Severity of disease and risk of malignant change in hereditary multiple exostoses

Abstract

We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used. There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe. The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable.

What is the Proportion of Patients With Multiple Hereditary Exostoses Who Undergo Malignant Degeneration?

“…Perhaps the most important complication of the benign lesions that are the hallmark of multiple hereditary exostoses is their malignant transformation to chondrosarcoma. Numerous studies have reported proportions from less than 1% to 25% for malignant degeneration of a benign exostosis to chondrosarcoma in patients who have multiple hereditary exostoses [3,4,[7][8][9][11][12][13][14]. In general, malignant transformation is rare and the true incidence has (1), and South Korea (1).…”

“…Previous studies have shown a wide range in the numbers of patients with multiple hereditary exostoses who have had malignant change to chondrosarcoma, and these studies [3,7,8,[12][13][14] cite proportions derived from smaller population clusters in seemingly isolated geographic areas. Historically, reported proportions of transformation have ranged from less than 1% to approximately 25% [3,4,[7][8][9][11][12][13][14]. Some of the larger studies we are aware of include rates of 4.9% in 529 patients [11], 0.38% in 526 patients [8], and 7% in 184 patients [4].…”

Osteochondroma and Spinal Cord Compression in a Patient With Hereditary Multiple Exostoses: A Case Report

“…12,18,28,29 Mutations of the genes exostosin-1 (EXT1) (8q23-q24) and exostosin-2 (EXT2) (11p11-p12) have associations with HME and malignant degeneration. 4,5,26,28,30 The EXT genes regulate chondrocyte maturation and differentiation. 31 The majority of osteochondromas are found in long bones and the appendicular skeleton; however, they can be found in any bone formed through endochondral ossification.…”

“…Many osteochondromas are asymptomatic; however, complications can involve bone, nerve, and soft tissues via mass effect or intrinsic change [1][2][3][4][5][6][7][8][9][10] (Fig 1).…”

Chondrogene Tumoren des Skeletts

“…Multiple kartilaginäre Exostosen oder multiple Osteochondrome (MIM #133700) sind autosomal-dominant vererbte, genetisch heterogene Erkrankungen, die durch Alterationen in einem der drei EXT-Gene verursacht werden, in etwa 2/3 der Fäl-le bei Männern vorkommen und eine Prä-valenz von 1/50.000 aufweisen [5]. Wäh-rend eine maligne Transformation in sporadisch vorkommenden Osteochondromen sehr selten ist, wird sie bei multiplen hereditären Osteochondromen oder Exostosen in bis zu 8% beobachtet [5,20] …”