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Articles » Syndromes » Holt-Oram syndrome
1999-05-17-15 Holt-Oram syndrome © Jeanty /

Holt-Oram syndrome

Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Definition: The Holt-Oram syndrome consists of congenital heart disease and anomalies of the upper limb (phocomelia (4.5%), radial ray aplasia, triphalangeal thumb, clinodactyly)[1]. 

Synonyms: Heart-hand syndrome. (This syndrome appears genetically distinct from the Heart-hand syndrome Type II and III).

Incidence:  Uncommon.

Etiology: Autosomal dominant with 100% penetrance and no evidence of reduced fitness. Increasing severity occurs in succeeding generations consistent with anticipation1.

Recurrence risk: 50%.

Diagnosis: The cardiac lesions include atrio (30-60%) and ventricular septal defects (fig. 1), patent ductus arteriosus, endocardial cushion defect, hypoplasia of the left ventricle and conduction disturbances. 17% have complex cardiac anomalies[2]. The radial ray aplasia varies from a difficult to diagnose triphalangeal thumb to more obvious club hand[3]. The absence of the thumb can also be recognized.

Figure 1: 1.3 mm VSD

Figure 2: A coronal view of the 4-digit hand.

Figure 3: The four digits of the hand are seen. The radial side is well visible (lower left side of the image) and the thumb is clearly absent.

Figure 4: On the other hand, a small skin tag is present at the place of the thumb (arrow).

Pathogenesis: Probable cardiomelic developmental field[4].

Genetic anomaly: Mutations in two of the T-box genes (TBX5 and TBX3) on chromosome 12q24.1[5] have been shown to be responsible for the congenital abnormalities associated with Holt Oram syndrome[6],[7],[8]. TBX5 is only involved in anterior limb development

Associated anomalies: See definition. A few inconstant anomalies such as renal anomalies have been reported too.

Differential diagnosis: The differential is usually that of the radial ray aplasia and could include the TAR syndrome, Fanconi anemia, VACTERL association, and the radial ray-choanal atresia.

Prognosis: Mainly related to the severity of the cardiac and orthopedic handicap.

Management: Usually no alteration of the prenatal care is needed. Great orthopedic progresses at pollicisation of the index finger to provide opposition have decreased the handicap of some of these children[9].


[1] 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

[2] Sletten LJ, Pierpont ME: Variation in severity of cardiac disease in Holt-Oram syndrome. Am J Med Genet 1996 Oct 16;65(2):128-32

[3] Brons JT, van Geijn HP, Wladimiroff JW, van der Harten JJ, Kwee ML, Sobotka-Plojhar M, Arts NF Prenatal ultrasound diagnosis of the Holt-Oram syndrome. Prenat Diagn 1988 Mar;8(3):175-81

[4] 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

[5] Bonnet D, Terrett J, Pequignot-Viegas E, Weissenbach J, Munnich A, Lyonnet S, Kachaner J Gene localisation in 12q12 in Holt-Oram atrio-digital syndrome. Arch Mal Coeur Vaiss 1995 May;88(5):661-6

[6] Campbell CE, Casey G, Goodrich K Genomic structure of TBX2 indicates conservation with distantly related T-box genes. Mamm Genome 1998 Jan;9(1):70-3

[7] Smith J: Brachyury and the T-box genes. Curr Opin Genet Dev 1997 Aug;7(4):474-80

[8] Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 1997 Jan;15(1):21-9

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

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