Holt-Oram syndrome
Holt-Oram syndrome is a genetic condition characterized by malformations of the upper limbs and the heart, occurring in approximately 1 in 100,000 individuals. It is primarily caused by mutations in the TBX5 gene, which plays a crucial role in heart and limb development during embryogenesis. The syndrome can be inherited in an autosomal dominant pattern, with a 50 percent chance of passing the mutation to offspring, although most cases arise from spontaneous mutations.
Individuals with Holt-Oram syndrome may present with a range of upper-limb deformities, including abnormalities of the carpal bones, as well as various heart defects, with about 75 percent of affected individuals experiencing heart-related anomalies such as atrial and ventricular septal defects. Diagnosis typically relies on clinical evaluation, including imaging studies of the hands and heart, and prenatal screening may be conducted for at-risk pregnancies. Treatment options vary based on the severity of symptoms, focusing on managing heart defects and addressing limb abnormalities through surgery, therapy, or prosthetics. Genetic counseling is recommended for families affected by the syndrome, highlighting the importance of understanding screening and reproductive options. Overall, individuals with Holt-Oram syndrome can lead fulfilling lives, though their life expectancy may be influenced by the severity of cardiac issues.
Holt-Oram syndrome
ALSO KNOWN AS: HOS1; heart-hand syndrome; atriodigital dysplasia
DEFINITION Holt-Oram syndrome is a genetic condition that results in upper-extremity and cardiac malformations. Approximately 1 in 100,000 individuals are thought to have Holt-Oram syndrome. The condition is caused by mutations in the TBX5 gene.
Risk Factors
A family history of Holt-Oram syndrome increases the risk of being affected or having an affected child. However, most cases of Holt-Oram syndrome are due to de novo (spontaneous) TBX5 gene mutations.
Etiology and Genetics
Mutations in the TBX5 gene cause Holt-Oram syndrome. TBX5 is located at 12q24.1 and codes for the protein T-box transcription factor TBX5, or T-box 5 for short, which is thought to be required for appropriate cardiac septation and forelimb development in early embryogenesis. A reduced gene dosage, either through or reduced DNA binding, is thought to result in clinical manifestations. In individuals who meet the clinical criteria for Holt-Oram syndrome, approximately 70 percent will have a mutation identified in their TBX5 gene. Mutations in this gene have also been found in individuals with isolated cardiac malformations without any limb abnormalities.
Holt-Oram is inherited in an autosomal dominant pattern. Each child of an affected individual has a 50 percent chance of inheriting the disease-causing mutation. In a cases of an apparent de novo mutation, the siblings of an affected child are likely not at an increased risk. However, cases of germline are theoretically possible and would significantly increase the recurrence risk.
Symptoms
The main clinical symptoms of Holt-Oram syndrome are upper-limb malformations and cardiac malformations. An abnormal carpal bone is present in all affected individuals, though this may only be identified by a posterior-anterior hand X-ray. Other upper-limb abnormalities may also be present and are variably expressed both between and within families. Clinical variability can range from triphalangeal thumb to phocomelia. Upper-limb anomalies may be unilateral or bilateral and can be seen both symmetrically and asymmetrically.
Cardiac anomalies are also variably expressed and show reduced penetrance. Approximately 75 percent of individuals with Holt-Oram syndrome have a heart malformation, most commonly ostium secundum atrial septal defects and ventricular septal defects, though complex congenital heart malformations such as tetralogy of Fallot, hypoplastic left heart, endocardial cushion defects, and truncus arteriosus have also been reported. Cardiac conduction disease such as heart block can also occur and can also be progressive.
Screening and Diagnosis
Diagnosis of Holt-Oram syndrome is generally made based on clinical observations. Individuals who are on the mild end of the clinical spectrum may not realize that they are affected until another, more severely affected family member is diagnosed. Upper-limb and hand X-rays may be useful in detecting limb abnormalities. Cardiac evaluation includes an echocardiogram for structural defects, an electrocardiogram (ECG or EKG) for cardiac conduction abnormalities, and a chest radiograph to identify pulmonary hypertension.
For pregnancies at risk for Holt-Oram syndrome, fetal ultrasound can screen for limb and cardiac abnormalities. The sensitivity and specificity of ultrasound screening is unknown, so Holt-Oram syndrome should be considered as a differential diagnosis for any low-risk pregnancies where cardiac and upper-limb malformations are detected by fetal ultrasound. In families where molecular testing of the TBX5 gene has identified a causative mutation, through a chorionic villus sampling in the first trimester or an amniocentesis in the second trimester is available. Because of the wide range of clinical features found in Holt-Oram syndrome, the clinical severity of an affected fetus cannot be predicted prenatally. Preimplantation genetic diagnosis may also be available at select centers.
Treatment and Therapy
Treatment of Holt-Oram syndrome depends on the degree of clinical severity. A cardiologist can assess any structural heart anomalies and provide regular screening for conduction defects. If any cardiac anomalies are identified, then appropriate treatment can be implemented. This may include surgery for a structural heart defect or medication for congestive heart failure. An orthopedic team can assess individuals with severe upper-limb abnormalities to determine if surgery, prostheses, or physical and occupational therapy is indicated. Social and psychological support may also be necessary, especially in individuals with severe limb defects.
Prevention and Outcomes
There is no known prevention for Holt-Oram syndrome. Genetic counseling should be offered for at-risk pregnancies to discuss screening, diagnosis, and reproductive options.
Individuals with Holt-Oram syndrome are not at an increased risk for intellectual disabilities or other birth defects. The life expectancy for individuals with Holt-Oram syndrome depends on the presence and severity of structural or functional cardiac abnormalities.
Bibliography
Chryssostomidis, Gregory, et al. "Diversity of Congenital Cardiac Defects and Skeletal Deformities Associated with the Holt-Oram Syndrome." International Journal of Surgery Case Reports 5.7 (2014): 389–92. Print.
Jones, Kenneth Lyons, Marilyn Crandall Jones, and Miguel Del Campo Casanelles. Smith’s Recognizable Patterns of Human Malformation. 7th ed. Philadelphia: Saunders, 2013. Print.
Kelly, Evelyn B. Encyclopedia of Human Genetics and Disease. Santa Barbara: Greenwood, 2013. Print.
Krauser, Ashley F. Holt-Oram Syndrome, StatPearls, 14 Aug. 2023.
McDermott, Deborah A., Jamie C. Fong, and Craig T. Basson. "Holt-Oram Syndrome." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 4 Apr. 2013. Web. 25 July 2014. Reddy, Rasagnya M. et al. "A Rare Variant and Unusual presentation of Holt Oram Syndrome in a Child." Cureus, Nov. 2022, www.ncbi.nlm.nih.gov/pmc/articles/PMC9719589/. Accessed 9 Sept. 2024.
Rimoin, David L., Reed E. Pyeritz, and Bruce R. Korf. Emery and Rimoin’s Principles and Practice of Medical Genetics. 6th ed. Waltham: Academic, 2013. Digital file.
Turnpenny, Peter, and Sian Ellard. Emery’s Elements of Medical Genetics. 14th ed. Philadelphia: Churchill, 2012. Print.