Holt-Oram Syndrome
Summary
Clinical characteristics.
Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% 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. 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 diagnosis of HOS is established in a proband with 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 for arrhythmias may require medication, surgery, and/or pacemaker implantation. Pharmacologic treatment for individuals with pulmonary hypertension. Cardiac surgery for congenital heart defects is standard; affected individuals and families are also likely to benefit from programs providing social support to those with limb anomalies.
Prevention of secondary complications: A cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis.
Surveillance: Annual ECG for all affected individuals, annual Holter monitor for individuals with known conduction disease, and echocardiogram every one to five years for those with septal defects or as directed by a cardiologist.
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. Approximately 85% of affected individuals have HOS as the result of a de novo pathogenic variant. Offspring of an affected individual are at a 50% risk of being affected. In pregnancies at 50% risk, detailed high-resolution prenatal ultrasound examination may detect upper-limb malformations and/or congenital heart malformations. Prenatal molecular genetic testing may be used to confirm a diagnosis if the TBX5 pathogenic variant has been identified in an affected relative.
Diagnosis
Clinical diagnostic criteria for Holt-Oram syndrome have been established and validated through molecular genetic testing [McDermott et al 2005].
Suggestive Findings
Holt-Oram syndrome (HOS) should be suspected in individuals with the following limb anomalies, cardiac findings, and family history:
- Upper-limb malformation involving the carpal bone(s) and, variably, the radial and/or thenar bones
- Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric.
- An abnormal carpal bone, present in all affected individuals and identified by performing a posterior-anterior hand x-ray [Poznanski et al 1970, Basson et al 1994], may be the only evidence of disease.
- 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 of a first-degree relative with a congenital heart defect or cardiac conduction disease
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, vertebra, craniofacies, auditory system (ear malformations ± hearing loss), lower limb, anus, and eye.
Establishing the Diagnosis
The diagnosis of Holt-Oram syndrome is established in a proband with either a preaxial radial ray anomaly and a personal or family history of cardiac septation and/or conduction defects or, if clinical findings are insufficient, a heterozygous pathogenic variant in TBX5 identified by molecular genetic testing (see Table 1).
Molecular testing approaches can include single-gene testing and – if the phenotype includes features that are atypical for Holt-Oram syndrome – a multigene panel. Though rare, chromosome rearrangements involving 12q24 have been reported in individuals with Holt-Oram syndrome [Li et al 1997, Basson et al 1999].
- Single-gene testing. Sequence analysis of TBX5 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes TBX5 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in Holt-Oram Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TBX5 | Sequence analysis 3 | >70%4 |
| Gene-targeted deletion/duplication analysis 5 | <1% 6 | |
| Unknown 7 | NA |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Individuals meeting the strict diagnostic criteria of upper-limb defect and personal and/or family history of structural or conductive heart disease have a heterozygous TBX5 pathogenic variant predicted to cause disease [McDermott et al 2005, Debeer et al 2007]. Lower pathogenic variant detection rates (30%-40%) reported in some studies likely result from the inclusion of individuals who would not meet the strict diagnostic criteria outlined above [Cross et al 2000, Brassington et al 2003].
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Deletion of one or more exons or the entire gene was detected in about 2% of individuals with HOS who did not have a pathogenic variant identified by sequence analysis/variant scanning [Borozdin et al 2006].
- 7.
That current molecular analysis fails to identify a heterozygous pathogenic variant in TBX5 in up to 30% of individuals with HOS suggests the presence of pathogenic variants in noncoding regions or regulatory regions around TBX5 [McDermott et al 2005, Debeer et al 2007].
Clinical Characteristics
Clinical Description
Holt-Oram syndrome is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease [Holt & Oram 1960].
Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia, a malformation in which the hands are attached close to the body; intermediate presentations resulting from abnormal development of the bones involved may also be observed. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, and sloping shoulders and restriction of shoulder joint movement.
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 block, and/or atrial fibrillation. Cardiac conduction disease can be progressive.
A congenital heart malformation is present in 75% 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].
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 atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.
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, and infective endocarditis.
Genotype-Phenotype Correlations
It has been reported that pathogenic missense variants at the 5' end of the T-box (which binds the major groove of the target DNA sequence) are associated with more serious cardiac defects.
Pathogenic missense variants at the 3' end of the T-box (which binds the minor groove of the target DNA) result in more pronounced limb defects. Caution is warranted, however, in applying these population-based associations to individuals in whom pathogenic variants may not predict specific phenotypes [Basson et al 1999, Brassington et al 2003].
In addition, genotypes do not appear to predict the progressive hemodynamic course associated with any particular cardiac septal defect.
Penetrance
The upper-limb malformations in HOS are fully penetrant.
Congenital heart malformations occur in approximately 75% of affected individuals [Basson et al 1999]. Conduction defects may occur in the presence or absence of structural heart defects.
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 per 100,000 births [Elek et al 1991, Barisic et al 2014].
HOS has been reported from a number of countries worldwide and in individuals of different racial and ethnic backgrounds [Boehme & Shotar 1989, Yang et al 2000, Barisic et al 2014, Kimura et al 2015].
Differential Diagnosis
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 [Newbury-Ecob et al 1996, Allanson & Newbury-Ecob 2003, Bressan et al 2003].
Table 2.
Disorders to Consider in the Differential Diagnosis of Holt-Oram Syndrome (HOS)
| Disorder/Condition | Gene(s) / Genetic Mechanism | MOI | Clinical Description | Comments |
|---|---|---|---|---|
| Duane-radial ray syndrome | SALL4 | AD |
|
|
| Acro-renal-ocular syndrome | AD |
| ||
| Ulnar-mammary syndrome (OMIM 181450) | TBX3 | AD |
| |
| Townes-Brocks syndrome | SALL1 | AD |
| |
| Heart-hand syndrome II (Tabatznik syndrome) 1 | Not identified | AD |
| |
| Heart-hand syndrome III (Spanish type) (OMIM 140450) | Not identified | AD |
| |
| Long thumb brachydactyly syndrome (OMIM 112430) | Not identified | AD |
| |
| Heart-hand syndrome, Slovenian type (OMIM 610140) | LMNA | AD |
| |
| Fanconi anemia | >20 genes 2 | AR AD XL |
| |
| Thrombocytopenia-absent radius syndrome (TAR) | RBM8A 3 | AR |
| Other findings in TAR, (esp hematologic & neurologic) & frequent involvement of lower limbs differentiate TAR from HOS. |
| 22q11.2 deletion syndrome (del22q11.2) | Deletion of 22q11.2 DGCR | AD |
| Other features in del22q11.2 incl palatal abnormalities (69%), learning difficulties (70%-90), & immune deficiency (77%), distinguish del22q11.2 from HOS. |
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DGCR = DiGeorge chromosome region; ESRD = end-stage renal disease; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Silengo et al [1990]
- 2.
Genes known to be associated with Fanconi anemia: BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC2
- 3.
The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis.
Other Diagnoses to Consider in the Differential Diagnosis of HOS
Disorders of unknown cause
- VACTERL (vertebral defects, anal atresia, cardiac malformation, tracheo-esophageal fistula with esophageal atresia, renal anomalies, and limb anomalies)
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) [Matthews & McCoy 2003, McDermott et al 2005, 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].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Holt-Oram syndrome (HOS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Holt-Oram Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Musculoskeletal | Physical examination for limb involvement | Hand & upper-limb radiographs may be recommended by orthopedist to aid in management of radial ray malformations. |
| Cardiac | Chest radiography | To identify enlarged pulmonary arteries caused by pulmonary hypertension or cardiomegaly &/or evidence of congestive heart failure |
| Echocardiography | To identify septal defects or other structural cardiac anomalies | |
| ECG | To identify cardiac conduction disease | |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
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.
A cardiologist can assist in determining the need for antiarrhythmic medications and surgery. Individuals with severe heart block may require pacemaker implantation. Pharmacologic treatment for affected individuals with pulmonary hypertension may be appropriate. Individuals with pulmonary hypertension and/or structural heart malformation may require tertiary care center cardiology follow up. Cardiac surgery, if required for congenital heart defect, is standard.
The orthopedic team may be able to guide individuals in decisions regarding surgery for improved upper-limb and hand function as well as physical and occupational therapy options. Those individuals born with severe upper-limb malformations may be candidates for surgery to improve function, such as pollicization (creation of a thumb-like digit by moving another digit into the thenar position) in individuals with thumb aplasia/hypoplasia [Vaienti et al 2009]. Children with severe limb shortening may benefit from prostheses as well as from physical and occupational therapy.
Individuals and families are also likely to benefit from programs providing social support to those with limb anomalies.
Prevention of Secondary Complications
A cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis (SBE).
Surveillance
Table 4.
Recommended Surveillance for Individuals with Holt-Oram Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Cardiac | ECG | Annually in individuals at risk of developing a conduction defect |
| ECG combined w/Holter monitor | Annually in individuals w/known conduction disease to assess progression | |
| Echocardiogram | Every 1-5 yrs – may be recommended by the managing cardiologist depending on nature & significance of potential septal defects. |
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, ECG, and hand x-rays (anterior/posterior 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.