Thrombocytopenia-absent radius (TAR) syndrome

Thrombocytopenia-absent radius (TAR) syndrome

Overview

Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder characterized by the congenital absence of the radius bone in both forearms (with thumbs present) and low platelet count (thrombocytopenia), causing bleeding risks. It is an autosomal recessive condition, often involving mutations in the RBM8A gene. While the first year of life presents the highest risk for severe hemorrhage, prognosis improves as platelet counts often normalize over time. 

Symptoms

Hematologic (Blood): Thrombocytopenia, causing low platelet counts, usually appears at birth or within the first few weeks/months of life. It causes petechiae (tiny purple spots), bruising, and potential hemorrhage. This often improves after the first year.

Skeletal (Limbs): Bilateral absence of the radius (the forearm bone on the thumb side) is a defining feature, resulting in short, malformed forearms. Unlike similar conditions, thumbs are present.

Associated Skeletal Anomalies: Other bones may be affected, including the ulna (shortened/absent), humerus, or shoulder joints. Lower limb abnormalities (e.g., knee dislocation, hip abnormalities) can affect mobility.

Dietary: Roughly 50% of affected individuals have a cow's milk allergy, which can trigger further decreases in platelet levels.

Other Symptoms: Potential heart defects (e.g., Atrial Septal Defect), kidney abnormalities, or facial features like a small jaw (micrognathia). 

Causes 

Genetic Mutation (RBM8A): The primary cause is a combination of a rare, noncoding variant (hypomorphic allele) in one copy of the RBM8A gene and a deletion of the same gene on the other copy (chromosome 1q21.1).

Inheritance: The syndrome is inherited in an autosomal recessive manner. Often, one parent carries the deletion and the other carries the mutation, although the deletion can occur spontaneously.

Protein Reduction: The genetic changes reduce the amount of RNA-binding motif protein 8A (RBM8A), which is essential for normal development and cell function. 

Low Platelets (Thrombocytopenia): Often present at birth or within the first few months, leading to severe bleeding risks (e.g., bruising, petechiae, intracranial hemorrhage).

Radial Aplasia: Bilateral absence of the radius bone is a defining skeletal feature, usually with thumbs present.

Cow’s Milk Allergy: Approximately 47% of cases involve a cow's milk allergy, which can trigger or worsen the low platelet count.

Other Potential Causes: While RBM8A is the main culprit, researchers suggest potential genetic heterogeneity, meaning other, undiscovered gene variations may contribute in some cases. 

Complications

Hematologic (Blood/Platelet issues):

Thrombocytopenia: Severe low platelet count (hypomegakaryocytic) leading to easy bruising, petechiae, and frequent nosebleeds.

Hemorrhage: The leading cause of death in infants, often occurring within the first 14 months, including intracranial hemorrhage.

Transient Nature: Thrombocytopenia typically improves after the first year of life, with platelet counts often returning to normal, though it may persist, notes Pathology Outlines.

Skeletal Anomalies:

Upper Limbs: Bilateral absence of the radius (radial aplasia) is universal, with the ulna and humerus often underdeveloped.

Hands: While thumbs are present (a key differentiator), other hand anomalies like syndactyly (fused fingers) may occur.

Lower Limbs: Partial absence of lower limbs (e.g., fibula aplasia), hip dislocations, and clubfoot.

Cardiovascular (Heart) Defects (Approx. 30% of cases):

Atrial Septal Defect (ASD) and Ventricular Septal Defect (VSD).

Tetralogy of Fallot.

Gastrointestinal and Nutritional:

Cow's Milk Allergy (CMPA): Occurs in over 60% of cases and can trigger severe thrombocytopenia episodes.

Failure to Thrive: Poor weight gain, chronic vomiting, or diarrhea.

Other Complications:

Genitourinary: Renal malformations or hydronephrosis.

Craniofacial: Micrognathia (small jaw) or cleft palate.

Dental: Increased risk of enamel hypoplasia and trauma. 

Risk Factors

Genetic Mechanism: It is not a simple autosomal recessive trait. It requires the inheritance of a 1q21.1 microdeletion (often inherited from an unaffected parent or de novo) on one chromosome and a hypomorphic (low-functioning) allele of the 

 gene on the other chromosome.

Recurrence Risk:

If a parent is a carrier of the null allele (deletion) and the other is a carrier of  the hypomorphic allele, there is a 25% risk for each child.

If one parent has the null allele and the other is homozygous for the hypomorphic allele, the risk for each child is 50%.

Parent-to-Child Transmission: While usually inheriting from carriers, apparent transmission from an affected parent to a child has been observed due to the common nature of the mutation in the population. 

Diagnosis

Clinical Presentation:

Bilateral Radial Aplasia: The most defining skeletal feature, where both radius bones are missing, but the thumbs are present.

Thrombocytopenia: Low platelet counts are often severe in the first few weeks of life, with counts typically improving after the first year.

Associated Anomalies: Potential for heart defects, cow's milk allergy, or kidney abnormalities.

Imaging & Lab Tests:

Radiography (X-rays): Confirm the bilateral absence of the radius, often with shortened or malformed ulna.

Blood Tests: Complete Blood Count (CBC) to document severe thrombocytopenia, typically in the first 4 months of life.

Bone Marrow Aspiration: Often shows a reduction in the number and size of megakaryocytes.

Genetic Testing:

Molecular analysis identifies a 500-kb or 200-kb microdeletion in the 1q21.1 region (including the RBM8A gene) in combination with a low-expression (hypomorphic) allele, which confirms the diagnosis.

Treatment

Platelet Transfusions: Primarily needed during the first 1–2 years of life when thrombocytopenia is most severe. Transfusions are typically given when platelet counts are very low or bleeding occurs.

Preventive Measures: Avoid cow's milk, as it frequently causes gastrointestinal issues that worsen thrombocytopenia.

Medications: Platelet-stimulating agents (e.g., romiplostim) have shown potential, while steroids or intravenous immunoglobulin (IVIG) may be used in specific cases.

Long-term Outlook: Platelet counts often stabilize and reach normal levels by age two or as the child gets older. 

Orthopedic and Structural Treatment 

Limb Support: Splinting or casting during infancy can improve hand and arm function.

Surgery: Orthopedic interventions, including bone grafting or tendon transfers, can be performed to improve hand and arm function.

Adaptive Devices: Prosthetics or assistive devices for daily living (eating, dressing). 

Type of Doctor Department : A pediatric hematologist