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Holt-Oram Syndrome
Introduction
Holt-Oram, also known as hand-heart syndrome I, was first described in 1960 by Mary Clayton Holt and Samuel Oram as a constellation of malformations that they observed in four generations of one family. The original description included atrial septal defects and a thumb anomaly that lay in the same plane as the finger. Individuals affected by this disorder have the classically described upper limb anomaly and heart defects (mostly atrial septal defects), but may additionally present with pectus excavatum or carinatum and vertebral anomalies. Holt-Oram is now known to occur because of a mutation in the TBX5 gene located on 12q24.1 and is a rare autosomal dominant syndrome characterized by high penetrance and variable expression.
Disorder
Definition
Hallmark features of Holt-Oram syndrome include cardiovascular defects, most of which are atrial septal defects (up to 60%), and radial arm malformation affecting the thumb. Other possible cardiac anomalies include arrhythmias and complex cardiac malformations, most commonly atrioventricular canal defects and tetralogy of Fallot. Other potential syndromic features include variable upper limb anomalies and skeletal anomalies. This syndrome has been associated with over 70 unique mutations in the transcription factor TBX5 located on 12q24.1.
Prevalence and Epidemiology
Holt-Oram syndrome has a mean prevalence of 0.7 : 100,000 and is typically diagnosed prenatally or in the early years of life. There is high regional variation; in Ireland, the prevalence is 0.2 : 100,000 and in Belgium, 1.4 : 100,000. There appears to be a significant lower prevalence rate in more modern reports (post-2001) compared to earlier epidemiologic studies; however, this finding has no obvious explanation. The male-to-female ratio is close to 1 : 1.
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