Thrombocytopenia Absent Radius Syndrome

Clinical characteristics: Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.

Diagnosis/testing: The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis.

Management: Treatment of manifestations: Orthopedic intervention as needed to maximize limb function. Platelet transfusion for thrombocytopenia as needed; to reduce the risks of alloimmunization and infection, avoid platelet transfusion in older individuals whose platelet counts exceed a particular threshold (10 platelets/nL). Standard treatments for cardiac and genitourinary anomalies. Avoidance of cow's milk to reduce the severity of gastroenteritis and to avoid exacerbations of thrombocytopenia. Central venous catheter as an alternative to repeated venipuncture.

Surveillance: Platelet count when evidence of increased bleeding tendency (bruising, petechiae) occurs. Assess for gastrointestinal manifestations in children, which may indicate cow's milk allergy, at each visit. Serum electrolytes, blood urea nitrogen, and creatinine to assess kidney function per nephrologist.

Agents/circumstances to avoid: Avoid cow's milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children). Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs or aspirin should be avoided or used with caution.

Genetic counseling: TAR syndrome is caused by compound heterozygosity for a null allele and an RBM8A hypomorphic allele and is inherited in an autosomal recessive manner. However, because null alleles are rare (and often occur de novo in the proband) and RBM8A hypomorphic alleles are common, inheritance of TAR syndrome is associated with several features unusual in autosomal recessive disorders: a paucity of affected sibs, apparent parent-to-child transmission, and affected second- and third-degree relatives. The risk to sibs of a proband varies depending on the genetic status of the parents; for example:

1. If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an RBM8A hypomorphic allele, each sib of an affected individual has at conception a 25% chance of being affected.

2. If one parent is known to be heterozygous for a null allele and the other parent has biallelic RBM8A hypomorphic alleles, each sib of an affected individual has at conception a 50% chance of being affected.

3. If one parent is known to be heterozygous for an RBM8A hypomorphic allele and the other parent has two normal RBM8A alleles, each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier of an RBM8A hypomorphic allele and a 50% chance of being unaffected and not a carrier.

Individuals who are heterozygotes (carriers) for one TAR syndrome-related pathogenic variant (either an RBM8A hypomorphic allele or a null allele) are asymptomatic; individuals with biallelic RBM8A hypomorphic alleles are asymptomatic. Once the causative null allele and RBM8A hypomorphic allele have been identified in an affected family member, carrier testing for at-risk relatives as well as prenatal and preimplantation genetic testing are possible.