Thrombocytopenia cerebellar hypoplasia short stature
Overview
A very rare syndrome characterized mainly by short stature, low blood platelets and abnormal brain development.
Symptoms
- Abnormal brain development - Infant feeding problems - Mental retardation - Retarded fetal growth - Small head
Diagnosis
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. As an alternative, the contiguous gene model is based on the premise that phenotypic findings are related when genes responsible for each defect are geographically related in a chromosome. This mechanism, if true, would be independent of the anatomic association and the degree of involvement in either system. 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 et al (1997) and Sekine et al (1998) showed comparable or increased levels of thrombopoietin in patients with TAR compared with healthy control subjects. 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. In 2000, Letestu et al suggested that the defect was a blockage in cell differentiation at an early stage. Other theories for platelet hypoproduction include an abnormal response to stimulators of megakaryocytopoiesis involving an abnormal signal-transduction pathway, decreased numbers and sizes of megakaryocytic progenitor cells (Sekine et al, 1998), abnormal progenitor cells with a maturational defect or receptor defect, and the presence of humoral or cellular inhibitors of megakaryocytopoiesis. No causative mutation has been identified despite investigations of the c-mpl gene in patients with TAR. 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 et al (2002) did not detect mutations in the coding sequence of HOX genes known to affect radial development. Although no mutation is known, the observation that platelet counts improve during infancy and that they may even normalize with age, has led to the suggestion that abnormal genes may be developmentally regulated. TAR syndrome is generally considered an autosomal recessive disease. Some have suggested that the inheritance pattern may be autosomal dominant with variable penetrance. Urban et al (1998) postulated that, given the phenotypic overlap between Roberts syndrome and TAR syndrome, allelic heterogeneity might cause both. In this postulate, TAR syndrome is the compound heterozygous form, with a mild and a severe mutation, whereas Roberts syndrome is the homozygous form with the severe mutation. However, genetic heterogeneity and environmental factors cannot be completely ruled out.