Abstract 1100

Congenital radioulnar synostostis (RUS) is a rare anomaly characterized by fusion of the radius and ulna. RUS occurs more frequently in males than females, and is bilateral in 50% of cases. Since 1793, there have been > 400 cases reported. Literature review revealed 7 rare syndromes with RUS and hematologic problems including our newly named RUS-H Syndrome: 1) Diamond-Blackfan Anemia (DBA) associated with normochromic, macrocytic anemia in early infancy and erythroblastopenia; 2) Amegakaryocytic Thrombocytopenia Radioulnar Syndrome (ATRUS, HoxA11 mutation) with thrombocytopenia since birth requiring stem-cell transplantation; 3) IVIC Syndrome with mild thrombocytopenia and leukocytosis; 4) WT Syndrome involving a wide array of hematologic abnormalities including easy bruising, hypoplastic anemia, pancytopenia, Acute Lymphoblastic Leukemia (ALL), and Acute Myeloblastic Leukemia (AML); 5) Cohen Syndrome with neutropenia and fluctuating thrombocytopenia; 6) Noonan Syndrome with abnormal bleeding and easy bruising; and 7) RUS-H Syndrome (not involving HoxA11 mutations) associated with a spectrum of hematologic abnormalities including easy bruising, recurrent epistaxis, neutropenia, thrombocytopenia, ALL and aplastic anemia. This is a subsequent report to our ASH 2010 abstract.

All 7 syndromes are associated with hand abnormalities. Six of the 7 syndromes (not Cohen) are associated with hearing loss/ear abnormalities. Four syndromes (DBA, ATRUS, WT, and RUS-H) have an increased risk of hematological malignancy. DBA, IVIC, Cohen, and Noonan have abnormalities of the eye and genitourinary system. DBA, WT, Cohen, and Noonan Syndromes are associated with dysmorphic facial features. ATRUS, IVIC, Cohen, and Noonan Syndromes all exhibit lower limb abnormalities. DBA, Cohen, Noonan, and RUS-H are associated with short stature. DBA, IVIC, Noonan, and RUS-H Syndromes are associated with kidney abnormalities and structural heart defects. Three Syndromes (DBA, IVIC, and Cohen) have cranial abnormalities. DBA IVIC, and Noonan Syndrome have structural defects of the shoulder. IVIC, Cohen, and Noonan Syndromes are associated with spinal anomalies. Two Syndromes (DBA and Noonan Syndrome) are associated with liver, spleen, and neck abnormalities. Cohen and Noonan Syndrome are associated with developmental delays. Lastly, WT and Noonan Syndrome are associated with skin abnormalities (Figure 1).

This abstract highlights the association of RUS, other congenital abnormalities, and hematologic problems in previously described syndromes and in the novel RUS-H Syndrome. DBA, Cohen, and Noonan Syndrome are the most common of the 7 syndromes, with DBA estimated at 5 per 1,000,000; Cohen Syndrome predicted to have a prevalence of <1,000; and Noonan Syndrome predicted to have a prevalence of <1 in 2,500; however, RUS in DBA, Cohen, and Noonan Syndrome is limited to case reports. RUS-H Syndrome has been identified in 12 families in the United States, Canada, and England. IVIC and WT Syndromes have been reported in 4 families total, and ATRUS with an identified HoxA11 mutation has been reported in at least 2 families.

Since RUS may often be missed on routine physical examination, we recommend specific evaluation of pronation/supination in patients with hematological problems of unknown etiology. Additionally, we recommend that a targeted genetic panel be developed to detect mutations that are known for syndromes involving RUS, blood abnormalities, and other similar orthopedic entities that have cross-over manifestations like Thrombocytopenia-Absent Radii (TAR) Syndrome. This panel might consist of mutations associated with DBA (RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 mutations), with ATRUS (HoxA11 mutation), with IVIC Syndrome (SALL4 mutations), with Cohen Syndrome (8q22.2q22.3/COH1 deletion), with Noonan Syndrome (PTPN11, SOS1, RAF1, KRAS, NRAS, and BRAF mutations) and with TAR Syndrome (RBM8A null allele and noncoding SNP). The causative mutations of WT and RUS-H Syndromes have yet to be discovered. Genetic analysis of 6 of the 12 families with RUS-H Syndrome did not reveal a HoxA11 mutation. Broader sequencing techniques are underway for all 12 families in our RUS-H cohort, with hopeful detection of a new candidate gene as the unifying causative factor for the abnormalities in limb formation and hematopoiesis.

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Disclosures:

Bussel:Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy.

Topics:
abnormal hematology findings, acute lymphocytic leukemia, amegakaryocytic thrombocytopenia, anemia, hypoplastic, anemia, macrocytic, aplastic anemia, cohen syndrome, congenital abnormality, congenital anomaly of ear, contusions

Author notes

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Asterisk with author names denotes non-ASH members.

© 2012 by The American Society of Hematology
2012
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