Ollier disease is a rare skeletal disorder. It is characterized by the occurrence of multiple enchondromas with a marked unilateral predominance mainly affecting medulla of the metaphyses and diaphyses of the short and long tubular bones of the limbs, especially the hands and feet. The risk of malignant transformation is suggested to be up to 35%. We hypothesise that Ollier disease is a mosaic condition as it is polyostotic and because of its unilateral predominance. Here we aimed to identify molecular defects in Ollier disease related enchondromas and chondrosarcomas using high resolution single nucleotide polymorphism (SNP) array approach. Affymetrix SNP 6.0 was performed on 67 samples which include 10 blood samples and 3 matched blood-saliva samples as a control; 13 enchondromas and 26 chondrosarcomas of different grades from 30 Ollier patients and normal DNA from 12 Ollier patients for paired comparison.

All samples were divided into three groups: normals, enchondromas and chondrosarcomas. The number of numerical genomic changes in the chromosomes were not different for the enchondromas (p=0.36) while large genomic aberrations were seen in chondrosarcomas as compared to normals (p=0.01). Copy number variation (CNV) analysis showed 95K amplification at 4q13 in 5 out of 13 enchondromas and a 2K deletion at 14q11 in 6 out of 13 enchondromas. Paired loss of heterozygosity (LOH) analysis failed to show LOH in 5 enchondromas at higher resolution. Paired LOH was observed at 3q, 5p, 6p, 6q, 7q, 9p, 12p, 13p and 13q in 7 high grade chondrosarcomas associated with loss of chromosomes.

The results of this study indicate involvement of chromosomes 4 and 14 for the development of enchondromas. We were unable to detect LOH in enchondromas at 1Mb resolution containing approximately 500 SNP probes. High grade chondrosarcomas showed LOH at different chromosomes. In future, we will study LOH and CNV changes at gene level and select candidate genes.

Multiple Hereditary Exostoses is a rare skeletal chondrodysplasia characterized by the presence of a variable number of osteochondromas, usually mostly affecting the long bones but possibly located anywhere. Appearance and growth of exostoses is parallel to the patient’s growth, essentially ending when skeletal maturity is reached.

Its clinical expression is well known and may vary from asymptomatic to severe deformities and is rarely complicated by trasformation to secondary chondrosarcoma (0.5–2%). Research in the field of genetics has lead to identification of 2 responsible genes, EXT1 and EXT2, located respectively on chromosome 8 and 11, both coding for transmembrane glycoproteins involved in the synthesis of heparan-sulfate chains.

A third rare abnormality (EXT3) has been located on chromosome 19 but the responsible gene has not been identified yet.

Seems logical to investigate the genetic basis of the disease and the correlation with clinical aspects, either severity of the deformities and consequent functional impairment and potential for chondrosarcoma.

At the authors’ Institution a total of 550 patients with Multiple Hereditary Exostoses are presently filed. Genetic screening by DHPLC (Denaturing High Performance Liquid Chromatography) and clinicoradiographic orthopedic evaluation has been carried out on 200 patients. So far, 45 mutations have been identified (35 in EXT1 and 10 in EXT2) in 167 patients, 20 of which presented with negative family history and are therefore considered “de-novo” mutations.

Comparison of the clinical data and prospective long term follow-up will possibly clarify different prognosis and risk of secondary chondrosarcoma for different genotypes.