Knowledge on rare diseases and orphan drugs

The prevalence of thrombocytopenia-absent radius (TAR) syndrome is estimated at around 1/100,000-200,000 people.

Individuals with TAR syndrome almost always have bilateral absence or hypoplasia of the radii. The thumbs are always present, which is highly specific for TAR syndrome. Upper limbs may be more severely affected (hypoplasia or absence of the ulnae and/or humeri, fingers syndactyly, fifth-finger clinodactyly). Lower limbs are affected in almost 50% of cases with variable severity (hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, absence of the patella). The most severe limb involvement is tetraphocomelia. Thrombocytopenia is congenital or develop within the first few weeks to months of life. Usually, platelet counts remain low during the first two years of life; then, they increase but do not normalize. Additional recurrent manifestations include: cardiac anomalies (atrial and/or ventricular septal defect, patent foramen ovale), gastro-intestinal involvement (cow's milk allergy, increased susceptibility to gastro-enteritis), genitourinary anomalies (kidney agenesis or malrotation, horseshoe kidney, hydronephrosis, pyelectasis). Other rare manifestations include Mayer-Rokitansky-Kuster-Hauser syndrome, rib and vertebral anomalies, Langerhans cell histiocytosis, transient leukemoid reaction, acute myeloid or lymphoblastic leukemia. Cognitive development is usually normal.

TAR syndrome is caused by compound heterozygosity for a null (most often a 1q21.1 deletion including RBM8A) and a hypomorphic RBM8A allele.

Diagnosis is made on the clinical signs and confirmed by molecular genetic testing.

The main differential diagnoses are other disorders associated with radial aplasia, with a genetic etiology (Holt-Oram syndrome, ESCO2-spectrum disorder, Fanconi anemia, RAPADILINO syndrome, SALL4-related disorders), or not (VACTERL association, thalidomide embryopathy, fetal valproate spectrum disorder).

Antenatal diagnosis may be suspected by fetal ultrasound examination identifying radial anomalies, and confirmed by molecular genetic testing.

TAR syndrome is inherited in an autosomal recessive manner. Penetrance is complete, with variable expressivity. Several characteristics are unusual in autosomal recessive disorders: null alleles are rare and can occur de novo in the proband, the percentage of affected sibs is consequently lower than expected; hypomorphic alleles are common, therefore an apparent parent-to-child transmission can be observed resulting in pseudo-dominant inheritance. Biallelic carriers of hypomorphic variants are asymptomatic.

There is no curative treatment for TAR syndrome. Symptomatic treatment of manifestations and prevention of complications include: early detection of thrombocytopenia, prevention of bleeding and hemorrhage, platelet transfusions in case of severe thrombocytopenia, surgical interventions if required to manage cardiac, urinary or skeletal malformations, avoidance of cow's milk.

Prognosis is variable and mainly conditioned by the severity of thrombocytopenia and its complications (intracranial, digestive hemorrhage). Cardiac defects, renal malformations, acute complications of cow's milk intolerance, acute leukemia can also affect the prognosis.

Last update: August 2023 - Expert reviewer(s): Dr Simon BOUSSION | ITHACA* - Pr Florence PETIT | ITHACA*

* European Reference Network