Clinical Guidance

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 . However, these hypotheses have not been confirmed by more recent studies . 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 . 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 .

Source: GeneReviews — "Holt-Oram Syndrome"

Penetrance

Penetrance of HOS is most commonly complete, but rare families with reduced penetrance have been reported .

Source: GeneReviews — "Holt-Oram Syndrome"

Diagnostic Criteria

Clinical diagnostic criteria for Holt-Oram syndrome (HOS) have been established and validated through molecular genetic testing .

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

Source: GeneReviews — "Holt-Oram Syndrome"

Differential Diagnosis

Disorders of Known Genetic Cause of Interest in the Differential Diagnosis of HOS Diagnoses summarized in 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 may also cause what appears to be clinically typical HOS, as many of the associated disorders have wide clinical variability. Table 2. Disorders of Known Genetic Cause of Interest in the Differential Diagnosis of Holt-Oram Syndrome

Management Guidelines

No clinical practice guidelines for Holt-Oram syndrome (HOS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

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

Table 3.

Holt-Oram Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Musculoskeletal

| Physical exam for limb involvement | Hand upper-limb radiographs may be recommended by orthopedist to aid in mgmt 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

EKG | To identify cardiac conduction disease

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of HOS to facilitate medical personal decision making

HOS = Holt-Oram syndrome; MOI = mode of inheritance

1. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

The management of individuals with HOS op...

Source: GeneReviews — "Holt-Oram Syndrome"

Clinical Guidance

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

Source: GeneReviews — "Holt-Oram Syndrome"

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.

Source: GeneReviews — "Holt-Oram Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 5. Recommended Surveillance for Individuals with Holt-Oram Syndrome

Source: GeneReviews — "Holt-Oram Syndrome"