development. Curr Top Dev Biol. 2017. 122:195-221. [QxMD MEDLINE Link].
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. 1998 Oct-Dec. 40(4):613-8. [QxMD MEDLINE Link].
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. 1999 May. 92(5):667-9. [QxMD MEDLINE Link].
Franklin AD, Lorinc AN, Donahue BS. Malignant hyperthermia-like manifestations in a two-month-old child with Holt-Oram syndrome undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 2014 Oct. 28(5):1326-7. [QxMD MEDLINE Link].
Barisic I, Boban L, Greenlees R, et al. Holt Oram syndrome: a registry-based study in Europe. Orphanet J Rare Dis. 2014 Oct 25. 9:156. [QxMD MEDLINE Link].
Goldfarb CA, Wall L, Manske PR, et al. Radial longitudinal deficiency: the incidence of associated medical and musculoskeletal conditions. J Hand Surg [Am]. 2006 Sep. 31(7):1176-82. [QxMD MEDLINE Link].
Baban A, Pitto L, Pulignani S, et al. Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation. Am J Med Genet A. 2014 Jun. 164A(6):1419-24. [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].
Chryssostomidis G, Kanakis M, Fotiadou V, et al. Diversity of congenital cardiac defects and skeletal deformities associated with the Holt-Oram syndrome. Int J Surg Case Rep. 2014. 5(7):389-92. [QxMD MEDLINE Link].
Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW. Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations. Cardiol Young. 2015 Aug. 25(6):1093-8. [QxMD MEDLINE Link].
Mglinets VA. [Hand dermatoglyphics in patients with isolated triphalangia and Holt-Oram syndrome]. Genetika. 1995 Aug. 31(8):1147-53. [QxMD MEDLINE Link].
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. 2007 May 1. 143A(9):1012-4. [QxMD MEDLINE Link].
Smets K, Mortier G, Zecic A. Perinatal/neonatal case presentation: unexpected severe respiratory insufficiency in a newborn with Holt-Oram Syndrome. J Perinatol. 2005 Nov. 25(11):745-6. [QxMD MEDLINE Link].
Ross SB, Bagnall RD, Yeates L, Sy RW, Semsarian C. Holt-Oram syndrome in two families diagnosed with left ventricular noncompaction and conduction disease. HeartRhythm Case Rep. 2018 Apr. 4(4):146-51. [QxMD MEDLINE Link]. [Full Text].
Allanson JE, Newbury-Ecob RA. Holt-Oram syndrome: is there a "face"?. Am J Med Genet A. 2003 May 1. 118(4):314-8. [QxMD MEDLINE Link].
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, 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].
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].
Benson DW, Basson CT, MacRae CA. New understandings in the genetics of congenital heart disease. Curr Opin Pediatr. 1996 Oct. 8(5):505-11. [QxMD MEDLINE Link].
Bohm M. Holt-Oram syndrome. Circulation. 1998 Dec 8. 98(23):2636-7. [QxMD MEDLINE Link]. [Full Text].
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. 2006 Sep. 27(9):975-6. [QxMD MEDLINE Link].
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. 2006 Sep 1. 140(17):1880-6. [QxMD MEDLINE Link].
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. 2002 Oct. 50(5):312-4. [QxMD MEDLINE Link].
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. 2003 Jul. 73(1):74-85. [QxMD MEDLINE Link]. [Full Text].
Brockhoff CJ, Kober H, Tsilimingas N, et al. Holt-Oram syndrome. Circulation. 1999 Mar 16. 99(10):1395-6. [QxMD MEDLINE Link]. [Full Text].
Bruneau BG, Logan M, Davis N, et al. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol. 1999 Jul 1. 211(1):100-8. [QxMD MEDLINE Link].
Cheng TO. Persistent left superior vena cava in Holt-Oram syndrome. Int J Cardiol. 2000 Oct. 76(1):83, 81-2. [QxMD MEDLINE Link].
DuPre CT, Fincher RM. Holt-Oram syndrome associated with hypoplastic peripheral vasculature and midsystolic click. South Med J. 1993 Apr. 86(4):453-6. [QxMD MEDLINE Link].
Ekure EN, Okoromah CN, Briggs E, Ajenifuja OA. Holt-Oram syndrome with hypoplastic left heart syndrome in an African child. Niger Postgrad Med J. 2004 Sep. 11(3):190-2. [QxMD MEDLINE Link].
Fan C, Liu M, Wang Q. Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. J Biol Chem. 2003 Mar 7. 278(10):8780-5. [QxMD MEDLINE Link]. [Full Text].
Gruenauer-Kloevekorn C, Reichel MB, Duncker GI, Froster UG. Molecular genetic and ocular findings in patients with Holt-Oram syndrome. Ophthalmic Genet. 2005 Mar. 26(1):1-8. [QxMD MEDLINE Link].
Hatcher CJ, Kim MS, Mah CS, et al. TBX5 transcription factor regulates cell proliferation during cardiogenesis. Dev Biol. 2001 Feb 15. 230(2):177-88. [QxMD MEDLINE Link].
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. 2004 Apr 1. 126(1):93-8.
Heinritz W, Moschik A, Kujat A, et al. Identification of new mutations in the TBX5 gene in patients with Holt-Oram syndrome. Heart. 2005 Mar. 91(3):383-4. [QxMD MEDLINE Link]. [Full Text].
Heinritz W, Shou L, Moschik A, Froster UG. The human TBX5 gene mutation database. Hum Mutat. 2005 Oct. 26(4):397. [QxMD MEDLINE Link].
Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J. 1960 Apr. 22:236-42. [QxMD MEDLINE Link].
Horb ME, Thomsen GH. Tbx5 is essential for heart development. Development. 1999 Apr. 126(8):1739-51. [QxMD MEDLINE Link]. [Full Text].
Hurst JA, Hall CM, Baraitser M. The Holt-Oram syndrome. J Med Genet. 1991 Jun. 28(6):406-10. [QxMD MEDLINE Link].
Keller BB. Developmental structure-function insights from Tbx5(del/+) mouse model of Holt-Oram syndrome. Am J Physiol Heart Circ Physiol. 2005 Sep. 289(3):H975-6. [QxMD MEDLINE Link]. [Full Text].
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. 2005 Sep. 26(3):176-83. [QxMD MEDLINE Link].
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. 1995 Feb. 48(2):133-6. [QxMD MEDLINE Link].
Koutlas ED, Papageorgiou AA, Athyros VG. Holt-Oram syndrome with malformations of renal and cerebral arteries. Acta Cardiol. 1996. 51(4):373-6. [QxMD MEDLINE Link].
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. 2005 May 1. 134(4):439-42. [QxMD MEDLINE Link].
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. 2005 Jun 8. 101(3):503-5. [QxMD MEDLINE Link].
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. 2003 Mar. 48(3):153-9. [QxMD MEDLINE Link].
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. [Full Text].
McDermott DA, He J, Song YS, et al. Update: PGD and Holt-Oram syndrome. Am J Med Genet A. 2005 Jul 15. 136(2):223. [QxMD MEDLINE Link].
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. 2004 Aug. 131(16):4107-16. [QxMD MEDLINE Link]. [Full Text].
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. 2005 Dec 13. 102(50):18034-9. [QxMD MEDLINE Link]. [Full Text].
Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID. Holt-Oram syndrome: a clinical genetic study. J Med Genet. 1996 Apr. 33(4):300-7. [QxMD MEDLINE Link].
Pizard A, Burgon PG, Paul DL, Bruneau BG, Seidman CE, Seidman JG. Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum. Mol Cell Biol. 2005 Jun. 25(12):5073-83. [QxMD MEDLINE Link]. [Full Text].
Plageman TF, Yutzey KE. Microarray analysis of Tbx5-induced genes expressed in the developing heart. Dev Dyn. 2006 Oct. 235(10):2868-80. [QxMD MEDLINE Link].
Porsch M, Hofmeyer K, Bausenwein BS, et al. Isolation of a Drosophila T-box gene closely related to human TBX1. Gene. 1998 Jun 8. 212(2):237-48. [QxMD MEDLINE Link].
Schneider MD, Schwartz RJ. Heart or hand? Unmasking the basis for specific Holt-Oram phenotypes. Proc Natl Acad Sci U S A. 1999 Mar 16. 96(6):2577-8. [QxMD MEDLINE Link]. [Full Text].
Shono S, Higa K, Kumano K, Dan K. Holt-Oram syndrome. Br J Anaesth. 1998 Jun. 80(6):856-7. [QxMD MEDLINE Link]. [Full Text].
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. 2005 Aug. 68(2):155-60. [QxMD MEDLINE Link].
Terrett JA, Newbury-Ecob R, Smith NM, et al. A translocation at 12q2 refines the interval containing the Holt-Oram syndrome 1 gene. Am J Hum Genet. 1996 Dec. 59(6):1337-41. [QxMD MEDLINE Link]. [Full Text].
Tucker KJ, Murphy J, Conti JB, Curtis AB. Syncope and sinus arrest associated with the upper limb-cardiovascular (Holt-Oram) syndrome. Pacing Clin Electrophysiol. 1994 Oct. 17(10):1678-80. [QxMD MEDLINE Link].
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. 1997 Jul-Aug. 135(4):368-75. [QxMD MEDLINE Link].
Wilson GN. Correlated heart/limb anomalies in Mendelian syndromes provide evidence for a cardiomelic developmental field. Am J Med Genet. 1998 Apr 1. 76(4):297-305. [QxMD MEDLINE Link].
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. 1999 Jan 1. 55(1):10-20. [QxMD MEDLINE Link].
Zaragoza MV, Lewis LE, Sun G, et al. Identification of the TBX5 transactivating domain and the nuclear localization signal. Gene. 2004 Apr 14. 330:9-18. [QxMD MEDLINE Link].
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. 2005 Sep. 289(3):H992-H1001. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

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.