A case of congenital bone marrow failure with radio-ulnar synostosis

Abstract

Bone marrow failure is often associated with skeletal defects, as seen in Fanconi anemia [1], Diamond-Blackfan anemia [2], or thrombocytopenia-absent radius syndrome [3]. Congenital amegakaryocytic thrombocytopenia with radio-ulnar synostosis has been reported to be related with HOXA11 mutation [4]. We present a boy with congenital bone marrow failure with radio-ulnar synostosis, but without HOXA11 mutation. A boy, born to non-consanguineous parents, was delivered via Cesarean section at 31 weeks’ gestation for hydrops fetalis resulting from severe anemia. He had severe anemia (hemoglobin 2.7 g/dl), severe neutropenia (white blood cells 3,220/ll with 1.5% neutrophils), and moderate thrombocytopenia (platelets 89,000/ll) at birth. Neutrophils continued to be nearly absent and platelet counts progressively decreased below 20,000/ll by 2 weeks of age. He had no hepatosplenomegaly, lymphadenopathy, or cafe-au-lait spot, but had hydrocele testicle, sensorineural hearing loss, and overlapping fingers without abnormalities of bone. Supination of his bilateral forearms was restricted and X-rays revealed bilateral proximal radio-ulnar synostosis (Fig. 1). Bone marrow aspiration showed aplasia without dysplasia. Chromosomal analysis revealed a 46, XY, inv(9)(p12q13) karyotype, which is considered to be normal variant without physiologic role. He lacked a family history of hematological or skeletal disorders. No excessive chromosomal breakage was detected by mitomycin C stimulation, and no mutation was found for the Shwachman–Bodian–Diamond syndrome (SBDS) gene. He had repeated bacterial and viral infections after birth, requiring antibiotics and prophylactic antifungal agents. He also needed repeated transfusions of red blood cells and platelets until 8 months of age when he underwent a 5/6 human leukocyte antigen (HLA)-matched unrelated bone marrow transplantation (BMT). Pretransplant conditioning was with fludarabine, cyclophosphamide, and thoracicabdominal irradiation (2 Gy). Prophylaxis for graft-versushost disease (GVHD) was short-term methotrexate and tacrolimus. Engraftment was prompt and grade 1 acute cutaneous GVHD was observed. By 20? days following BMT, he became independent of all transfusions. He has had normal hematological studies for 14 months after BMT. Limb formation is regulated by HOX genes during embryonic development. The most 50 members of the HOXA and HOXD clusters (HOXA9–HOXA13 and HOXD9–HOXD13) are particularly important in limb development [5]. HOX genes are also well known to be associated with hematopoiesis and leukemogenesis [6]. The effects of Hoxa10 and Hoxd11 were found to be on forearm development from studies of mutant mice [7, 8]. Radio-ulnar synostosis with congenital thrombocytopenia has been reported to be associated with HOXA11 mutation [4], which prompted us to examine HOX genes. However, we detected no mutations of HOXA11 and HOXD11. Of the three patients with radio-ulnar synostosis and thrombocytopenia reported by Thompson et al. [9], one H. Yoshida Y. Hashii T. Okuda S. Kusuki E. Sato H. Ohta (&) K. Ozono Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan e-mail: ohta@ped.med.osaka-u.ac.jp