Background
Thrombocytopenia-absent radius (TAR) syndrome is a rare condition in which thrombocytopenia is associated with bilateral radial aplasia. TAR syndrome was first described in 1951. An autosomal recessive inheritance pattern was proposed because TAR affected more than one member of some families. In 1969, TAR was defined as a syndrome and further classified as the association of hypomegakaryocytic thrombocytopenia and absent radii. The expression varies and includes abnormalities in the GI, skeletal, hematologic, and cardiac systems. [1, 2, 3] See the images below.


Pathophysiology
Some have proposed that the association of seemingly disparate skeletal and hematologic abnormalities is related to the simultaneous development of the heart, the radii, and the megakaryocytes at 6-8 weeks' gestation. The similarity of TAR syndrome to congenital rubella suggests intrauterine injury when the involved systems develop, but a common etiologic agent has not been identified.
The exact pathophysiology of the thrombocytopenia is still unclear. The platelet abnormality reflects platelet hypoproduction, for which numerous explanatory theories have been proposed. One suggestion is that a failure in production of humoral or cellular stimulators of megakaryocytopoiesis (eg, thrombopoietin) is responsible for inhibiting platelet production. However, studies by Ballmaier and colleagues and Sekine and associates showed comparable or increased levels of thrombopoietin in patients with TAR compared with healthy control subjects. [4, 5] These findings suggest that the thrombocytopenia is due to a lack of response to thrombopoietin, especially given the observation of normal thrombopoietin receptor expression on megakaryocytes; this raises the question of a defect in c-Mpl signaling.
Many mutations have been postulated; however, despite investigations of the c-mpl gene in patients with TAR, no mutations have been found in this gene. [6] Another proposed candidate gene is a HOX gene. The HOX family of genes plays a major role in embryogenesis and cell differentiation, including differentiation of hematopoietic cell lines. However, Fleischman and colleagues did not detect mutations in the coding sequence of HOX genes known to affect radial development. [7] Subsequently, an interstitial microdeletion of chromosome 1q was identified in 30 patients with TAR syndrome. [8] All patients and 75% of unaffected parents in this cohort had the microdeletion, suggesting co-inheritance of an additional modifier gene for disease expression.
Albers and colleagues applied high-throughput sequencing in 5 unrelated patients with TAR syndrome and the chromosome 1q21.1 deletion. [9] They discovered one low frequency single nucleotide polymorphism (SNP) in the noncoding 5' untranslated (UTR) region of the gene RBM8A in 4 of the cases and another low frequency noncoding SNP in the first intron of the same gene. These findings were further confirmed in 48 individuals with TAR syndrome. The investigators found coinheritance of the 1q21.1 deletion with either SNP, causing significant decreases in the level of Y14, a protein encoded by RBM8A. [10] The exact mechanism for which decreased levels of Y14 produces the phenotype associated with TAR syndrome remains to be elucidated. Y14 is part of the exon-junction complex (EJC), a set of proteins associated with transcript export, localization, and splicing, playing a critical in embryonic development. [11, 12] Some studies have suggested defects in signal transduction downstream of thrombopoietin.
A study by Manukjan et al indicated that in patients with TAR syndrome, those with the 5’UTR SNP in RBM8A have a significantly lower platelet count than do patients with the intron-1 SNP in this gene. [13]
TAR syndrome was initially considered an autosomal recessive disease. Some have suggested that the inheritance pattern may be autosomal dominant with variable penetrance.
Epidemiology
Frequency
United States
TAR syndrome rarely occurs in the United States.
International
The frequency of TAR syndrome is 0.42 case per 100,000 live births in Spain.
Mortality/Morbidity
The major cause of mortality in TAR syndrome is hemorrhage. The incidence of hemorrhage is limited to the first 14 months of life. In a study by Hedberg and associates, 18 of 20 deaths in 76 patients were due to hemorrhagic events; most of patients who died had platelet counts < 10 X 109/L. [14]
Bleeding and hemorrhage can also result in clinically significant morbidity, especially intracranial hemorrhage. Hand and upper-extremity function is usually good if radial aplasia is the only skeletal abnormality. However, patients require plastic surgery, occupational therapy, and physiotherapy.
Race
No ethnic or racial predilection is reported.
Sex
The male-to-female ratio is 1:1. Greenhalgh and associates reported an excess of females (27:7), [15] as did Hall and colleagues (26:14). [16]
Age
TAR syndrome is congenital, and patients usually present with symptomatic thrombocytopenia in the first week of life.
Prognosis
The prognosis in TAR is better than in congenital amegakaryocytic thrombocytopenia (CAMT). Survival in TAR plateaus at greater than 70% after age 4 years. The platelet count improves after age 1 year (unlike in CAMT), so platelet transfusion is rarely needed after that.
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Infant with thrombocytopenia-absent radius syndrome. The arms and forearms are shortened, with radial deviation of both hands because of the absence of bilateral radii. The legs are normal. See also Media files 2 and 3.
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Same infant as in Media files 1 and 3. Close-up photograph of arm and forearm (volar aspect). Note the petechiae.
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Same infant as in Media files 1 and 2. Close-up photograph of arm and forearm (dorsal aspect).