Radioulnar Synostosis With Amegakaryocytic Thrombocytopenia 2

A number sign (#) is used with this entry because of evidence that radioulnar synostosis with amegakaryocytic thrombocytopenia-2 (RUSAT2) is caused by heterozygous mutation in the MECOM gene (165215) on chromosome 3q26.

Description

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is characterized by thrombocytopenia that progresses to pancytopenia, in association with congenital proximal fusion of the radius and ulna that results in extremely limited pronation and supination of the forearm (summary by Niihori et al., 2015).

For a discussion of genetic heterogeneity of radioulnar synostosis with amegakaryocytic thrombocytopenia, see RUSAT1 (605432).

Clinical Features

Sugita et al. (2007) described a 1-year-old Japanese girl who presented with systemic petechiae at birth and was found to have thrombocytopenia. Bone marrow examination showed absence of megakaryocytes but was otherwise normal. She also had fifth-finger clinodactyly and limited pronation and supination of the upper extremities; x-rays showed bilateral proximal radioulnar synostosis. Her platelet count remained low and she developed pancytopenia by age 5 months. At 1.5 years of age she underwent successful allogeneic bone marrow transplantation, with continued complete remission on bone marrow examination 9 months later.

Yoshida et al. (2010) reported a Japanese boy who was born with severe anemia and neutropenia, as well as moderate thrombocytopenia that progressively worsened over the next 2 weeks. Bone marrow aspiration showed aplasia without dysplasia. Supination of forearms was restricted, and x-rays revealed bilateral proximal radioulnar synostosis. Additional features in this patient included sensorineural hearing loss, overlapping fingers without bony abnormality, and testicular hydrocele. The boy had no hepatosplenomegaly, lymphadenopathy, or cafe-au-lait spots, and there was no family history of hematologic or skeletal disorders. He had multiple bacterial and viral infections after birth and required repeated transfusions of red blood cells and platelets; he underwent bone marrow transplantation at 8 months of age, following which his hematologic studies normalized.

Niihori et al. (2015) studied a 3-year-old Japanese girl who presented at birth with ecchymosis and severe anemia and thromobocytopenia. She had no dysmorphic features or signs suggestive of hematologic malignancy or infection. Bone marrow examination showed a hypocellular marrow with no megakaryocytes. Skeletal survey revealed bilateral synostosis of the proximal radius and ulna, bony defect of the fifth fingers, and brachymesophalangy of the fourth digits. The patient underwent HLA-matched cord blood transplantation at 4 months of age; 2 years later she was healthy with no hematologic problems.

Molecular Genetics

In a 3-year-old Japanese girl with radioulnar synostosis and amegakaryocytic thrombocytopenia who had undergone cord blood transplantation and was negative for mutation in the HOXA11 gene (142958), Niihori et al. (2015) performed whole-exome sequencing on peripheral blood collected prior to transplantation and identified a heterozygous missense mutation in the MECOM gene (T756A; 165215.0001). Analysis of the MECOM gene in 2 more Japanese children with RUSAT who were negative for mutation in HOXA11 revealed heterozygosity for 2 different missense mutations: H751R (165215.0002) in the Japanese girl originally described by Sugita et al. (2007), and R750W (165215.0003) in the boy previously reported by Yoshida et al. (2010). The mutations were not found in unaffected relatives, 382 ethnically matched controls, or in public variant databases.