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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2014

Open Access 01-12-2014 | Research

Holt Oram syndrome: a registry-based study in Europe

Authors: Ingeborg Barisic, Ljubica Boban, Ruth Greenlees, Ester Garne, Diana Wellesley, Elisa Calzolari, Marie-Claude Addor, Larraitz Arriola, Jorieke EH Bergman, Paula Braz, Judith LS Budd, Miriam Gatt, Martin Haeusler, Babak Khoshnood, Kari Klungsoyr, Bob McDonnell, Vera Nelen, Anna Pierini, Annette Queisser-Wahrendorf, Judith Rankin, Anke Rissmann, Catherine Rounding, David Tucker, Christine Verellen-Dumoulin, Helen Dolk

Published in: Orphanet Journal of Rare Diseases | Issue 1/2014

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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.

Results

A 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.

Conclusions

HOS 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.
Literature
1.
2.
McDermott DA, Fong JC, Basson CT: Holt-Oram syndrome. Gene Reviews at Gene Tests: Medical Genetics Information Resource (database online). , University of Washington, Copyright, Seattle, 1997-2008. (Updated 4/4/13). http://​www.​genetests.​org, [http://​www.​genetests.​org]
3.
Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE: Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997, 15: 30-35. 10.1038/ng0197-30.CrossRefPubMed
4.
Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, Silengo M, Pereira A, Krieger J, Mesquita SF, Kamisago M, Morton CC, Pierpont ME, Müller CW, Seidman JG, Seidman CE: Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci U S A. 1999, 96: 2919-2924. 10.1073/pnas.96.6.2919.CrossRefPubMedPubMedCentral
5.
McDermott DA, Bressan MC, He J, Lee JS, Aftimos S, Brueckner M, Gilbert F, Graham GE, Hannibal MC, Innis JW, Pierpont ME, Raas-Rothschild A, Shanske AL, Smith WE, Spencer RH, St John-Sutton MG, van Maldergem L, Waggoner DJ, Weber M, Basson CT: TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res. 2005, 58: 981-986. 10.1203/01.PDR.0000182593.95441.64.CrossRefPubMed
6.
Böhm J, Heinritz W, Craig A, Vujic M, Ekman-Joelsson BM, Kohlhase J, Froster U: Functional analysis of the novel TBX5 c.1333delC mutation resulting in an extended TBX5 protein. BMC Med Genet. 2008, 9: 88-10.1186/1471-2350-9-88.CrossRefPubMedPubMedCentral
7.
Muru K, Kalev I, Teek R, Sõnajalg M, Kuuse K, Reimand T, Ounap K: A Boy with Holt-Oram syndrome caused by novel mutation c.1304delT in the TBX5 gene. Mol Syndromol. 2011, 1: 307-310. 10.1159/000330109.CrossRefPubMedPubMedCentral
8.
Fan C, Duhagon MA, Oberti C, Chen S, Hiroi Y, Komuro I, Duhagon PI, Canessa R, Wang Q: Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome. J Med Genet. 2003, 40: e29-10.1136/jmg.40.3.e29.CrossRefPubMedPubMedCentral
9.
Fan C, Liu M, Wang Q: Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. J Biol Chem. 2003, 278: 8780-8785. 10.1074/jbc.M208120200.CrossRefPubMedPubMedCentral
10.
Postma AV, van de Meerakker JB, Mathijssen IB, Barnett P, Christoffels VM, Ilgun A, Lam J, Wilde AA, Lekanne Deprez RH, Moorman AF: A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circ Res. 2008, 102: 1433-1442. 10.1161/CIRCRESAHA.107.168294.CrossRefPubMed
11.
Porto MP, Vergani N, Carvalho AC, Cernach MC, Brunoni D, Perez AB: Novel mutations in the TBX5 gene in patients with Holt-Oram syndrome. Genet Mol Biol. 2010, 33: 232-236. 10.1590/S1415-47572010005000051.CrossRefPubMedPubMedCentral
12.
Boogerd CJ, Dooijes D, Ilgun A, Mathijssen IB, Hordijk R, van de Laar IM, Rump P, Veenstra-Knol HE, Moorman AF, Barnett P, Postma AV: Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome. Cardiovasc Res. 2010, 88: 130-139. 10.1093/cvr/cvq178.CrossRefPubMed
13.
Patel C, Silcock L, McMullan D, Brueton L, Cox H: TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome. Eur J Hum Genet. 2012, 20: 863-869. 10.1038/ejhg.2012.16.CrossRefPubMedPubMedCentral
14.
Smemo S, Campos LC, Moskowitz IP, Krieger JE, Pereira AC, Norbrega MA: Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum Mol Genet. 2012, 21: 3255-3263. 10.1093/hmg/dds165.CrossRefPubMedPubMedCentral
15.
Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, Traill TA, Seidman JG, Seidman CE: The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med. 1994, 330: 885-891. 10.1056/NEJM199403313301302.CrossRefPubMed
16.
Newbury-Ecob R, Leanage R, Raeburn JA, Young ID: The Holt-Oram syndrome: a clinical genetic study. J Med Genet. 1996, 33: 300-307. 10.1136/jmg.33.4.300.CrossRefPubMedPubMedCentral
17.
Sletten LJ, Pierpont MEM: Variation in severity of cardiac disease in Holt-Oram syndrome. Am J Med Genet. 1996, 65: 128-132. 10.1002/(SICI)1096-8628(19961016)65:2<128::AID-AJMG9>3.0.CO;2-O.CrossRefPubMed
18.
Smith AT, Sack GH, Taylor GJ: Holt-Oram syndrome. J Pediatr. 1979, 95: 538-543. 10.1016/S0022-3476(79)80758-1.CrossRefPubMed
19.
20.
Elek C, Vitéz M, Czeizel E: Holt-Oram syndrome. Orv Hetil. 1991, 132: 73-74. 77-78PubMed
21.
22.
Greenlees R, Neville A, Addor MC, Amar E, Arriola L, Bakker M, Barisic I, Boyd P, Calzolari E, Doray B, Draper E, Vollset SE, Garne E, Gatt M, Haeusler M, Kallen K, Khoshnood B, Latos-Bielenska A, Martinez-Frias ML, Materna-Kiryluk A, Dias CM, McDonnell B, Mullaney C, Nelen V, O'Mahony M, Pierini A, Queisser-Luft A, Randrianaivo-Ranjatoe'lina H, Rankin J, Rissman A, et al: Paper 6: EUROCAT Member Registries: Organization and Activities. Birth Defects Res A Clin Mol Teratol. 2011, 91: S51-S100. 10.1002/bdra.20775.CrossRefPubMed
23.
Barisic I, Tokic V, Loane M, Bianchi F, Calzolari E, Garne E, Wellesley D, Dolk H: Descriptive epidemiology of Cornelia de Lange syndrome in Europe. Am J Med Genet. 2008, 146A: 51-59. 10.1002/ajmg.a.32016.CrossRefPubMed
24.
Barisic I, Odak L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Arriola L, Bergman J, Bianca S, Boyd PA, Draper ES, Gatt M, Haeusler M, Khoshnood B, Latos-Bielenska A, McDonnell B, Pierini A, Rankin J, Rissmann A, Queisser-Luft A, Verellen-Dumoulin C, Stone D, Tenconi R: Fraser syndrome: epidemiological study in a European population. Am J Med Genet. 2013, 161A: 1012-1018. 10.1002/ajmg.a.35839.CrossRefPubMed
25.
Barisic I, Odak L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Arriola L, Bergman J, Bianca S, Doray B, Khoshnood B, Klungsoyr K, McDonnell B, Pierini A, Rankin J, Rissmann A, Rounding C, Queisser-Luft A, Scarano G, Tucker D: Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe.Eur J Hum Genet 2014, doi:10.1038/ejhg.2013.287.,
26.
Stoll C, Dott B, Alembik Y, Roth MP: Associated malformations among infants with radial ray deficiency. Genet Couns. 2013, 24: 223-234.PubMed
27.
Brons JT, van Geijn HP, Wladimiroff JW, van der Harten JJ, Kwee ML, Sobotka-Plojhar M, Arts NF: Prenatal ultrasound diagnosis of the Holt-Oram syndrome. Prenat Diagn. 1988, 8: 175-181. 10.1002/pd.1970080303.CrossRefPubMed
28.
Law KM, Tse KT: Prenatal sonographic diagnosis of familial Holt-Oram syndrome associated with type B interrupted aortic arch. Hong Kong Med J. 2008, 14: 317-320.PubMed
29.
Holmes LB: Congenital heart disease and upper-extremity deformities. A report of two families. N Engl J Med. 1965, 272: 437-44. 10.1056/NEJM196503042720901.CrossRefPubMed
30.
Gall JC, Stem AM, Cohen MM, Adams MS, Davidson RT: Holt-Oram syndrome: clinical and genetic study of a large family. Am Hum Genet. 1966, 18: 187-200.
31.
Poznanski AK, Gall JC, Stern AM: Skeletal manifestations of the Holt-Oram syndrome. Radiology. 1970, 94: 45-54. 10.1148/10.1148/94.1.45.CrossRefPubMed
32.
Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD: Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997, 15: 21-29. 10.1038/ng0197-21.CrossRefPubMed
33.
Lehner R, Goharkhay N, Tringler B, Fasching C, Hengstschläger M: Pedigree analysis and descriptive investigation of three classic phenotypes associated with Holt-Oram syndrome. J Reprod Med. 2003, 48: 153-159.PubMed
34.
Brassington AM, Sung SS, Toydemir RM, Le T, Roeder AD, Rutherford AE, Whitby FG, Jorde LB, Bamshad MJ: Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am J Hum Genet. 2003, 73: 74-85. 10.1086/376436.CrossRefPubMedPubMedCentral
35.
Tseng YR, Su YN, Lu FL, Jeng SF, Hsieh WS, Chen CY, Chou HC, Peng SS: Holt-Oram syndrome with right lung agenesis caused by a de novo mutation in the TBX5 gene. Am J Med Genet A. 2007, 143A: 1012-1014. 10.1002/ajmg.a.31672.CrossRefPubMed
36.
Garavelli L, De Brasi D, Verri R, Guareschi E, Cariola F, Melis D, Calcagno G, Salvatore F, Unger S, Sebastio G, Albertini G, Rivieri F, Soli F, Superti-Furga A, Gentile M: Holt-Oram syndrome associated with anomalies of the feet. Am J Med Genet A. 2008, 146A: 1185-1189. 10.1002/ajmg.a.32170.CrossRefPubMed
37.
Faria MH, Rabenhorst SH, Pereira AC, Krieger JE: A novel TBX5 mutation (V263M) in a family with atrial septal defects and postaxial hexadactyly. Int J Cardiol. 2008, 130: 30-35. 10.1016/j.ijcard.2008.06.090.CrossRefPubMed
38.
Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, Haan EA, Chan A: Reproductive technologies and the risk of birth defects. N Engl J Med. 2012, 366: 1803-1813. 10.1056/NEJMoa1008095.CrossRefPubMed
39.
Tararbit K, Lelong N, Thieulin AC, Houyel L, Bonnet D, Goffinet F, Khoshnood B: The risk for four specific congenital heart defects associated with assisted reproductive techniques: a population-based evaluation. Hum Reprod. 2013, 28: 367-374. 10.1093/humrep/des400.CrossRefPubMedPubMedCentral
40.
Vermeiden JP, Bernardus RE: Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection?. Fertil Steril. 2013, 99: 642-651. 10.1016/j.fertnstert.2013.01.125.CrossRefPubMed
41.
Kochanski A, Merritt TA, Gadzinowski J, Jopek A: The impact of assisted reproductive technologies on the genome and epigenome of the newborn. J Neonat Perinat Med. 2013, 6: 101-108.
Metadata
Title
Holt Oram syndrome: a registry-based study in Europe
Authors
Ingeborg Barisic
Ljubica Boban
Ruth Greenlees
Ester Garne
Diana Wellesley
Elisa Calzolari
Marie-Claude Addor
Larraitz Arriola
Jorieke EH Bergman
Paula Braz
Judith LS Budd
Miriam Gatt
Martin Haeusler
Babak Khoshnood
Kari Klungsoyr
Bob McDonnell
Vera Nelen
Anna Pierini
Annette Queisser-Wahrendorf
Judith Rankin
Anke Rissmann
Catherine Rounding
David Tucker
Christine Verellen-Dumoulin
Helen Dolk
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2014
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-014-0156-y

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