Clinical characteristics.

Holt-Oram syndrome (HOS) is characterized by the association of upper-limb defects, congenital heart malformations, and cardiac conduction disease. Upper-limb malformations are usually bilateral/asymmetric, rarely unilateral or bilateral/symmetric, and affect the radial ray. They can range from thenar hypoplasia, triphalangeal thumb(s), or absent thumb(s) to radial agenesis/hypoplasia to phocomelia. Deformities of the carpal and thenar bones, abnormalities of the shoulders and/or elbows, and vertebral defects can occur. A congenital heart malformation is present in 90% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease (30%). While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

Diagnosis/testing.

The clinical diagnosis of HOS is established by the presence in a proband of a preaxial radial ray anomaly and a personal or family history of cardiac septation and/or conduction defects. More than 70% of individuals who meet strict clinical diagnostic criteria have an identifiable heterozygous pathogenic variant in TBX5.

Management.

Treatment of manifestations: Management involves a multidisciplinary team of specialists in medical genetics, cardiology, orthopedics, and hand surgery. Treatment of upper-limb malformations per orthopedist can include surgery, physical therapy, occupational therapy, and/or prostheses in those with severe limb shortening. Social and psychological support for affected individuals and families; standard treatment for congenital heart malformation per cardiologist and cardiac surgeon; anticoagulants and antibiotic prophylaxis for bacterial endocarditis if recommended by cardiologist; treatment for arrhythmias may require medication, surgery, and/or pacemaker implantation; pharmacologic treatment for individuals with pulmonary hypertension per cardiologist and/or intensivist.

Surveillance: Assess limb function and activities of daily living per orthopedist, physical therapist, and/or occupational therapist; annual EKG in those at risk of developing a conduction defect; annual EKG combined with Holter monitor for individuals with known conduction disease; echocardiogram according to the absence/presence of congenital heart defect and history of heart surgery, every five years in the absence of congenital heart defects to assess for rare cardiomyopathy; surveillance in those with pulmonary hypertension per cardiologist and/or intensivist.

Agents/circumstances to avoid: Certain medications may be contraindicated in individuals with arrhythmias, cardiomyopathy, and/or pulmonary hypertension.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in relatives at risk to identify those who would benefit from appropriate cardiac management.

Pregnancy management: Affected women who have not undergone cardiac evaluation should do so prior to pregnancy or as soon as the pregnancy is recognized; those with a known history of a structural cardiac defect or cardiac conduction abnormality should be followed by a cardiologist during pregnancy.

Genetic counseling.

HOS is inherited in an autosomal dominant manner. Some individuals diagnosed with HOS have an affected parent; up to 60% of affected individuals represent simplex cases. Significant intrafamilial variability in limb and heart defect severity is observed among affected family members. Offspring of an individual with HOS have a 50% risk for HOS. If the TBX5 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. If the pathogenic variant in the family is not known, prenatal ultrasound (US) examination evaluating for characteristic limb and cardiac manifestations is recommended (a normal US examination does not eliminate the possibility of HOS in the fetus).

Suggestive Findings

HOS should be suspected in individuals with the following limb anomalies, cardiac findings, and family history:

• Upper-limb anomaly involving the radial ray, and, variably, the carpal bone(s) and/or the thenar bones; most commonly bilateral/asymmetric but rarely unilateral or bilateral/symmetric
• Congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum
• Cardiac conduction disease
• Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Note: Congenital malformations involving the following structures or organ systems are not typically within the spectrum of HOS and should prompt the clinician to consider alternate diagnoses: ulnar ray only, kidney, craniofacies, auditory system (ear malformations with or without hearing loss), lower limb, anus, and eye.

Establishing the Diagnosis

Clinical Description

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformations, and cardiac conduction disease [Holt & Oram 1960].

Upper-limb malformations are most commonly bilateral/asymmetric but may also be unilateral or bilateral/symmetric. Upper-limb malformations can range from triphalangeal, hypoplastic, or absent thumb(s) to phocomelia, a malformation in which the hands are attached close to the body; intermediate presentations including digitalized thumb and syndactyly of the thumb and the index finger may also be observed. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, radioulnar synostosis, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, clavicle defects and sloping shoulders, and restriction of shoulder joint movement. However, bifid thumb has not been reported in any molecularly confirmed individuals with HOS.

While all individuals have an upper-limb defect, the broad range of severity of these findings is such that some individuals with the mildest upper-limb malformations and mild or no congenital heart malformation may escape diagnosis. These individuals may only be diagnosed when a more severely affected relative is born or when symptoms develop in middle age as a result of cardiac abnormalities such as pulmonary hypertension, high-grade atrioventricular (AV) block, and/or atrial fibrillation.

A congenital heart malformation is present in 90% of individuals with HOS and most commonly involves the septum. Atrial septal defect (ASD) and ventricular septal defect (VSD) can vary in number, size, and location. ASDs can present as a common atrium and are often associated with cardiac chamber isomerism; that is, the defining features of the cardiac chambers, based on their anatomic location, are altered (e.g., what may be considered right atrium based on its anatomic location may not have the atrial appendage morphology typical of the right atrium).

Some individuals with severe congenital heart malformation may require surgery early in life to repair significant septal defects [Sletten & Pierpont 1996, Møller Nielsen et al 2024].

Other individuals may have complex congenital heart malformations [Faria et al 2008, Baban et al 2014, Barisic et al 2014]; conotruncal malformations, though observed in HOS, are not common and may be caused by other genetic defects.

Cardiac conduction disease. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree AV block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

Other features. Additional features less commonly reported in individuals with TBX5-related HOS include chest wall abnormalities (thorax hypoplasia and pectus excavatum) and spine abnormalities (scoliosis and vertebral fusions) [Al-Qattan & Abou Al-Shaar 2015, Vanlerberghe et al 2019].

The natural history of HOS varies by individual and largely depends on the severity of the congenital heart malformation. Potential complications (which can be life-threatening if not recognized and appropriately managed) include congestive heart failure, pulmonary hypertension, arrhythmias, heart block, atrial fibrillation, infective endocarditis, and cardiomyopathy.

Genotype-Phenotype Correlations

Various genotype-phenotype correlations have been suggested: missense variants at the 5' end of the T-box are associated with more serious cardiac defects, whereas missense variants at the 3' end of the T-box are associated with more pronounced limb defects [Basson et al 1999]. However, these hypotheses have not been confirmed by more recent studies [Barnett & Postma 2014, Vanlerberghe et al 2019]. A tendency for more complex congenital heart disease in those with a missense pathogenic variant compared to individuals with a truncating variant has been reported [Baban et al 2014, Vanlerberghe et al 2019].

TBX5 gain-of-function variants have been associated with a specific phenotype with radial head dislocation/subluxation without thumb involvement, scapular dysplasia, and paroxysmal atrial fibrillation [Postma et al 2008, Vanlerberghe et al 2024].

In addition, genotypes do not appear to predict the progressive hemodynamic course associated with any particular cardiac septal defect.

Penetrance

Penetrance of HOS is most commonly complete, but rare families with reduced penetrance have been reported [Brassington et al 2003, Boogerd et al 2010, Vanlerberghe et al 2019].

Nomenclature

HOS has been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures.

Prevalence

HOS is the most common of the heart-hand syndromes. The estimated prevalence of HOS is between 0.7 and 1 in 100,000 births [Elek et al 1991, Barisic et al 2014].

Disorders of Known Genetic Cause of Interest in the Differential Diagnosis of HOS

Diagnoses summarized in Table 2 can be considered when anomalies involving the ulna, lower limbs, kidneys, genitourinary system, vertebrae, craniofaces, and auditory or ocular systems are present.

Note: SALL4 pathogenic variants may rarely cause what appears to be clinically typical Holt-Oram syndrome (HOS) (i.e., radial ray malformations & cardiac malformations); however, further clinical investigations frequently demonstrate features considered exclusionary of HOS (e.g., renal anomalies, Duane anomaly, sensorineural hearing loss). SALL4 pathogenic variants are more commonly associated with Duane-radial ray syndrome (Okihiro syndrome) and acro-renal-ocular syndrome. It is presumed that pathogenic variants in other genes included in Table 2 may also cause what appears to be clinically typical HOS, as many of the associated disorders have wide clinical variability.

Other Diagnoses to Consider in the Differential Diagnosis of HOS

Disorders of unknown genetic cause

• VACTERL (vertebral defects, anal atresia, cardiac malformation, tracheoesophageal fistula with esophageal atresia, renal anomalies, and limb anomalies). Radial hypoplasia/aplasia, radioulnar synostosis, thumb hypoplasia/aplasia, and triphalangeal thumb have been described in affected individuals. Costovertebral anomalies are frequent. Congenital heart defects, kidney malformations, anal atresia, tracheoesophageal fistula, or esophageal atresia may also be observed.
• OATS / Goldenhar syndrome. Associated features may include radial hypoplasia/aplasia, thumb hypoplasia/aplasia, and triphalangeal thumb or preaxial polydactyly. Vertebral anomalies may be associated. Hemifacial microsomia, microtia, preauricular tag/pits, and oral cleft are characteristic features.

Teratogen exposure

• Thalidomide. Exposure to thalidomide in pregnancy places the fetus at risk for severe upper- and lower-limb defects (e.g., phocomelia, amelia), cardiac defects, and malformations in other systems not observed in HOS (renal, ocular, auditory, gastrointestinal, and craniofacial) [Vianna et al 2013].
• Valproate. Exposure to valproate, particularly in the first trimester, places the fetus at risk for major congenital defects including congenital heart defects that can overlap those seen in HOS; however, the other malformations seen (e.g., polydactyly, spina bifida) are not features of HOS [McDermott et al 2005, Wyszynski et al 2005].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HOS, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The management of individuals with HOS optimally involves a multidisciplinary team approach with specialists in medical genetics, cardiology, and orthopedics, including a specialist in hand surgery (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Certain medications may be contraindicated in individuals with arrhythmias, cardiomyopathy, and/or pulmonary hypertension. People with such disorders require individual assessment by a cardiologist.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from appropriate cardiac management. Evaluations can include:

• Molecular genetic testing if the TBX5 pathogenic variant in the family is known;
• Echocardiography, EKG, and hand radiographs (anteroposterior view) if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with HOS who have a known history of a structural cardiac defect or cardiac conduction abnormality should be followed by a multidisciplinary team (including a cardiologist) during pregnancy. Affected women who have not undergone cardiac evaluation should do so prior to pregnancy if possible, or as soon as the pregnancy is recognized.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Holt-Oram syndrome (HOS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with HOS have an affected parent [Barisic et al 2014].
• Up to 60% of individuals with HOS represent simplex cases (i.e., the only family member known to be affected) [Vanlerberghe et al 2019].
• Evaluation of the parents of a proband who appears to be the only affected family member (i.e., a simplex case) is recommended in order to determine the clinical status of the parents and inform recurrence risk assessment. Evaluations include:
  • Echocardiography, EKG, and hand radiographs (anteroposterior view);
  • Molecular genetic testing if a TBX5 pathogenic variant has been identified in the proband. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of cardiac symptoms, or late onset of cardiac symptoms in an affected parent. Therefore, de novo occurrence of a TBX5 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous the TBX5 pathogenic variant.
• If a molecular diagnosis has been established in the proband, the TBX5 pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [Vanlerberghe et al 2019].* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a TBX5 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the TBX5 pathogenic variant identified in the proband, the risk to the sibs is 50%. Significant intrafamilial variability in limb and heart defect severity is observed among affected family members.
• If the parents are clinically unaffected and the proband has a known TBX5 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to the sibs of a proband appears to be low but slightly greater than the general population risk of approximately 1/100,000 because of the possibility of parental gonadal mosaicism.
• If the parents are clinically unaffected (based on appropriate clinical evaluation) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Offspring of a proband are at 50% risk for HOS.
• Because of the significant variability in limb and heart defect severity observed in individuals with HOS, both among and within families with the same TBX5 pathogenic variant, the phenotype of affected offspring cannot be accurately predicted.

Other family members. The risk to other family members depends on the status of the proband's parents; if a parent is affected/has the pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic testing for at-risk asymptomatic adult family members requires prior identification of the TBX5 pathogenic variant in the family.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If the TBX5 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. If the TBX5 pathogenic variant is identified in a fetus, molecular genetic testing should be followed by detailed ultrasound (US) evaluation. Because of the significant variable expressivity observed in individuals with HOS both among and within families with the same pathogenic variant, the severity of upper-limb defects and congenital heart malformations cannot be accurately predicted by molecular genetic testing alone.

If the pathogenic variant in the family is not known, US examination evaluating for characteristic limb and cardiac manifestations (including fetal echocardiogram) is recommended. Note: A normal US examination does not eliminate the possibility of HOS in the fetus.

For pregnancies not known to be at increased risk for HOS. If a routine US examination has identified limb and cardiac manifestations characteristic of HOS, HOS and the disorders discussed in the differential diagnosis should be considered (see Differential Diagnosis).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

T-box transcription factor TBX5 functions as a transcription factor that has an important role in both cardiogenesis and limb development. TBX5 can interact with other transcription factors including NKX2.5 and GATA4, and these interactions may participate in regulating cardiogenesis. In limb buds, TBX5 is specifically expressed in upper limbs, and activates FGF10 expression at an early stage of development for upper-limb bud induction, and at later stages for muscle and tendon patterning. Accurate TBX5 expression regulation is crucial for limb and cardiac development.

It is hypothesized that most nonsense, frameshift, and splice site pathogenic variants lead to mutated TBX5 mRNAs that are degraded, resulting in haploinsufficiency. Some missense pathogenic variants result in transcripts that have diminished DNA-binding activity. Both result in reduced functional TBX5, which leads to disease [Hatcher & Basson 2001]. By contrast, studies reporting pathogenic variants predicting either an elongated TBX5 or an intragenic TBX5 duplication suggest the possibility of a dominant-negative effect on downstream targets [Böhm et al 2008, Patel et al 2012]. Researchers who recently elucidated the crystal structure of the TBX5 T-box domain in its DNA-unbound and DNA-bound forms have identified an inducible C-terminal element within the T-box domain that may be required for the interaction of TBX5 with DNA [Stirnimann et al 2010].

Mechanism of disease causation. Loss of function or dominant-negative interference with function

Note: TBX5 gain-of-function variants have been associated with a specific phenotype with radial dislocation/subluxation without thumb involvement, scapular dysplasia, and paroxysmal atrial fibrillation [Postma et al 2008, Vanlerberghe et al 2024].

Author Notes

Dr Vanlerberghe (rf.ellil-uhc@ehgrebrelnav.ecnemelc), Prof Petit (rf.ellil-uhc@titep.ecnerolf), and Dr Brunelle (rf.ellil-uhc@ellenurb.enirrep) are actively involved in clinical and molecular research regarding individuals with Holt-Oram syndrome (HOS). They would be happy to communicate with persons who have any questions regarding diagnosis of HOS or other considerations.

Dr Vanlerberghe is also interested in hearing from clinicians treating families affected by radial defects in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Brunelle to inquire about review of TBX5 variants of uncertain significance.

Acknowledgments

To Prof Florence Petit and Dr Perrine Brunelle, clinical and molecular geneticists, respectively, for their expertise and contribution to this work, and the research team RADEME at Lille University.

Author History

Craig T Basson, MD, PhD; Novartis Institutes for BioMedical Research (2004-2025)
Jamie C Fong, MS, CGC; University of California, San Francisco (2004-2025)
Deborah A McDermott, MS, CGC; Consultant, Human Genetics and Genetic Counseling (2004-2025)
Florence Petit, MD, PhD (2025-present)
Clémence Vanlerberghe, MD, PhD (2025-present)

Revision History

• 31 July 2025 (sw) Comprehensive update posted live
• 23 May 2019 (sw) Comprehensive update posted live
• 8 October 2015 (me) Comprehensive update posted live
• 4 April 2013 (me) Comprehensive update posted live
• 4 January 2011 (me) Comprehensive update posted live
• 21 September 2006 (me) Comprehensive update posted live
• 20 July 2004 (me) Review posted live
• 23 December 2003 (cb) Original submission

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