From the Guidelines
Holt-Oram syndrome is a genetic disorder characterized by upper limb abnormalities and congenital heart defects, caused by mutations in the TBX5 gene, as noted in the 2019 American College of Cardiology/American Heart Association guideline for the management of adults with congenital heart disease 1.
Clinical Features and Genetic Abnormality
The syndrome is associated with upper limb skeletal abnormalities and a high incidence of congenital heart disease (CHD), affecting approximately 75% of individuals with the condition 1. The genetic abnormality responsible for Holt-Oram syndrome is a mutation in the TBX5 gene.
Common Cardiac Findings
Common cardiac findings in individuals with Holt-Oram syndrome include:
- Atrial septal defects (ASD)
- Ventricular septal defects (VSD)
- Mitral valve (MV) disease
These cardiac defects can significantly impact the quality of life and morbidity of affected individuals, emphasizing the need for early diagnosis and management.
Management and Treatment
Management of Holt-Oram syndrome requires a multidisciplinary approach, involving cardiologists, orthopedic surgeons, geneticists, and other specialists. Treatment focuses on addressing specific cardiac and skeletal issues through:
- Surgical correction of heart defects
- Orthopedic interventions to improve limb function
- Cardiac medications as needed
Regular cardiac monitoring is essential throughout life, even in mildly affected individuals, to prevent complications and improve outcomes. Genetic counseling is also recommended for affected individuals and their families to understand inheritance risks for future pregnancies.
From the Research
Definition and Characteristics of Holt-Oram Syndrome
Holt-Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations 2, 3, 4. The syndrome is characterized by upper limb deformities and cardiac malformations, with atrial septal defects being a common cardiac anomaly 3, 5.
Skeletal Malformations
Skeletal malformations associated with Holt-Oram syndrome can vary in severity and include:
- Triphalangia of the thumb
- Prono-supination defects of the forearms
- Dorsolumbar scoliosis
- Shortened forearms
- Phocomelia
- Absent thumbs 2, 4, 6
Cardiac Malformations
Cardiac malformations associated with Holt-Oram syndrome can also vary and include:
- Atrial septal defects
- Ventricular septal defects
- Ostium primum ASD
- Tetralogy of Fallot
- Dilated cardiomyopathy
- Conduction system disease
- Rhythm abnormalities 3, 4, 5
Inheritance and Diagnosis
Holt-Oram syndrome is an autosomal dominant condition, meaning that a single copy of the mutated gene is enough to cause the condition 2, 3, 4. Diagnosis is typically confirmed by genetic studies, and family screening is necessary after diagnosis due to the risk of autosomal dominant inheritance 2.