Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation.

Abstract

The association of bone marrow failure and skeletal defects has been frequently noted, but the genetic basis for most of these syndromes remains unclear1. We have identified an unusual association of amegakaryocytic thrombocytopenia and radio-ulnar synostosis in two unrelated and nonconsanguinous families that are of different ethnic backgrounds (Fig. 1a). The fathers and all affected children in both families have the same skeletal defect, proximal fusion of the radius and ulna (Fig. 1b), resulting in extremely limited pronation and supination of the forearm. Three children also had symptomatic thrombocytopenia, with bruising and bleeding problems since birth, necessitating correction by bone marrow or umbilical-cord stem-cell transplantation. The fathers had normal platelet counts and no history of bleeding or bruising. This set of clinical findings appears distinct from any other syndromes of bone marrow failure and skeletal malformations, including thrombocytopenia with absent radii (TAR) syndrome and Fanconi anaemia1, 2, 3. So far, proximal radial-ulnar synostosis has not been associated with the TAR syndrome, which, as its name implies, typically has a more pronounced radial defect. The absence of excessive diepoxybutane-induced chromosomal breakage before stem cell transplantation from our patients is not consistent with Fanconi anaemia.