Clinical Guidance

Individuals with TAR syndrome have one null allele and a hypomorphic allele on opposite homologous chromosomes. The hypomorphic allele is usually located in the 5' UTR, intron 1, or 3' UTR. Only limited genotype-phenotype correlations have been described:

• The hypomorphic allele has been associated with lower platelet counts and hemoglobin values below the lower reference value; the low hemoglobin levels could not be fully attributed to increased bleeding as a result of thrombocytopenia .

• Individuals with intronic hypomorphic allele had higher platelet counts, even during the first months of life, which eventually reached the reference range. Individuals with the c.67+32GC allele also had normal hemoglobin levels.

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"

Penetrance

Penetrance appears to be complete in individuals who have biallelic RBM8A pathogenic variants (a heterozygous null allele and a hypomorphic allele).

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"

Diagnostic Criteria

Suggestive Findings

Thrombocytopenia absent radius (TAR) syndrome should be suspected in individuals with:

• Bilateral absence of the radii with the presence of both thumbs

• Thrombocytopenia, usually 50 platelets/nL (normal range: 150-400 platelets/nL)

Establishing the Diagnosis

The diagnosis of TAR syndrome is established in a proband with and a null heterozygous variant (most often a 500-kb deletion or 200-kb deletion including RBM8A at chromosome band 1q21.1) in a compound heterozygous state with a heterozygous RBM8A hypomorphic allele identified by molecular genetic testing .

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"

Differential Diagnosis

Hereditary disorders of known genetic cause that include radial aplasia as a component manifestation and can show some overlap with thrombocytopenia absent radius (TAR) syndrome are summarized in . However, among the group of genetic disorders associated with radial aplasia, the presence of both thumbs is highly specific of TAR syndrome.

Table 3.

Genetic Disorders Associated with Radial Aplasia in the Differential Diagnosis of Thrombocytopenia Absent Radius Syndrome

Gene(s) | Disorder | MOI | Limb Malformations | Other Key Features

23 genes1 | Fanconi anemia | ARADXL2 | Unilateral or bilateral malformations of upper limbs (e.g., hypoplastic thumb hypoplastic radius) lower limbs | Growth deficiency, variable congenital anomalies, BMF, risk for malignancy

ESCO2

| ESCO2 spectrum disorder (from Robe...

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"

Management Guidelines

Clinical practice guidelines for anesthesia and dental care in thrombocytopenia absent radius (TAR) syndrome have been published . Individuals with TAR syndrome have a high anesthetic risk. Considerations include potential difficulties with vascular and airway access, risk for bleeding due to altered platelet count and function, and potential congenital cardiac defects. All risks should be assessed carefully before surgery. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with TAR syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Thrombocytopenia Absent Radius Syndrome

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"

Clinical Guidance

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 including aspirin should be avoided or used with caution.

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"

Surveillance Guidelines

Table 6.

Recommended Surveillance for Individuals with Thrombocytopenia Absent Radius Syndrome

System/Concern | Evaluation | Frequency

Thrombocytopenia

| Platelet count | In those w/signs of bleeding tendency (bruising, petechiae)

Gastrointestinal

manifestations | • Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.

• Assess for episodes of severe gastroenteritis.

| During childhood, at each visit

Renal function in those

w/renal malformation | Assess renal function w/serum electrolyte concentrations, BUN, creatinine | Frequency of renal function assessment to be determined by nephrologist, depending on the malformation

BUN = blood urea nitrogen

Source: GeneReviews — "Thrombocytopenia Absent Radius Syndrome"