Manifestations of Hereditary Multiple Exostoses Jonathan R. Stieber, MD, and John P. Dormans, MD Abstract The solitary osteochondroma, a common pediatric bone tumor, is a cartilage-capped to 2 individuals per 100,000.6,9-11 Ap- exostosis. Hereditary multiple exostosis is an autosomal dominant disorder man- preciably higher prevalences of be- ifested by the presence of multiple osteochondromas. Linkage analysis has implicated tween 100 and 1,310 per 100,000 have mutations in the EXT gene family, resulting in an error in the regulation of normal been identified in isolated populations, chondrocyte proliferation and maturation that leads to abnormal bone growth. Al- such as the Chamorros (Guam) and though exostoses are benign lesions, they are often associated with characteristic pro- the Ojibway Indian community of gressive skeletal deformities and may cause clinical symptoms. The most common Pauingassi (Manitoba, Canada), re- deformities include short stature, limb-length discrepancies, valgus deformities of spectively.1,12 the knee and ankle, asymmetry of the pectoral and pelvic girdles, bowing of the ra- dius with ulnar deviation of the wrist, and subluxation of the radiocapitellar joint. For certain deformities, surgery can prevent progression and provide correction. Pa- Pathophysiology tients with hereditary multiple exostosis have a slight risk of sarcomatous trans- formation of the cartilaginous portion of the exostosis. HME is an inherited autosomal dom- J Am Acad Orthop Surg 2005;13:110-120 inant disorder with usually full pen- etrance.13 Although early studies of HME populations indicated higher prevalence among males, more re- Osteochondromas are common bone HME and helping to differentiate the cent studies of nuclear families dem- tumors seen in children and adoles- disorder from Ollier’s disease (mul- onstrate no evidence of gender pre- cents. These tumors consist of carti- tiple enchondromatosis). dominance.14,15 Linkage analysis has lage-capped exostoses found prima- The term “multiple exostoses” was identified two genes most strongly as- rily at the metaphyses of the most given to the condition by Virchow in rapidly growing ends of long bones.1,2 1876.6 Numerous synonyms have been Most patients have only a solitary le- used for this disorder, including os- sion, but others may have hereditary teochondromatosis, multiple hered- Dr. Stieber is Resident Physician, Department of multiple exostoses (HME), an auto- itary osteochondromata, multiple con- Orthopaedic Surgery, Monmouth Medical Cen- somal dominant disorder manifested genital osteochondromata, diaphyseal ter, Long Branch, NJ. Dr. Dormans is Chief, De- by multiple lesions that are more fre- aclasis, chondral osteogenic dyspla- partment of Orthopaedic Surgery, The Children’s quently associated with characteris- sia of direction, chondral osteoma, de- Hospital of Philadelphia, and Professor, Depart- ment of Orthopaedic Surgery, University of Penn- tic skeletal deformities. forming chondrodysplasia, dyschon- sylvania School of Medicine, Philadelphia, PA. The first description of a patient droplasia, exostosing disease, exostotic with multiple exostoses is attributed dysplasia, hereditary deforming chon- None of the following authors or the departments to Hunter in his 1786 Lectures on the drodysplasia, multiple osteomatoses, with which they are affiliated has received anything Principles of Surgery.3 In 1814, Boyer and osteogenic disease.6 of value from or owns stock in a commercial com- pany or institution related directly or indirectly published the first description of a to the subject of this article: Dr. Stieber and Dr. family with HME, followed by Guy’s Dormans. description of a second family in Epidemiology 1825.4-7 By the late 1800s, most of the Reprint requests: Dr. Dormans, The Children’s clinical aspects of the disease had The true prevalence of HME is un- Hospital of Philadelphia, 2nd Floor Wood Build- ing, 34th Street and Civic Center Boulevard, Phil- 5 been described. Ehrenfried intro- known because patients with mild adelphia, PA 19104-4399. duced HME into the American liter- multiple asymptomatic lesions may ature in 1915,5 and, in 1943, Jaffe8 not be diagnosed. The estimated prev- Copyright 2005 by the American Academy of made a significant contribution by alence of HME in Caucasians, the most Orthopaedic Surgeons. further elucidating the pathology of thoroughly studied population, is 0.9 110 Journal of the American Academy of Orthopaedic Surgeons Jonathan R. Stieber, MD, and John P. Dormans, MD sociated with HME: EXT1 on 8q24.1 a second signaling molecule, parathy- 1). Thus, HME may be explained by and EXT2 on 11p13.16 Mutations in roid hormone–related peptide (PTHrP). a defect in HSPG biosynthesis that EXT1 and EXT2 account for approx- PTHrP then binds to proliferating and causes a local error in the normal neg- imately one half and one third of HME prehypertrophic chondrocytes and ative feedback loop regulating chon- cases, respectively.6,7,9,11,17 Multiple ex- postpones cell differentiation and apo- drocyte proliferation and maturation ostoses also are a distinguishing fea- ptosis. This negative feedback loop fa- that, consequently, results in prema- ture of Langer-Giedion syndrome vors normal longitudinal cartilage ture differentiation and abnormal bone (trichorhinophalangeal syndrome type growth and persists until decreased growth at the growth plate.19,20 II), which is caused by a deletion of expression of Ihh or PTHrP disrupts HSPGs produced by EXT proteins both EXT1 and the adjacent TRPS1 the equilibrium, leading to chondro- also have been implicated as corecep- gene. cyte apoptosis and resulting ossifica- tors for fibroblast growth factor EXT1 is ubiquitously expressed in tion. EXT proteins are thought to syn- (FGF), which regulates endochondral many different tissues throughout the thesize HSPGs, which are necessary bone development. Abnormalities in body, but the effects of EXT1 muta- for the normal diffusion and/or sig- FGF signaling are responsible for a tions seem to be limited to growing naling by Ihh in the growth plate (Fig. number of skeletal dysplasias, includ- bone.6 The localized foci of osteochon- dromas in a heterozygous individual are thought to be caused by either sporadic loss of heterozygosity be- cause of inactivation of the remain- ing normal allele of EXT1 or EXT2, or by a second corresponding muta- tion outside the EXT1 and EXT2 lo- ci.18 EXT1 and EXT2 previously were thought to act as tumor-suppressor genes coding for proteins that inhibit abnormal cell transformation. Recent evidence suggests, however, that they instead regulate chondrocyte matu- ration and differentiation necessary for normal endochondral ossification within the growth plate. The mole- cules encoded by EXT1 and EXT2 are endoplasmic reticulum–resident type II transmembrane glycoproteins.19 These glycoproteins are involved in the regulation of cell-surface heparan sulfate proteoglycans (HSPGs) that, in turn, are integral to the diffusion of several families of cell-signaling molecules.19 According to recent models, a com- plex paracrine feedback loop exists within the growth plate in which lo- cal molecular signaling controls the Figure 1 The growth plate during endochondral bone formation. Prehypertrophic chon- rate of chondrocyte proliferation and drocytes (pre) localized within the growth plate produce Indian hedgehog (Ihh), a cell-signaling differentiation.19 Normal prehyper- molecule, which diffuses to the receiving cells via heparan sulfate proteoglycans that are gly- cosylated by EXT1 and EXT2. Ihh binding induces chondrocyte proliferation by upregulat- trophic chondrocytes in the growth ing a second signaling molecule, parathyroid hormone–related peptide (PTHrP). PTHrP binds plate produce Indian hedgehog (Ihh), to the parathyroid/PTHrP receptor on a subpopulation of proliferating (pro) and prehyper- a signaling molecule that stimulates trophic chondrocytes, thereby inducing production of an antiapoptotic protein. In the ab- sence of negative feedback, chondrocytes differentiate into hypertrophic chondrocytes (hyp), chondrocyte proliferation upon bind- which undergo apoptosis (apop) before being replaced by bone-forming osteoblasts. (Repro- ing to osteogenic cells in the metaphy- duced with permission from Duncan G, McCormick C, Tufaro F: The link between heparan seal perichondrium. Ihh binding by sulfate and hereditary bone disease: Finding a function for the EXT family of putative tumor suppressor proteins. J Clin Invest 2001;108:511-516.) these cells signals the upregulation of Vol 13, No 2, March/April 2005 111 Manifestations of Hereditary Multiple Exostoses ing achondroplasia, hypochondropla- sia, and thanatophoric dysplasia. Mutations in EXT1 and EXT2 may impair HSPG synthesis, leading to di- minished FGF signaling and abnor- mal chondrocyte proliferation at sites of exostosis formation.16 More re- search is required to fully elucidate the mechanism behind exostosis for- mation in HME. Clinical Presentation Patients with HME have multiple cartilage-capped exostoses that may be sessile or pedunculated (Fig. 2). Sessile exostoses are broad-based and characterized by a diameter that is greatest at the base contiguous with the cortex, whereas pedunculated le- sions are marked by a diameter that increases following a tapered stalk. Al- though usually located at the most rap- Figure 2 A, Anteroposterior radiograph of a pedunculated osteochondroma. B, Anteropos- terior radiograph of a sessile osteochondroma. idly growing ends of long bones,