Pediatric Holt-Oram Syndrome 

  • Author: Poothirikovil Venugopalan, MBBS, MD, FRCP(Glasg), FRCPCH; Chief Editor: Steven R Neish, MD, SM   more...
 
Updated: Jun 23, 2010
 

Background

Holt-Oram syndrome (HOS) (OMIM 142900) is a heart–upper limb malformation complex with an autosomal dominant inheritance and near-complete penetrance but variable expression. Holt and Oram first described this syndrome in 1960. Approximately 40% of cases represent new mutations.

See the image below depicting Holt-Oram syndrome in an infant.

Photograph showing hypoplastic right thumb of the Photograph showing hypoplastic right thumb of the right hand of a 6-month-old infant with Holt-Oram syndrome.
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Pathophysiology

Defective development of the embryonic radial ray (eg, aplasia, hypoplasia, fusion, other anomalous development) results in a wide spectrum of phenotypes, including triphalangeal or absent thumbs, foreshortened arms, and phocomelia. The syndrome is associated with defective development of cardiac structures that results in atrial septal defect (ASD), most commonly the secundum type (as shown below); heart block of varying degree; or both.[1]

A 2-dimensional echocardiographic picture taken frA 2-dimensional echocardiographic picture taken from subxiphoid window showing a large secundum atrial septal defect (arrow) in a 7-year-old boy with Holt-Oram syndrome. ASD = Atrial septal defect; RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle.

The responsible gene has been mapped to band 12q24.1, which encodes the human transcription factor TBX5. A full list of the described mutations is available at the TBX5 Gene Mutation Database, an online locus-specific database that contains germline and somatic mutations of the TBX5 gene. One of the recently added loci is c.373G>A, which results in the missense mutation p.Gly125Arg; this is a novel mutation, in that it is associated with a gain-of-function mechanism and is associated with paroxysmal atrial fibrillation and no structural heart disease.[2]

TBX5 genotyping has high sensitivity and specificity for HOS if stringent diagnostic criteria are used in assigning the clinical diagnosis. Mutations of this gene introduce a premature stop codon and result in truncated protein versions. Consequent abnormal expression of the cardiac and limb-specific T-box transcription factors lead to the malformations described in HOS. The T-box gene family is a group of related genes that play a critical role in human embryonic development.[3]

A cardiomelic developmental field has also been postulated to relate the genetic heterogeneity of HOS (and other similar syndromes) to a cascade of molecules, including the brachyury, sonic hedgehog, bone morphogenetic protein, retinoic acid receptor, and transforming growth factor beta families.

Disturbed fetal limb muscle development has also been reported and may underlie the bony malformations.

Expression widely varies in different generations. Ogur et al reported variable clinical expression of HOS in 3 generations.[4] The grandfather presented with phocomelia of arms, with 3 digits on each hand, congenital heart defect, and narrow shoulders. His son presented with cardiac conduction disturbance with no congenital heart or skeletal defect. His granddaughter developed ventricular septal defect (VSD) and moderate radial deviations of both hands, with no obvious hypoplasia of the extremities. Cachat et al reported a father and 2 sons in a French family with HOS who presented with different types of atrial septal defects (ASD): ostium primum ASD, secundum ASD, and sinus venosus ASD, respectively.

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Epidemiology

Frequency

United States

The incidence rate is unknown.

International

In Hungary, the birth prevalence is 0.95 per 100,000 total births. About 350 cases have been reported worldwide. A recent report identified this syndrome in 4% of patients with radial longitudinal deficiency.[5]

Mortality/Morbidity

No valid figures are available because the condition, in and of itself, has no specific mortality or morbidity. The mortality and morbidity relate directly to the associated congenital abnormalities, particularly those of the heart. For example, mortality and morbidity of a secundum ASD is negligible throughout childhood, including patients who undergo procedures to close the ASD. Please see the appropriate respective articles for mortality and morbidity figures on specific cardiac defects.

Causes of death include cardiac malformation and heart block. See the respective article for each cardiac abnormality for a discussion of cause of death.

Race

No valid data are available.

Sex

Both sexes are equally affected, although the defects tend to be more severe in females.

Age

Malformations are present at birth. Age at presentation varies according to the extent of the abnormality externally visible and the type of associated heart defect, if any.

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Contributor Information and Disclosures
Author

Poothirikovil Venugopalan, MBBS, MD, FRCP(Glasg), FRCPCH,  Consulting Staff, Department of Child Health, University Hospital of North Tees and Hartlepool, UK

Poothirikovil Venugopalan, MBBS, MD, FRCP(Glasg), FRCPCH, is a member of the following medical societies: British Cardiac Society, Paediatrician with Cardiology Expertise Special Interest Group, Royal College of Paediatrics and Child Health, and Royal College of Physicians and Surgeons of Glasgow

Disclosure: Nothing to disclose.

Specialty Editor Board

Ira H Gessner, MD  Professor Emeritus, Pediatric Cardiology

Ira H Gessner, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Heart Association, American Pediatric Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

John W Moore, MD, MPH  Professor of Clinical Pediatrics, Section of Pediatric Cardiology, Department of Pediatrics, University of California San Diego School of Medicine; Director of Cardiology, Rady Children's Hospital

John W Moore, MD, MPH is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, and Society for Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Gilbert Z Herzberg, MD  Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; Consulting Staff, Department of Pediatrics, Sound Shore Medical Center

Gilbert Z Herzberg, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Chief Editor

Steven R Neish, MD, SM  Director of Pediatric Cardiology Fellowship Program, Associate Professor, Department of Pediatrics, Baylor College of Medicine

Steven R Neish, MD, SM is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, and American Heart Association

Disclosure: Nothing to disclose.

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Photograph showing hypoplastic right thumb of the right hand of a 6-month-old infant with Holt-Oram syndrome.
Photograph of the left hand of a 6-month-old infant with Holt-Oram syndrome showing total aplasia of the left thumb.
Plain radiograph of the right forearm and hand of a 5-month-old infant with Holt-Oram syndrome showing hypoplastic radius and ulna and only 4 metacarpals.
A 2-dimensional echocardiographic picture taken from subxiphoid window showing a large secundum atrial septal defect (arrow) in a 7-year-old boy with Holt-Oram syndrome. ASD = Atrial septal defect; RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle.
Color Doppler echocardiographic picture taken from subxiphoid window showing the large left-to-right flow of blood (arrow) across the atrial septal defect. The red color pattern depicts flow direction from left atrium (LA) to right atrium (RA). ASD = Atrial septal defect; RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle.
 
 
 
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