Holt-Oram Syndrome

Excerpt

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).