Hereditary multiple exostoses and enchondromatosis

Hereditary multiple exostoses and enchondromatosis

Best Practice & Research Clinical Rheumatology Vol. 22, No. 1, pp. 45–54, 2008 doi:10.1016/j.berh.2007.12.004 available online at http://www.sciencedi...

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Best Practice & Research Clinical Rheumatology Vol. 22, No. 1, pp. 45–54, 2008 doi:10.1016/j.berh.2007.12.004 available online at

4 Hereditary multiple exostoses and enchondromatosis Ste´phanie Pannier


Laurence Legeai-Mallet *

PhD INSERM U781, Hoˆpital Necker, Enfants Malades, 149 rue de Se`vres, 75015 Paris, France

Hereditary multiple exostoses (HME) is an autosomal-dominant disorder characterized by the development of benign tumours, multiple osteochondromas (exostoses), growing outward from the metaphyses of long bones. Birth prevalence is estimated to be one in 50 000, and the severity of the disease is variable. Osteochondromas may cause complications including pain, deformities and shortening of the long bones, restricted motion of joints, nerve or blood vessel compression, and malignant transformation (5% of cases) in adulthood. HME is a genetically heterogeneous disorder and is associated with mutations in EXT1 or EXT2 genes, which are both tumour suppressor genes. EXT genes encode glycosyltransferases, termed ‘exostosins’, which are involved in the biosynthesis of heparan sulphate. Enchondromatosis (or Ollier disease) is characterized by the presence of intra-osseous benign cartilaginous tumours. The estimated prevalence of the disease is one in 100 000. An asymmetrical distribution of cartilage lesions is observed in the disease. The number, size and location of the enchondromas can be extremely variable between patients. Clinical problems caused by enchondromas include skeletal deformities, limb length discrepancy, pain and the potential risk for malignant change to chondrosarcoma (20–50% of cases). The condition in which multiple enchondromas is associated with haemangiomas is known as ‘Maffucci syndrome’. Ollier disease and Maffucci syndrome are not usually inherited disorders. Key words: osteochondromas; enchondromas; chondrosarcomas; EXT1; EXT2; PTHR1.

Hereditary multiple exostoses (HME) (MIM 133700 and 133701) is an autosomaldominant disorder characterized by multiple benign cartilaginous tumours (osteochondromas or exostoses) growing outward from the metaphyses of long bones (Figures 1 and 2). These protuberances undergo endochonchondral ossification. The onset of the disease is from early childhood (2–3 years) to puberty, with 40% of * Corresponding author. Tel.: þ33 1 44 49 40 00x97830; Fax: þ33 1 47 34 34 85. E-mail address: [email protected] (L. Legeai-Mallet). 1521-6942/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.

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Figure 1. Radiographic aspect of osteochondromas. The lower part of the femur and the upper part of the tibia of an 11-year-old girl affected with hereditary multiple exostoses (sessile exostoses).

patients affected before 10 years of age. Bones formed via intramembranous formation are not involved.1 The prevalence of HME has been estimated to be at least one in 50 000 in the general population2, and penetrance is estimated to be 96%. Most published instances of non-penetrance have occurred in females.3 Ollier disease or enchondromatosis (MIM 166000) is a non-hereditary disorder that usually presents in childhood, characterized by the presence of multiple

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Figure 2. Symmetrical localization of the osteochondromas at the bone surface.

enchondromas with asymmetrical localizations and variable severity. Enchondromas are common intra-osseous, usually benign, cartilaginous tumours that develop in close proximity to the physis ( Figures 3 and 4). The estimated prevalence of Ollier disease is one in 100 000.4 The vertebrate skeleton, composed of cartilage and bone, is the product of cells from three distinct embryonic lineages. The neuronal crest gives rise to the craniofacial skeleton, the sclerotome generates most of the axial skeleton, and the lateral plate mesoderm forms the appendicular skeleton. The organogenesis phase of skeletal development is controlled by transcription factors, growth factors, cytokines and extracellular matrix molecules. Endochondral ossification is the process by which the skeletal cartilage anlagen are replaced by bone. The anlagen elongate and expand in width by proliferation of chondrocytes and deposition of cartilage matrix. Shortly after their formation, chondrocytes in the central region of the cartilage undergo further maturation to hypertrophic chondrocytes. Angiogenic factors secreted by hypertrophic chondrocytes induce sprouting angiogenesis from the perichondrium. With the vessels come osteoblasts, osteoclasts and haematopoietic cells. This is in the formation of primary ossification centres in the bone.5 HEREDITARY MULTIPLE EXOSTOSES Clinical description The number of exostoses that develop in an affected person varies widely even within families. Involvement is usually symmetrical (Figure 2). Exostoses grow in size and

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Figure 3. Radiographic aspect of enchondromas. The lower part of the femur and the upper part of the tibia of a 13-year-old boy affected with severe enchondromatosis.

ossify gradually during skeletal development, and stop growing with skeletal maturity6, after which no new exostoses develop. The long bones of the limbs are more severely affected than the ribs, spine, scapula and pelvis. In decreasing order of frequency, the commonly affected sites are the shoulders, knees and ankles. Deformities of the legs, forearms (resembling Madelung deformity) and hands (e.g. short metacarpal) are frequent manifestations. These deformities are associated with asymmetrical bone growth of leg and forearms.

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Figure 4. Assymetrical localization of enchondromas. Localization of enchondromas in the centre of the bone.

Exostoses arise more frequently in the metaphyseal areas of the proximal and distal femur, proximal and distal tibia (Figure 1), proximal humerus, distal radius and distal ulna; lesions of the proximal radius, proximal ulna and distal humerus are relatively rare. In the scapula, exostoses arise along the growth areas of the body, in proximity to the epiphyses of the coracoid process and acromion. Exostoses arising in ribs are broad based and flat, usually developing near the anterior cartilaginous ends. In the pelvis, the apophyseal region of the ilium is a common site of occurrence. The metatarsals, metacarpals and phalanges may be involved. In the short tubular bones, exostoses have the appearance of small flat tumefactions. The calcaneus is occasionally involved, but the other tarsal and carpal bones are not usually affected. In the vertebral column, exostoses develop in proximity to secondary ossification centres.7 An exostosis may be sessile or pedunculated. Sessile exostoses have a broad-based attachment to the cortex (Figure 1). The pedunculated variants have a pedicle arising from the cortex that is usually directed away from the adjacent growth plate. The pedunculated form is more likely to irritate overlying soft tissue, such as tendons, and compress peripheral nerves or vessels. The marrow and cancellous bone of the host bone and the exostosis are continuous. Osteochondromas may cause complications, including osseous and cosmetic deformities, fracture, bursa formation and impingement on adjacent structures (tendons, nerves, vessels). Spinal cord compression resulting from osteochondroma is an extremely serious complication of HME. Patients with hereditary exostoses are usually short statured with mild limb length discrepancies. The most severe complication is malignant transformation of exostoses into low-grade chondrosarcomas, which occurs in 5% of cases. Axial sites, such as the

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pelvis, scapula, ribs and spine, are usually the location of degeneration of exostoses to chondrosarcomas. Aetiology of hereditary multiples exostoses HME is a heterogeneous disorder inherited as an autosomal-dominant trait. Three loci have been identified to date: EXT1 (MIM 133700) and EXT2 (MIM 133701), mapped to chromosomes 8q23–q24 and 11p11–p12, respectively8,9; and EXT3, located on the short arm of chromosome 19.10 Loss of heterozygosity at the EXT1, EXT2 and EXT3 loci has been observed among patients with EXT-related and unrelated chondrosarcomas, suggesting that EXT genes are tumour suppressors in chondrosarcomas.11 Some evidence suggests that EXT1 and EXT2 may have tumour suppressing activity.12 Both human EXT1 and EXT2 have been cloned.13,14 The EXT gene products may be referred to as ‘exostosins’.15–17 Exostosin-1 (EXT1) and exostosin-2 (EXT2) possess a glycosyltransferase activity, and are involved in heparan sulphate biosynthesis. Several studies have concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these two genes cause premature termination of the EXT proteins, whereas mis-sense mutations are rare.18 In several studies, more mutations were detected in EXT1 genes than in EXT2 genes in Caucasian and Japanese patients.19–23 After performing sequencing analysis in some families, it was not possible to detect the disease-causing mutation. The existence of a third EXT gene (EXT3) could be a possibility.19–23 Genotype–phenotype correlations Several studies have identified more severe disease in individuals with EXT1 mutations than EXT2 mutations on the basis of short stature, skeletal deformity (shortened forearm or bowing, knee deformity) and function (elbow, forearm and knee range of motion).20,24 The risk of chondrosarcoma may also be higher in individuals with an EXT1 mutation than in those with an EXT2 mutation20, but EXT1 mutations are responsible for most cases of HME. Differential diagnosis Multiple exostoses occur in three other inherited conditions, which are considered as differential diagnoses for HME. Metachondromatosis (MIM 156250) is inherited in an autosomal-dominant manner. In contrast to HME, the exostoses of metachondromatosis point toward the joints and frequently regress spontaneously. Exostoses do not result in shortening of affected long bones or produce bowing, joint deformity or subluxation as seen in HME. Langer-Giedion syndrome is a contiguous gene deletion syndrome involving EXT1 and TRPS1 genes (trichorhinophalangeal syndrome I, MIM 190350). Affected individuals have exostoses, mental retardation, craniofacial abnormalities (laterally protruding ears, broad nasal bridge and bulbous nose, sparse hair) and digital anomalies (coneshaped epiphyses). DEFECT 11 or Potocki-Shaffer syndrome (MIM 601224) is a contiguous gene deletion syndrome involving EXT2 and ALX4 (homeobox) genes. Affected patients have multiple exostoses, an ossification defect of the skull (enlarged parietal foramina), craniofacial dysostosis and mental retardation.

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Management including treatment In the absence of clinical problems, exostoses require no therapy; however, surgery is often necessary when it is painful, when it interferes with joint or muscle function, when it presses on nerves or vessels, or when it is causing deformity. In children and adults, annual surveillance of the axial sites (size, pain) of the osteochondromas is recommended. Monitoring the size of adult exostoses is important, particularly those involving the pelvis, due to the risk of malignant transformation into chondrosarcomas. Genetic counselling Affected individuals have a 50% risk of transmitting the disorder to their offspring. The request for prenatal diagnosis of HME is not common. HME does not affect intellect or life span. In particular cases, after careful discussion between parents and physician, pregnancy termination could be considered. ENCHONDROMATOSIS OR OLLIER DISEASE Clinical description Enchondromas are common benign cartilage tumours of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis, often with unilateral predominance. There is a form characterized by enchondromas located mainly at the extremities (hand). Palpable bony masses develop that may cause angular deformity and asymmetrical growth (Figure 4). The masses increase in size as the child grows, along with asymmetrical shortening of a limb. Affected bones are often shortened and deformed. Indeed, bone shortening may be the only clinical sign of the disease. These bone shortenings are often associated with bone bending and curving, and may lead to limitations in joint motility. Enchondromas frequently affect the long tubular bones, particularly the tibia, femur, phalanges, ilium and flat bones.25 The association of multiple enchondromas with haemangiomas, the proliferation of blood vessels, is referred to as ‘Maffucci syndrome’.26 Enchondromas are located in the epiphysis, the adjacent parts of the metaphysis and the bone shaft (Figure 3). Deformities resulting from the tumours include shortening caused by lack of epiphyseal growth, broadening of the metaphyses, and bowing of the long bones. They are initially localized close to the growth plate cartilage and then migrate progressively towards the diaphysis. The epiphyseal region next to an affected metaphysis may show irregularities.27 Enchondromas result in severe growth abnormalities (more severe than those observed in multiple exostoses). Affected diaphyses are short and massively enlarged, and these may show bending close to the metaphysis. In childhood, the lesions are subjected to pathological fractures. Enchondromas in Ollier disease present a risk of malignant transformation into chondrosarcomas. The reported incidence of malignant transformation of enchondromas in Ollier disease ranges from 20% to 50%.28 Central chondrosarcoma, located centrally in the medullary cavity, may lead to sarcomatous change in an underlying enchondroma. Malignant degeneration is greater in Maffucci syndrome, the prognosis of which is more severe than that of Ollier disease.

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Aetiology of enchondromatosis Enchondromatosis is usually a non-hereditary disorder that appears spontaneously. The exact cause of Ollier disease is not known, although it may be inherited as an autosomal-dominant genetic trait. Three genetic studies have reported on enchondromatosis. Cytogenetic analyses showed deletion or loss of heterozygosity in chondrosarcomas28,29, and Hopyan et al described an identical heterozygous mutation (R150C) in the parathyroid hormone receptor 1 (PTHR1) gene which was found in two unrelated patients with Ollier disease.30 However, an extensive study of enchondromas and chondrosarcomas from 31 enchondromatosis patients from different countries found no abnormality of PTHR1 protein expression and no instance of the R150C mutation or other causative mutation in the PTHR1 gene.31 In most cases of enchondromatosis, PTHR1 does not seem to be causative for the disease. Differential diagnosis The differential diagnosis may include HME. The most important criterion to distinguish enchondromas from osteochondromas is the localization of bone lesions; osteochondromas are located at the bone surface, and enchondromas are located in the centre of bones. Management including treatment In the absence of clinical problems, Ollier disease requires no treatment. Surgery is indicated in the case of complications, such as pathological fractures, growth defect and malignant transformation. For example, distortion of knees and unequal leg length may require serial surgery. In children and adults, annual surveillance of the enchondromas is recommended. A periodic surveillance of the brain and abdomen for occult lesions is indicated in patients who have enchondromatosis. Genetic counselling Ollier disease is usually a non-familial disorder. Practice points  HME diagnosis is based on clinical and/or radiographic findings of multiple exostoses in one or more members of a family  in children and adults, annual surveillance of the axial sites of the osteochondromas is recommended  in adults, monitoring the size of the exostose and pain is important, due to the risk of malignant transformation (5%)  enchondromatosis diagnosis is based on clinical and/or radiographic findings of cartilaginous tumours in patient  in children and adults, annual surveillance of enchondromas is recommended  in adults, signs of malignant transformation should be investigated carefully (20–50%)

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Research agenda  identification of the third EXT gene in some families without EXT1 or EXT2 mutations  understanding the development of bony outgrowths: the process causing the premature differentiation of chondrocytes leads to the formation of exostoses  EXT-null mouse models to study the relationship of the disease to mutations in EXT1 and EXT2 genes32

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