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 EKG 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.