Holt Oram Syndrome

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Synonyms for Holt Oram Syndrome: Atriodigital Dysplasia, Cardiac-Limb Syndrome, Cardiomelic Syndrome, Familial Heart Disease with Skeletal Malformations, Heart-Hand Syndrome, Hand-Heart Syndrome, Pseudothalidomide Syndrome, Upper Limb–Cardiovascular Syndrome, Thumb Abnormality.

An Pediatr (Barc). 2006 Jun;64(6):578-82.
Holt-Oram syndrome: characterization of a novel mutation
Fernandez Garcia-Moya L, Lapunzina Badia P, Delicado Navarro A, Sharif A, Cross G, Mori Alvarez MA, de Torres Perezhidalgo ML,
Palomares Bralo M, Garcia Sanchez P, Garcia-Guereta Silva L, Lopez Pajares I.
Servicio de Genetica Medica, Hospital Universitario La Paz, Madrid, Spain.

INTRODUCTION: Cardiomyelic syndromes encompass congenital heart disease and skeletal malformations of the upper limbs and are related to mutations in transcription factors with T-Box domains. Holt-Oram syndrome is caused by a dominant mutation in the TBX5 gene that alters the three-dimensional structure of the protein and its DNA binding function. Several point mutations and deletions in TBX5 have been reported in patients with the Holt-Oram syndrome phenotype. PATIENTS AND METHODS: The proband was a boy with a large atrial septal defect ostium secundum type and a ventricular septal defect, diagnosed by clinical findings (heart murmur) and echocardiography. He also presented slightly hypoplastic thumbs with distal bilateral placement and an implantation index of 0.19 (compared with an average of 0.50 for his gestational age at birth). The boy was referred to the department of medical genetics to rule out 22q11.2 microdeletion syndrome. RESULTS: Karyotype and fluorescence in situ hybridization at locus D22S75 were both normal. Because of his clinical findings, molecular study for Holt-Oram syndrome was indicated, leading to the finding of a mutation at intron 7 of TBX5, probably producing a splicing alteration of the gene and resulting in a protein truncated at its C-terminal end. The proband's parents presented the wild type sequence of the gene, thus indicating that the mutation was produced de novo, although a possible germinal mosaicism in the parents could not be ruled out. CONCLUSIONS: Holt-Oram syndrome is the most frequent cause of cardiomyelic syndrome. All children with heart malformations and abnormalities of the upper limbs such as absent, hypoplastic, distally placed or triphalangic thumbs should undergo molecular studies for this syndrome.

Thorac Cardiovasc Surg. 2002 Oct;50(5):312-4.
Cardiac malformations associated with the Holt-Oram syndrome--report on a family and review of the literature
Bossert T, Walther T, Gummert J, Hubald R, Kostelka M, Mohr FW.
Universitat Leipzig, Herzzentrum, Klinik fur Herzchirurgie, Germany. Tbossert11@aol.com

The Holt-Oram syndrome (HOS) is characterized by mild-to-severe congenital cardiac defects and skeletal abnormalities of the upper limb. The most common cardiac disorder is an ostium secundum atrial septal defect (ASD), followed by ventricular septal defect (VSD) and ostium primum ASD. Electrocardiographic abnormalities, such as various degrees of atrioventricular block, have also been reported. In addition, hypoplastic peripheral vessels of the upper limbs have been observed. Here, we will report about a family with three sons having HOS, and we will detail the cardiac spectrum of HOS as reported in the literature.

Arch Mal Coeur Vaiss. 1999 May;92(5):667-9.
Three different types of atrial septal defects in the same family
Cachat F, Rapatsalahy A, Sekarski N, Hurni M, von Segesser L, Payot M.
Unite de cardiologie pediatrique, departement de pediatrie, centre hospitalier universitaire Vaudois, Lausanne-CHUV, Suisse.

Most of the time atrial septal defects (ASD) are sporadic. Familial forms are characterised by the same type of the ASD, and are frequently associated by other cardiac, osteoarticular (Holt-Oram syndrome) or atrioventricular conductions abnormalities (ostium secundum ASD with prolonged PR, sinus venosus ASD with sinusal bradyarrhythmia). This report describes a family in which the father and his two children present an ASD, each one of a different type (ostium primum ASD, ostium secundum ASD, sinus venosus ASD), without any other associated malformations. To the best of our knowledge, this is the first report of a family in which three different ASD types are present.

J Med Genet. 1996 Apr;33(4):300-7.
Holt-Oram syndrome: a clinical genetic study
Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID.
Centre for Medical Genetics, City Hospital, Nottingham, UK.

A clinical and genetic study of the Holt-Oram syndrome (HOS) has been carried out in the United Kingdom involving 55 cases designated Holt-Oram syndrome, together with their parents and sibs. Data from the clinical assessment of both familial and isolated cases were used to define the HOS phenotype and to outline the spectrum of abnormalities, especially factors affecting severity. Skeletal defects affected the upper limbs exclusively and were bilateral and asymmetrical. They ranged from minor signs such as clinodactyly, limited supination, and sloping shoulders to severe reduction deformities of the upper arm (4.5%). The radial ray was predominantly affected than the right. All affected cases showed evidence of upper limb involvement. Cardiac defects were seen in 95% of familial cases and included both atrial septal defect (ASD, 34%) and ventricular septal defect (VSD, 25%); 39% had only ECG changes. Cardiac involvement ranged from asymptomatic conduction disturbances to multiple structural defects requiring surgery in infancy. Sudden death could be caused by heart block. Inheritance was autosomal dominant with 100% penetrance and no evidence of reduced fitness. Increasing severity occurred in succeeding generations consistent with anticipation.

Acta Chir Belg. 1995 Sep-Oct;95(5):229-36.
Radial club hand and Holt-Oram syndrome
Elbaum R, Royer M, Godart S.
Department of paediatric surgery, Centre Hospitalier Etterbeek-Ixelles, Brussels, Belgium.

The authors describe the case of a young African girl born with a radial club hand associated with a pedicled floating thumb, no other orthopaedic malformation was detected. A ventricular septal defect necessitated surgery in emergency. In front of such malformative association, the Holt-Oram syndrome has been evoked. The aim of this study has been to review the etiology and classification of this rather rare malformative association, as well as to describe the therapeutic attitudes and surgical techniques proposed by various authors towards the radial club hand (1, 3, 5, 6, 7, 12).

Cardiologia. 1995 Mar;40(3):199-203.
Holt-Oram syndrome: cardiological, radiological and genetic evaluation
Donadeo V, Solarino M, Alfieri O, Fucci C, Guanti G, Susca F, Brindicci G.
Divisione di Cardiologia, Centro Traumatologico Ortopedico, Bari.

A case of a 63-year-old woman with Holt-Oram syndrome is presented. The patient, operated at 38 years for correction of an interatrial defect of the ostium secundum type presented with upper extremity skeletal abnormalities, in particular on the left, and a severe mitral insufficiency with ruptured chordae tendinae of the posterior leaflet. Mitral valve reconstruction was followed by an unusual severe hemolytic anemia and acute secondary renal insufficiency. Valve replacement was therefore necessary. At present, the patient, whose karyotype is normal, is in NYHA functional class I.

South Med J. 1993 Apr;86(4):453-6.
Holt-Oram syndrome associated with hypoplastic peripheral vasculature and midsystolic click
DuPre CT, Fincher RM.
Medical College of Georgia, Department of Medicine, Augusta 30912.

Holt-Oram syndrome is a rare, autosomal dominant syndrome characterized by upper extremity skeletal abnormalities and cardiac defects. The most common skeletal anomalies involve the thumbs and range from minor radiographic abnormalities to phocomelia. The most common cardiovascular abnormality is ostium secundum ASD, followed by ventriculo-septal defect and ostium primum ASD. MVP and hypoplastic peripheral vasculature of the upper extremities have been reported only rarely. We have reported the case of a patient with HOS who has both hypoplastic peripheral upper extremity vasculature and evidence of MVP.

S Afr Med J. 1985 Jun 22;67(25):1013-4.
The upper limb-cardiovascular syndrome (Holt-Oram syndrome) in a South African family.
Marcus RH, Marcus BD, Levin SE.

The upper limb-cardiovascular syndrome is reported for the first time in a South African family. There were 6 affected members in 3 generations. Infradiaphragmatic total anomalous pulmonary venous drainage, with obstruction, was found in 1 child. This rare cardiac abnormality, which constitutes only 8,5% of all cases of total anomalous pulmonary venous drainage, itself an unusual abnormality, has not previously been reported in association with the Holt-Oram syndrome.

Chest. 1981 Jan;79(1):113-5.
Cross-sectional echocardiographic imaging of supracardiac total anomalous pulmonary venous drainage to a vertical vein in a patient with Holt-Oram syndrome
Sahn DJ, Goldberg SJ, Allen HD, Canale JM.

We report the unusual association of total anomalous pulmonary venous drainage in a three-year-old with Holt-Oram syndrome and a new technique for imaging vertical vein drainage of anomalously draining pulmonary veins by suprasternal cross-sectional echocardiography.

Jpn Heart J. 1975 Jul;16(4):480-7.
A family of Holt-Oram syndrome
Ito M, Misawa T, Fujino M, Ito S, Fukumoto T.

A family of Holt-Oram syndrome is reported. Twenty of 41 living members in the last 3 generations were examined. The propositus expressed typically the cardinal features of this syndrome: atrial septal defect, patent ductus arteriosus, cardiac arrhythmias and conduction block of various types, and hypoplasia of the left thumb. Two individuals were clinically diagnosed to have atrial septal defect without any upper limb anomaly, and 3 showed upper limb anomaly without any sign of congenital heart disease. Other 5 members showed only minor abnormalities, such as funnel chest or mild right ventricular hypertrophy on ECG and VCG. Some of the skeletal abnormalities observed were hitherto undescribed ones. These include generalized hypoplasia of left hand and downward displacement of right sterno-clavicular joint.

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