Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by distinctive malformations of the bones of the thumbs and forearms (upper limbs) and/or abnormalities of the heart.¹ This is an autosomal dominant condition first elaborated in 1960, which shows marked variability. The cardinal manifestations are dysplasia of the upper limbs and atrial septal defect.² In many infants with the disorder, the thumbs may be absent, hypoplasic or even have an extra bone (triphalangy). Affected infants may also have additional upper limb malformations such as underdeveloped (hypoplasia) or extra bones in the wrist; malformations of certain bones of the hands, and/or underdeveloped radius, ulna or humerus. Scapula, clavicles and/or other bones may also be abnormal.³ In most cases, infants with HOS have cardiac abnormalities that may include anatomical malformations of the heart and/or electrocardiographic conduction defects. In individuals with the disorder, atrial or ventricular septal defects (ASDs or VSDs) or both are the most common structural heart defects.² Individuals with HOS may have electrocardiographic conduction defects as a separate finding or in association with septal defects. The effects of such defects are highly variable, ranging from asymptomatic in some to serious complications in the others.² HOS is an autosomal dominant disorder. In approximately 60% of cases, it is inherited from an affected parent. In about 40% of cases, the disorder is the result of a spontaneous genetic change. The atrial involvement ranges from none to a large secundum defect with early severe hemodynamic abnormality. Other cardiac malformations have also been reported⁴ with VSDs being the most frequent. Other manifestations include dermatoglyphic abnormalities, pectus excavatum, hypoplastic peripheral arteries, and cardiac conduction disturbance, the last usually involves the AV node and presents in patients with septal defects.²

The diagosis of HOS is most likely to be missed in a patient with an unknown or unremarkable family history of a secundum septal defect and minimal or no thumb anomaly. In any sporadic case of ASD, the patient and the parents should be carefully examined for limb malformations.⁵ Detection of a subtle limb defect alters the recurrence risk in offspring of the proband from

the empirical risk of an isolated septal defect of 3 percent to nearly 50 percent of an autosomal dominant trait.⁶

Prenatal echocardiography is suggested for all the pregnant ladies having family history of congenital heart or limb defect. The severity of the reduction defect varies widely, from a proximally placed thumb to near total absence of the arm. Upper extremity deformity is usually bilateral, as it was in our case. Only about fifty percent of patients have the cardiac defect.² In the presented case the patient had atrial septal defect along with the absence of both thumbs. The skeletal and cardiac manifestations are not correlated in individuals and how a parent is affected is not a reliable predictor of effects on offspring.⁵ Presumably a large septal defect could be detected as well. Although the HOS bears some resemblance to the VATER association, the clear mendelian nature and lack of more extensive organ system involvement of the Holt-Oram indicate that the two conditions do not represent a pathogenetic spectrum.

References

1. Tawbin JA, Roberts R. Cardiovascular disease due to genetic abnormalities. In: Harst JW, ed. The Heart. New york: Mc GrowHill; 1998:1923.
2. Pyeritz RE. Genetics and cardiovascular disease. In: Braunwald E, ed. Heart Disease. 5th ed. Philadelphia: WB Saunders; 1997: 1661.
3. Kirklin JW, Barrottboyes BG. Atrial septal defect. In: Kirklin JW, Barrottboyes BG, eds. Cardiac Surgery. 2nd ed. New York: Churchil Livingston; 1992: 617
4. Gall JC, Stern AM, Cohen MM, et al. Holt-Oram syndrome Clinical and genetic study of a large family. Am J Hum. 1966; 18: 187.
5. Basson CT, Cowley GS, Soloman SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart- hand syndrome). N Engl J Med. 1994; 330: 885.
6. Veasy L. History and physical examination. In: Emmanoidides GC, Allan HD, eds. Moss and Adams Heart Disease in Infant, Children and Adolescence. Baltimore: William and Wilkins; 1995:132.

S. H. Voshtani, MD, M. Hossein-Akbar, MD, H. Khalili-Joafshani, Heshmat Cardiovascular Research Center, Guilan University of Medical Sciences, Rasht, Iran.

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