Article

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: 54.42). 04/1994; 330(13):885-91. DOI: 10.1056/NEJM199403313301302
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
104 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Study of monogenic congenital heart disease (CHD) has provided entry points to gain new understanding of heart development and the molecular pathogenesis of CHD. In this review, we discuss monogenic CHD caused by mutations of the cardiac transcription factor genes NKX2-5 and GATA4. Detailed investigation of these genes in mice and humans has expanded our understanding of heart development, shedding light on the complex genetic and environmental factors that influence expression and penetrance of CHD gene mutations.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 4(10). · 7.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterised by upper limb anomalies and congenital heart defects. We present epidemiological and clinical aspects of HOS patients using data from EUROCAT (European Surveillance of Congenital Anomalies) registries.Methods The study was based on data collected during 1990¿2011 by 34 registries. The registries are population-based and use multiple sources of information to collect data on all types of birth using standardized definitions, methodology and coding. Diagnostic criteria for inclusion in the study were the presence of radial ray abnormalities and congenital heart disease (CHD), or the presence of either radial ray anomaly or CHD, with family history of HOS.ResultsA total of 73 cases of HOS were identified, including 11 (15.1%) TOPFA and 62 (84.9%) LB. Out of 73 HOS cases, 30.8% (20/65) were suspected prenatally, 55.4% (36/65) at birth, 10.7% (7/65) in the first week of life, and 3.1% (2/65) in the first year of life. The prenatal detection rate was 39.2% (20/51), with no significant change over the study period. In 55% (11/20) of prenatally detected cases, parents decided to terminate pregnancy. Thumb anomalies were reported in all cases. Agenesis/hypoplasia of radius was present in 49.2% (30/61), ulnar aplasia/hypoplasia in 24.6% (15/61) and humerus hypoplasia/phocomelia in 42.6% (26/61) of patients. Congenital heart defects (CHD) were recorded in 78.7% (48/61) of patients. Isolated septal defects were present in 54.2 (26/48), while 25% (12/48) of patients had complex/severe CHD. The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births.ConclusionsHOS is a rare genetic condition showing regional variation in its prevalence. It is often missed prenatally, in spite of the existence of major structural anomalies. When discovered, parents in 45% (9/20) of cases opt for the continuation of pregnancy. Although a quarter of patients have severe CHD, the overall first week survival is very good, which is important information for counselling purposes.
    Orphanet Journal of Rare Diseases 10/2014; 9(1):156. · 3.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction The 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 Cases: Four consecutive patients 1-15 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. Discussion The 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. Conclusion Cardiovascular disorders, skeletal malformations and familial expression of the Holt-Oram syndrome, vary widely.
    International Journal of Surgery Case Reports. 01/2014;