The Clinical and Genetic Spectrum of the Holt-Oram Syndrome (Heart-Hand Syndrome)

Department of Medicine, Brigham and Women's Hospital, Boston, MA.
New England Journal of Medicine (Impact Factor: 55.87). 04/1994; 330(13):885-91. DOI: 10.1056/NEJM199403313301302
Source: PubMed


The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied by congenital cardiac defects. The cause of these disparate clinical features is unknown. To identify the chromosomal location of the Holt-Oram syndrome gene, we performed clinical and genetic studies.
Two large families with the Holt-Oram syndrome were evaluated by radiography of the hands, electrocardiography, and transthoracic echocardiography. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the genome to identify a locus that was inherited with the Holt-Oram syndrome in family members.
A total of 19 members of Family A had Holt-Oram syndrome with mild-to-moderate skeletal deformities, including triphalangeal thumbs and carpal-bone dysmorphism. All affected members of Family A had moderate-to-severe congenital cardiac abnormalities, such as ventricular or atrial septal defects or atrioventricular-canal defects. Eighteen members of a second kindred (Family B) had Holt-Oram syndrome with moderate-to-severe skeletal deformities, including phocomelia. Twelve of the affected members had no cardiac defects; six had only atrial septal defects. Genetic analyses demonstrated linkage of the disease in each family to polymorphic loci on the long arm of chromosome 12 (combined multipoint lod score, 16.8). These data suggest odds greater than 10(16):1 that the genetic defect for Holt-Oram syndrome is present on the long arm of chromosome 12 (12q2).
Mutations in a gene on chromosome 12q2 can produce a wide range of disease phenotypes characteristic of the Holt-Oram syndrome. This gene has an important role in both skeletal and cardiac development.

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    • "Holt-Oram syndrome is caused by mutations in TBX5 [2], a T-box transcription factor gene family member coded for by a gene on chromosome 12q2. There have been only two previously reported clinical cases of Holt-Oram syndrome associated with malignancy to date [3] [4], with parotid carcinoma and lymphosarcoma, respectively. "
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    ABSTRACT: Holt-Oram syndrome is an autosomal dominant disorder which is caused by mutations of TBX5 and is characterised by cardiac and skeletal abnormalities. TBX5 is part of the T-box gene family and is thought to upregulate tumour cell proliferation and metastasis when mutated. We report the first clinical case of prostate cancer in an individual with Holt Oram syndrome.
    08/2013; 2013(3):405343. DOI:10.1155/2013/405343
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    • "Holt-Oram Syndrome (HOS), also known as heart-hand syndrome, is a congenital autosomal dominant disorder that primarily affects the heart and upper limbs (Holt and Oram, 1960). HOS is the most common heart-hand syndrome, affecting nearly 1 in 100,000 total births (Basson and others, 1994). Approximately 75% of patients with HOS experience cardiac defects, most commonly ASD, ventricular septal defects (VSD), and/or defects in the cardiac conduction system (Basson and others, 1994; Benson and others, 1996; Cross and others, 2000; McDermott and others, 2005; Newbury-Ecob and others, 1996). "
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    ABSTRACT: Congenital heart defects affect nearly 1% of all newborns and are a significant cause of infant death. Clinical studies have identified a number of congenital heart syndromes associated with mutations in genes that are involved in the complex process of cardiogenesis. The African clawed frog, Xenopus, has been instrumental in studies of vertebrate heart development and provides a valuable tool to investigate the molecular mechanisms underlying human congenital heart diseases. In this review, we discuss the methodologies that make Xenopus an ideal model system to investigate heart development and disease. We also outline congenital heart conditions linked to cardiac genes that have been well studied in Xenopus and describe some emerging technologies that will further aid in the study of these complex syndromes.
    Birth Defects Research Part A Clinical and Molecular Teratology 06/2011; 91(6):495-510. DOI:10.1002/bdra.20793 · 2.09 Impact Factor
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    • "13, 6 On amino acid in neighboring an amino acid at the end of the amino acid is related to a deep track of DNA and any mutation in it is the real reason of cardiac disorders in HSO syndrome.5, 6, 14 Any change of amino acid at the carboxyl end may create a relationship with small DNA track and cause different shortages in upper organs.5, 6, 12, 25 "
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    ABSTRACT: The Holt-Oram Syndrome (HOS) or the Heart-Hand syndrome is considered as an overt autosomal hereditary disease with a complete influential effect and variable expression that emerges due to a genetic mutation. It can be vividly characterized by heart disorders and deficiencies in hand structure. Despite the existing genetic heterogeneity, the variable integration between HOS and the T-BX5 gene from the T-BOX Gene Complex has been observed during which various mutations have been reported in the affected patients. The T-BOX Gene Complex is located on chromosome 12 (12 q 24.1), and is able to encode a copying factor. That has a conservative motive with 180 amino acids. The deficiencies in only 1/3 of patients have been observed caused by the mutation of this gene. This case was a 10-year-old child with hand disorders, incomplete growth of clavicle, moving problems in elbow joint and shoulder, disorder in ventricle and auricle walls. The disease was diagnosed as HOS, based on clinical examination and drawing the family tree diagram. It was impossible to investigate molecular mutation due to inaccessibility to the patient. By investigating the family members and their deficiencies and imaging disorder variables according to different reports as well as parents' state of health, the HOS can be defined as an overt heredity resulting from a new mutation in the germinating layer of sexual cells in one of the parents. There is a weak possibility that the disease results from a mosaic mutation in the male parent's testicle or the female parent's ovum. In this case, the probability for the disease to be repeated in parents' next children will be guessed between 1 and 50%.
    ARYA Atherosclerosis 04/2011; 7(2):87-92.
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