eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Holt-Oram Syndrome

Author: Poothirikovil Venugopalan, MBBS, MD, FRCP (Glasg), FRCPCH, Consulting Staff, Department of Child Health, University Hospital of Hartlepool, UK
Contributor Information and Disclosures

Updated: Nov 7, 2008

Introduction

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.

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; heart block of varying degree; or both.  

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.1

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.

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.2 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.

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.3

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.

Clinical

History

  • Clinical features of Holt-Oram syndrome (HOS) vary depending on the severity of the cardiac and limb malformation.
  • Individuals with more severe congenital heart defects may present in the neonatal period. Abnormalities may also be detected in utero using fetal ultrasonography and fetal echocardiography.
  • Cardiac symptoms depend on the type of congenital heart defect. Atrial septal defect (ASD), the most common heart defect in HOS, causes no symptoms in the vast majority of affected individuals.
  • Severity of cardiac and limb malformations appears to be positively correlated in some studies; however, this has not been replicated in other studies.
  • In any sporadic case of ASD, the patient and parents should be examined for limb malformations, and the family history should be studied in detail.

Physical

Physical findings may include the following:

  • Musculoskeletal defects
    • Upper limbs are usually affected, although the importance of isolated lower limb involvement associated with specific mutations has been reported.4
    • Although bilateral, the left side is often more significantly affected.
    • The most severe form is phocomelia with rudimentary limbs.
    • Mildest forms include clinodactyly, limited supination, and sloping shoulders.
    • The most common defects include radial thumb anomalies ranging from absent thumbs to displaced (distally placed), duplicated, or triphalangeal thumbs. Carpal and metacarpal anomalies (especially the fourth) may also be present.
    • Hypoplasia of the radius manifests as short deformed forearm, although it may be so mild that it is detectable only on radiography of the forearm.
    • Sprengel deformity (upward displacement of the scapula) and hypoplasia of the shoulders, clavicles, and humerus have also been reported.
    • The number and location of hypoplastic muscles correlate with the severity of skeletal involvement. Accordingly, patients with hypoplasia of large and proximal muscles have phocomelia, and those with intrinsic hand muscle hypoplasia have only a triphalangeal thumb or no skeletal malformation.
    • Associated muscular hypoplasia that involves the hypothenar, wrist extensor, supinator, biceps brachii, triceps brachii, deltoid, pectoral, and trapezium muscles has also been reported.
    • Isolated (sporadic) patients have more severe involvement, which can include the ulnar ray.
  • Heart defects
    • The reported incidence ranges from 50-95%.
    • The most common lesion is a secundum ASD. Others include ventricular septal defect (VSD), atrioventricular (AV) block, pulmonic stenosis (including peripheral arterial), and mitral valve prolapse.
    • Approximately 17% of patients have more complex cardiac malformations, such as tetralogy of Fallot, hypoplastic left heart, endocardial cushion defects, and truncus arteriosus. Cardiac arrhythmias include paroxysmal tachycardia, prolonged PR interval, wandering atrial pacemaker, atrial ectopics, AV block, and sinus bradycardia. Syncope and sinus arrest have been reported. Multiple VSDs have also been reported.
    • According to Mglinets, "a specific feature of the syndrome is a change in the main palmar lines and their termination on the radial border of the hand not only in the absence of the thumb but also in the case of formation of the abortive xT-line, its radiants, and the axial triradius."5
    • Pulmonary hypoplasia has occasionally been reported and can present with neonatal respiratory distress.6,7  No other associated visceral anomaly has been reported.
  • Intelligence: Intelligence is normal.

A scoring system to assess severity has been recommended by Gall et al and modified by Gladstone and Sybert, as follows:

  • Scoring system to assess skeletal abnormalities in HOS
    • 0 - No abnormality on physical or radiological examination
    • 1 - Minor abnormalities, including reduced thenar eminence, clinodactyly, or hypoplasia of the thumb
    • 3 - Present arms and forearms, with one or more bones missing
    • 4 – Phocomelia
  • Scoring system to assess cardiac abnormalities in HOS
    • 0 - Asymptomatic, with no abnormal physical findings
    • 1 - Conduction defect
    • 2 - Structural heart abnormality that does not require surgery
    • 3 - Structural heart abnormality that requires surgery but is not life threatening
    • 4 - Potentially lethal malformation

More on Holt-Oram Syndrome

Overview: Holt-Oram Syndrome
Differential Diagnoses & Workup: Holt-Oram Syndrome
Treatment & Medication: Holt-Oram Syndrome
Follow-up: Holt-Oram Syndrome
Multimedia: Holt-Oram Syndrome
References
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References

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Further Reading

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Keywords

Holt-Oram syndrome, HOS, embryonic radial ray, triphalangeal thumbs, absent thumbs, foreshortened arms, phocomelia, TBX5, atriodigital hypoplasia, cardiac-limb syndrome, cardiomelic syndrome, heart-hand syndrome, upper limb–cardiovascular syndrome, ventricular septal defect, VSD, atrial septal defect, ASD

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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 Hartlepool, UK
Poothirikovil Venugopalan, MBBS, MD, FRCP (Glasg), FRCPCH is a member of the following medical societies: British Cardiac Society and Royal College of Physicians and Surgeons of Glasgow
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

John W Moore, MD, MPH, Professor of Clinical Pediatrics, Division of Pediatric Cardiology, Mattel Children's Hospital of University of California at Los Angeles
John W Moore, MD, MPH is a member of the following medical societies: Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

CME Editor

Gilbert Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College
Gilbert 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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