Introduction:
Holt-Oram syndrome is a genetic disorder that primarily causes skeletal abnormalities of the upper limbs along with heart problems such as septal defect and conduction disorder. Individuals affected by Holt-Oram syndrome develop at least one abnormality in the upper extremity, especially in the wrist bone and these abnormalities can be detected on a X-ray. Individuals may also have other features such as a missing thumb, or a long finger-like-looking thumb. The life expectancy of these individuals is normal but depends on the severity of heart diseases.
What Is Holt-Oram Syndrome?
Holt-Oram syndrome is a rare genetic disorder that causes heart problems and skeletal problems in the hands which occurs due to a mutation in the gene that provides information in the production of a protein called T-box 5 that has an important role in the development of upper limbs and heart before birth.
What Are the Other Names for Holt-Oram Syndrome?
The other names for Holt-Oram syndrome are:
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Cardiac-limb syndrome.
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Heart-hand syndrome, type 1.
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Atriodigital dysplasia.
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Atrio-digital syndrome.
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Ventriculo-radial syndrome.
What Are the Clinical Features of Holt-Oram Syndrome?
The clinical features of Holt-Oram syndrome include skeletal abnormalities that can affect one or both of the arms. If defects are present in both arms, they can be similar or different. In the case of different defects in both arms, the left side is usually more affected compared to the right side. The skeletal features of Holt-Oram syndrome include:
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Defect in the wrist bone.
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Long finger-like-looking thumb.
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Missing thumb.
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Complete or partial absence of bones in the forearm.
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Underdeveloped bones in the upper arm.
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Defect in the collarbone.
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Fusion of the hand bones.
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Sloping shoulders.
About 75 percent of individuals are affected by cardiovascular problems, which can be severe. Congenital heart malformations include:
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Atrial septal defect (presence of a hole in the upper wall or septum that separates the upper chamber of the heart) and ventricular septal defect (presence of a hole in the lower wall or septum that separates the lower chambers of the heart) is the most common abnormality.
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Cardiac conduction disorder in which there is a defect in the electrical system that controls heart rate. This can lead to bradycardia (slow heart rate) or fibrillation (irregular or abnormally rapid heart rate).
What Is the Cause of Holt-Oram Syndrome?
Holt-Oram syndrome occurs due to a mutation in the TBX5 (T-box transcription factor 5) gene. The Holt-Oram syndrome is inherited in an autosomal dominant pattern, in which one copy of the mutated gene in one parent is enough to cause this disorder. The features of this gene include:
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The TBX5 gene is located in the chromosome 12.
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This gene provides information in the production of a protein called T-box 5 which is important during the embryonic development of organs and tissues.
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The T-box 5 protein is also called a transcription factor because it regulates the activities of genes by binding to the specific sites in DNA (deoxyribonucleic acid).
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Therefore T-box 5 protein helps in the development and growth of the heart and upper limb by activating genes that are involved in it.
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The T-box 5 protein is especially important in the development of the septum or wall that separates the left and right sides of the heart and therefore divides the heart into four chambers.
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The T-box 5 protein is also important in the electric conduction of the heart that maintains the heart contractions.
Mutation in the T-box 5 gene causes disruption in the development of upper limbs and heart, therefore causing features of Holt-Oram syndrome.
What Is the Diagnosis of Holt-Oram Syndrome?
The diagnosis of Holt-Oram syndrome includes:
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Prenatal ultrasound which is done during pregnancy can reveal defects in the upper limb and the heart malformations. Prenatal molecular genetic testing can help in confirming the condition by diagnosing a mutation in the TBX5 gene.
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Radial ray anomalies in which there is a large number of defects in the upper limb including partial or complete absence of radius and ulna bones. X-rays, MRI (magnetic resonance imaging), or CT (computed tomography) scans can reveal these defects.
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History of a defect in the walls of the heart chamber along with conduction defects.
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Molecular genetic testing reveals a mutation in the TBX5 gene. Molecular genetic testing can be single-gene testing or by a multigene panel.
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Single-gene testing is done to identify changes in one gene such as small deletions, insertions, or duplications.
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Multigene panel testing is done to identify changes in several genes
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What Is the Differential Diagnosis of Holt-Oram Syndrome?
The differential diagnosis of Holt-Oram syndrome includes:
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Duane-Radial Ray Syndrome: A genetic condition that occurs due to a mutation in the SALL4 (spalt-like transcription factor 4) gene. The clinical features include radial ray malformation.
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Acro-Renal-Ocular Syndrome: A rare disorder that is characterized by radial ray malformation, renal abnormalities, and ophthalmic abnormalities.
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Ulnar-Mammary Syndrome: A genetic disorder that is characterized by defects in the bones of the forearm along with underdevelopment of breasts and nipples.
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Townes-Brocks Syndrome: A genetic condition that is characterized by foot malformations, heart abnormalities, imperforated anus, and renal impairment.
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Fanconi Anemia: A genetic disorder that is characterized by abnormalities in the thumb, forearm, eyes, ears, heart, nervous system, genitourinary system, and gastrointestinal system. It is caused by bone marrow failure.
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Teratogen Exposure: Exposure to Thalidomide and Valproate during pregnancy can result in limb and cardiovascular defects to the fetus.
What Is the Treatment for Holt-Oram Syndrome?
The treatment of Holt-Oram syndrome includes managing the manifestations and involves a multidisciplinary team of a cardiologist to treat the heart defects, an orthopedic surgeon to treat bone anomalies, and a medical geneticist to treat the genetic condition and to counsel the individuals and family about the risks of this condition. Management includes:
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Use of medications, surgical treatment, or pacemaker implantation to treat irregular heart rates.
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Surgical treatment for congenital heart defects such as atrial or ventricular septal defect.
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Occupational and physical therapy to improve the movements of limbs.
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Pharmacological treatment for pulmonary hypertension.
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Involvement of affected individuals and families in social programs that support people with limb anomalies.
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Use of antibiotic prophylaxis and anticoagulants to prevent secondary complications such as bacterial endocarditis (a bacterial infection that affects the innermost layer of the heart and the heart valves).
Conclusion:
Individuals with Holt-Oram syndrome should receive genetic counseling as it is inherited in an autosomal dominant pattern and there is a 50 percent of chance that the condition can be passed down to a child. The prognosis of individuals with Holt-Oram syndrome depends on the severity of heart defects.
