the holt oram syndrome is characterized by congenital cardiovascular malformations and skeletal abnormalities of the upper limbs , hence , the terms  heart - hand syndrome  and  heart upper - limb syndrome  . arm deformity covers a wide range of anomalies extending from minor abnormalities , through to serious , even handicapping , malformations . the most common cardiac manifestation is atrial septal defect ( asd ) ; however , other structural abnormalities and also rhythm disorders have been described . we herein present our experience in 4 consecutive patients over a 10 year period with the holt oram syndrome ( table 1 ) . a 15-year - old boy with tetralogy of fallot presented followed by a history of two previous aorto - pulmonary shunts and a stroke . physical examination revealed prominent kyphosis , and absent index , ring and little fingers of the right hand ( fig . 1 ) . electrocardiography ( ecg ) showed sinus rhythm ( sr ) , biatrial enlargement , right axis , right ventricular hypertrophy ( rvh ) and t wave abnormalities . echocardiography revealed a large ventricular septal defect ( vsd ) , pulmonary atresia and hypoplastic pulmonary arteries . the patient underwent a successful construction of a new central shunt , made an uneventful recovery and was discharged home in good condition . an asymptomatic 4-year - old girl presented with an asd . on examination she was found to have short both upper limbs and ring fingers . she was also diagnosed with mental retardation , psychomotor disorders and epilepsy in the context of trisomy 13 . ecg showed sinus atrial tachycardia , incomplete right bundle branch block ( rbbb ) and rvh . the patient underwent surgical closure of the defect and was discharged from hospital in excellent clinical condition . a 1-year - old boy presented with tetralogy of fallot . on examination , kyphosis , scoliosis , hypoplastic clavicles , pectus excavatum , syndactyly of the left thumb and index finger and forward displacement of the right thumb were noted ( fig . 2 ) . the ecg showed sr , ventricular premature complexes and abnormal right axis deviation . echocardiography revealed a large vsd , aortic overriding , right ventricular outflow tract obstruction , rvh and also a secundum asd . the patient underwent standard surgical correction , made a good overall recovery and was discharged home in good clinical condition . a 2-year - old girl presented with a canal type vsd , concomitant mitral cleft and a history of a pulmonary artery banding at the age of 1 month . physical examination revealed syndactyly of the left thumb and index finger and forward displacement of the right thumb ( fig . echocardiography revealed a large perimembranous vsd and a mitral cleft without a primum septal defect ( figs . 4 and 5 ) . a 15-year - old boy with tetralogy of fallot presented followed by a history of two previous aorto - pulmonary shunts and a stroke . physical examination revealed prominent kyphosis , and absent index , ring and little fingers of the right hand ( fig . 1 ) . electrocardiography ( ecg ) showed sinus rhythm ( sr ) , biatrial enlargement , right axis , right ventricular hypertrophy ( rvh ) and t wave abnormalities . echocardiography revealed a large ventricular septal defect ( vsd ) , pulmonary atresia and hypoplastic pulmonary arteries . the patient underwent a successful construction of a new central shunt , made an uneventful recovery and was discharged home in good condition . an asymptomatic 4-year - old girl presented with an asd . on examination she was found to have short both upper limbs and ring fingers . she was also diagnosed with mental retardation , psychomotor disorders and epilepsy in the context of trisomy 13 . ecg showed sinus atrial tachycardia , incomplete right bundle branch block ( rbbb ) and rvh . the patient underwent surgical closure of the defect and was discharged from hospital in excellent clinical condition . kyphosis , scoliosis , hypoplastic clavicles , pectus excavatum , syndactyly of the left thumb and index finger and forward displacement of the right thumb were noted ( fig . 2 ) . the ecg showed sr , ventricular premature complexes and abnormal right axis deviation . echocardiography revealed a large vsd , aortic overriding , right ventricular outflow tract obstruction , rvh and also a secundum asd . the patient underwent standard surgical correction , made a good overall recovery and was discharged home in good clinical condition . a 2-year - old girl presented with a canal type vsd , concomitant mitral cleft and a history of a pulmonary artery banding at the age of 1 month . physical examination revealed syndactyly of the left thumb and index finger and forward displacement of the right thumb ( fig . echocardiography revealed a large perimembranous vsd and a mitral cleft without a primum septal defect ( figs . 4 and 5 ) . the holt  oram syndrome is an autosomal dominant condition first described in 1960 by mary holt and samuel oram and was named after them a year later by victor mckusick , when describing a similar case . multiple transcription factors regulate specific programs of gene expression in heart development . of these , tbx5 , member of a family characterized by a highly conserved dna binding motif ( t - box ) participates in the specification of left / right ventricles and ventricular septum position during cardiogenesis . oram syndrome is caused by the mutation of a gene residing on the long arm of the chromosome 12q24 . it is argued , however , that heart - limb syndromes are expressed by mutation in different genes suggesting a genetically heterogeneous disease with just one locus mapping on this chromosome . tbx5 , nonetheless , directly or indirectly , alters the transcription of different genes in heart and limb . inward directed thumb as in the original description by holt and oram was found in 3 of our patients . however , a large number of different skeletal abnormalities have been reported . in particular , distally displaced , triphalangeal thumbs , hypoplastic thenar eminences , hypoplastic , absent or extra fingers , anomalies of the carpus , radial aplasia , phocomelia , hypoplasia of the clavicles and shoulders and pectus excavatum have been described . upper extremity deformity is in the preaxial radial ray distribution , usually bilateral , yet may be asymmetrical in severity , the left side usually being the worst . persistent ductus arteriosus , anomalous coronary arteries , mitral valve prolapse , persistent left superior vena cava , tetralogy of fallot , double outlet right ventricle and total anomalous pulmonary venous return have been described in patients with the holt also sinus node dysfunction , bradycardia , atrial fibrillation , atrioventricular block , rbbb , wolf - parkinson - white syndrome and even sudden cardiac death have been reported . hypoplastic and ectopic peripheral vessels are common , posing as a serious challenge in getting vascular access in these patients . a variety of morphological and anatomic criteria in conjunction of genetic analyses have led to the recognition of multiple heart - limb syndromes , with holt the association of a canal type vsd and mitral valve cleft with the holt  oram syndrome ( case # 4 ) has not been reported before to our knowledge . obviously , longevity of individuals with holt oram syndrome depends upon the identification and treatment of their cardiac maladies . in our case series , nevertheless , morbidity was minimal . since the majority of the clinical information available is provided mostly by isolated reports , further epidemiological and genetic analyses are required to determine the incidence and categorize the different types of heart limb syndromes . written informed consent was obtained from the patients for publication of these case reports and accompanying images . a copy of the written consent for each one separately is available for review by the editor - in - chief of this journal on request . vassiliki fotiadou md , theophili kousi md , christos apostolidis md , and prodromos azariadis md collected the data . cleo laskari md helped for data analysis and interpretation ; andrew c. chatzis md involved in study concept and design , data analysis and interpretation , writing and editing the paper and is the guarantor of the work.key learning pointsthe holt oram syndrome exhibits a variety of congenital cardiac anomalies and not only atrioventricular septal defects.although the syndrome affects predominately the upper limbs , it is also associated with other skeletal malformations.the trait may not be expressed in other family members . the holt  oram syndrome exhibits a variety of congenital cardiac anomalies and not only atrioventricular septal defects.although the syndrome affects predominately the upper limbs , it is also associated with other skeletal malformations.the trait may not be expressed in other family members . oram syndrome exhibits a variety of congenital cardiac anomalies and not only atrioventricular septal defects . although the syndrome affects predominately the upper limbs , it is also associated with other skeletal malformations .