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 .
 introductionthe holt  oram syndrome is a rare congenital disorder involving the skeletal and cardiovascular systems . 
 it is characterized by upper limb deformities and cardiac malformations , atrial septal defects in particular.presentation of casefour consecutive patients 115 years old with the holt  
 oram syndrome presented over a 10 year span for surgical treatment of their cardiac maladies . 
 the spectrum of the heart defects and skeletal deformities encountered in these patients are described and discussed.discussionthe holt  
 oram syndrome is an autosomal dominant condition ; however absence of the morphological features of the trait in close family members is not rare . although patients are known to predominately present with atrial septal defects , other cardiovascular anomalies , including rhythm abnormalities , are not uncommon . 
 skeletal disorders vary as well.conclusioncardiovascular disorders , skeletal malformations and familial expression of the holt  oram syndrome , vary widely . 
Introduction
Cases
Case 1
Case 2
Case 3
Case 4
Discussion
Conclusions
Conflict of interest
Funding
Ethical approval
Author contributions