HEREDITARY MULTIPLE EXOSTOSES (EXT) - MUTATIONAL STUDIES OF FAMILIAL EXTI CASES AND EXT-ASSOCIATED MALIGNANCIES

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that de velop from the growth centers of the long bones, EXT is genetically he terogeneous, with three loci, currently identified on chromosomes 8q24 .1, 11p13, and 19q, The EXT1 gene, located on chromosome 8q24.1, has b een cloned and is encoded by a 3.4-kb cDNA, Five mutations in the EXT1 gene have been identified-four germ-line mutations, including two unr elated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma, Four of the mutations identified resulted in frameshifts and premature termination codons, while the fifth muta tion resulted in a substitution of leucine for arginine. Loss of heter ozygosity (LOH) analysis of chondrosarcomas and chondroblastomas revea led multiple LOH events at loci on chromosomes 3q, 8q, 10q, and 19q, O ne sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, while a second underwent LOH for EXT2 and chromosome 10. A third chondrosarco ma underwent LOH for EXT1 and chromosome 3q, These results agree with previous findings that mutations at EXT1 and multiple generic events t hat include LOH at other loci may be required for thr development of c hondrosarcoma.