“Multiple Hereditary Exostoses due to o-glycosylation defects: first clinical and molecular studies in argentinean patients”.

DELGADO, MA., AZAR, N., ZECCHINI L., BECERRA, A., ROBLEDO, H.; BISTUÉ MILLÓN, M.B.; SARRIÓN, P.; DODELSON DE KREMER, R.; BALLCELS, S; GRINBERG, D.; ASTEGGIANO, CG.

Cancún, México

Congreso; VII Congreso Latinoamericano de Errores Innatos del Metabolismo y Pesquisa Neonatal; 2009

Sociedad Latinoamericana de Errores Innatos del Metabolismo y Pesquisa Neonatal.

MULTIPLE HEREDITARY EXOSTOSES DUE TO O-GLYCOSYLATION DEFECTS: FIRST CLINICAL AND MOLECULAR STUDIES IN ARGENTINEAN PATIENTS. Delgado, MA.(1), Azar, N. (1), Zecchini L.(4), Becerra, A.(1), Robledo, H.(2); Bistué Millón, M.B. (1); Sarrión, P.(5); Dodelson de Kremer, R. (1); Ballcels, S(5); Grinberg, D.(5); Asteggiano, CG. (1,3). (1) Centro de Estudio de las Metabolopatías Congénitas (CEMECO), Fac. Cs. Médicas, UNC,  Argentina, (2) Serv. Bioimágenes, Hospital de Niños de Córdoba, (3) Fac. Medicina, UCC, Argentina, (4) Serv. Traumatología, Hospital de Niños de Córdoba, (5) Dpto. Genética, Fac. Biol., Univ. Barcelona, España. Congenital Disorders of Glycosylation (CDG) is an increasing chapter of multisystemic diseases, with N- and O-glycosylation defects described. Multiple Hereditary Exostoses (MHE), one of the O-glycosylation defects, is an autosomal dominant disease characterized by benign cartilage-capped tumors (osteochondromas) with solitary (SO) or multiple (MO) presentation. The most important complication is malignant transformation to chondrosarcome (3-5%). MHE is produced by defects in glycosyltransferases, encoded by EXT1/EXT2 genes and involved in heparin sulphate (O-glycosaminoglycan) synthesis, whose impairment leads to exostoses formation.   Aim: To apply a clinical and molecular protocol to identify MHE patients with alterations in EXT1/EXT2 genes as well as to study the genotype-phenotype correlation in Argentinean patients. Materials and Methods: 12 patients were studied by clinical and complementary parameters. Genotyping of EXT1-EXT2 was performed from genomic-DNA and/or specific tissues (osteochondroma) by PCR and direct sequencing. Results: We identified four mutations in EXT1 in MO patients, three novel: one missense p.R346T and two nonsense p.L283X and p.F250F. Another mutation, previously described, 1 bp deletion p.L490R, leading to a frameshift. We are studying loss of heterozygocity in a patient with malignant transformation to chondrosarcome. Discussion: Our first findings allowed us to identify the molecular defect in four patients in EXT1. Molecular diagnosis allowed us to exclude other similar bone diseases and to associate mutations with malignant transformation of the tissue. MHE seems to be frequent in the Argentinean population and the progression of our research will provide a wider knowledge of this pathology in our country and Latin America.