manifestations of hereditary multiple exostoses · manifestations of hereditary multiple exostoses...

Manifestations of Hereditary Multiple Exostoses

Jonathan R. Stieber, MD, and John P. Dormans, MD

Abstract

Osteochondromas are common bonetumors seen in children and adoles-cents. These tumors consist of carti-lage-capped exostoses found prima-rily at the metaphyses of the mostrapidly growing ends of long bones.1,2

Most patients have only a solitary le-sion, but others may have hereditarymultiple exostoses (HME), an auto-somal dominant disorder manifestedby multiple lesions that are more fre-quently associated with characteris-tic skeletal deformities.

The first description of a patientwith multiple exostoses is attributedto Hunter in his 1786 Lectures on thePrinciples of Surgery.3 In 1814, Boyerpublished the first description of afamily with HME, followed by Guy’sdescription of a second family in1825.4-7 By the late 1800s, most of theclinical aspects of the disease hadbeen described.5 Ehrenfried intro-duced HME into the American liter-ature in 1915,5 and, in 1943, Jaffe8

made a significant contribution byfurther elucidating the pathology of

HME and helping to differentiate thedisorder from Ollier’s disease (mul-tiple enchondromatosis).

The term “multiple exostoses” wasgiven to the condition by Virchow in1876.6 Numerous synonyms have beenused for this disorder, including os-teochondromatosis, multiple hered-itary osteochondromata, multiple con-genital osteochondromata, diaphysealaclasis, chondral osteogenic dyspla-sia of direction, chondral osteoma, de-forming chondrodysplasia, dyschon-droplasia, exostosing disease, exostoticdysplasia, hereditary deforming chon-drodysplasia, multiple osteomatoses,and osteogenic disease.6

Epidemiology

The true prevalence of HME is un-known because patients with mildmultiple asymptomatic lesions maynot be diagnosed. The estimated prev-alence of HME in Caucasians, the mostthoroughly studied population, is 0.9

to 2 individuals per 100,000.6,9-11 Ap-preciably higher prevalences of be-tween 100 and 1,310 per 100,000 havebeen identified in isolated populations,such as the Chamorros (Guam) andthe Ojibway Indian community ofPauingassi (Manitoba, Canada), re-spectively.1,12

Pathophysiology

HME is an inherited autosomal dom-inant disorder with usually full pen-etrance.13 Although early studies ofHME populations indicated higherprevalence among males, more re-cent studies of nuclear families dem-onstrate no evidence of gender pre-dominance.14,15 Linkage analysis hasidentified two genes most strongly as-

Dr. Stieber is Resident Physician, Department ofOrthopaedic Surgery, Monmouth Medical Cen-ter, Long Branch, NJ. Dr. Dormans is Chief, De-partment of Orthopaedic Surgery, The Children’sHospital of Philadelphia, and Professor, Depart-ment of Orthopaedic Surgery, University of Penn-sylvania School of Medicine, Philadelphia, PA.

None of the following authors or the departmentswith which they are affiliated has received anythingof value from or owns stock in a commercial com-pany or institution related directly or indirectlyto the subject of this article: Dr. Stieber and Dr.Dormans.

Reprint requests: Dr. Dormans, The Children’sHospital of Philadelphia, 2nd Floor Wood Build-ing, 34th Street and Civic Center Boulevard, Phil-adelphia, PA 19104-4399.

Copyright 2005 by the American Academy ofOrthopaedic Surgeons.

The solitary osteochondroma, a common pediatric bone tumor, is a cartilage-cappedexostosis. Hereditary multiple exostosis is an autosomal dominant disorder man-ifested by the presence of multiple osteochondromas. Linkage analysis has implicatedmutations in the EXT gene family, resulting in an error in the regulation of normalchondrocyte proliferation and maturation that leads to abnormal bone growth. Al-though exostoses are benign lesions, they are often associated with characteristic pro-gressive skeletal deformities and may cause clinical symptoms. The most commondeformities include short stature, limb-length discrepancies, valgus deformities ofthe 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-tients with hereditary multiple exostosis have a slight risk of sarcomatous trans-formation of the cartilaginous portion of the exostosis.

J Am Acad Orthop Surg 2005;13:110-120

110 Journal of the American Academy of Orthopaedic Surgeons

sociated with HME: EXT1 on 8q24.1and EXT2 on 11p13.16 Mutations inEXT1 and EXT2 account for approx-imately one half and one third of HMEcases, respectively.6,7,9,11,17 Multiple ex-ostoses also are a distinguishing fea-ture of Langer-Giedion syndrome(trichorhinophalangeal syndrome typeII), which is caused by a deletion ofboth EXT1 and the adjacent TRPS1gene.

EXT1 is ubiquitously expressed inmany different tissues throughout thebody, but the effects of EXT1 muta-tions seem to be limited to growingbone.6 The localized foci of osteochon-dromas in a heterozygous individualare thought to be caused by eithersporadic 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 werethought to act as tumor-suppressorgenes coding for proteins that inhibitabnormal cell transformation. Recentevidence suggests, however, that theyinstead regulate chondrocyte matu-ration and differentiation necessaryfor normal endochondral ossificationwithin the growth plate. The mole-cules encoded by EXT1 and EXT2 areendoplasmic reticulum–resident typeII transmembrane glycoproteins.19

These glycoproteins are involved inthe regulation of cell-surface heparansulfate proteoglycans (HSPGs) that,in turn, are integral to the diffusionof several families of cell-signalingmolecules.19

According to recent models, a com-plex paracrine feedback loop existswithin the growth plate in which lo-cal molecular signaling controls therate of chondrocyte proliferation anddifferentiation.19 Normal prehyper-trophic chondrocytes in the growthplate produce Indian hedgehog (Ihh),a signaling molecule that stimulateschondrocyte proliferation upon bind-ing to osteogenic cells in the metaphy-seal perichondrium. Ihh binding bythese cells signals the upregulation of

a second signaling molecule, parathy-roidhormone–relatedpeptide (PTHrP).PTHrP then binds to proliferating andprehypertrophic chondrocytes andpostpones cell differentiation and apo-ptosis. This negative feedback loop fa-vors normal longitudinal cartilagegrowth and persists until decreasedexpression of Ihh or PTHrP disruptsthe equilibrium, leading to chondro-cyte apoptosis and resulting ossifica-tion. EXT proteins are thought to syn-thesize HSPGs, which are necessaryfor the normal diffusion and/or sig-naling by Ihh in the growth plate (Fig.

1). Thus, HME may be explained bya defect in HSPG biosynthesis thatcauses a local error in the normal neg-ative feedback loop regulating chon-drocyte proliferation and maturationthat, consequently, results in prema-ture differentiation and abnormal bonegrowth at the growth plate.19,20

HSPGs produced by EXT proteinsalso have been implicated as corecep-tors for fibroblast growth factor(FGF), which regulates endochondralbone development. Abnormalities inFGF signaling are responsible for anumber of skeletal dysplasias, includ-

Figure 1 The growth plate during endochondral bone formation. Prehypertrophic chon-drocytes (pre) localized within the growth plate produce Indian hedgehog (Ihh), a cell-signalingmolecule, 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-ing a second signaling molecule, parathyroid hormone–related peptide (PTHrP). PTHrP bindsto the parathyroid/PTHrP receptor on a subpopulation of proliferating (pro) and prehyper-trophic chondrocytes, thereby inducing production of an antiapoptotic protein. In the ab-sence of negative feedback, chondrocytes differentiate into hypertrophic chondrocytes (hyp),which undergo apoptosis (apop) before being replaced by bone-forming osteoblasts. (Repro-duced with permission from Duncan G, McCormick C, Tufaro F: The link between heparansulfate and hereditary bone disease: Finding a function for the EXT family of putative tumorsuppressor proteins. J Clin Invest 2001;108:511-516.)


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ing achondroplasia, hypochondropla-sia, and thanatophoric dysplasia.Mutations in EXT1 and EXT2 mayimpair HSPG synthesis, leading to di-minished FGF signaling and abnor-mal chondrocyte proliferation at sitesof exostosis formation.16 More re-search is required to fully elucidatethe mechanism behind exostosis for-mation in HME.

Clinical Presentation

Patients with HME have multiplecartilage-capped exostoses that maybe sessile or pedunculated (Fig. 2).Sessile exostoses are broad-based andcharacterized by a diameter that isgreatest at the base contiguous withthe cortex, whereas pedunculated le-sions are marked by a diameter thatincreases following a tapered stalk.Al-though usually located at the most rap-idly growing ends of long bones, thelesions also are frequently found inthe vertebral borders of the scapulae,ribs, and iliac crests. Osteochondro-mas have been observed in the tarsaland carpal bones; however, they areseldom apparent clinically. There isonly one reported case of an exosto-sis of the skull and no reported casesof a lesion arising from the facialbones,6,8 likely as a result of intramem-branous ossification at these locations.

Exostoses are initially diagnosed inthe first decade of life in more than80% of individuals with HME.21 Theyare commonly first discovered on thetibia or scapula because those are of-ten the most conspicuous locations.HME occasionally is diagnosed atbirth, but such an early diagnosis isusually the result of a specific searchin the presence of a positive familyhistory. The size and number of le-sions vary considerably between af-fected individuals, and patients withsmaller and fewer lesions may neverbecome symptomatic. The lesionstend to enlarge while the physes areopen at a growth rate proportionateto the overall growth of the patient;

cessation of growth usually occurs atskeletal maturity. Lesions have beeninfrequently reported to spontane-ously regress during the course ofchildhood and puberty. Recurrence ofan exostosis after surgical excision, al-though rare, may be attributed to in-complete removal of lesions contig-uous with the physis in growingchildren or to incomplete removal ofthe cartilaginous cap.6,22

Clinical Manifestations

Although exostoses are histological-ly benign lesions, they can cause a va-riety of clinical problems. Patientswith HME most frequently reportpain and cosmetic concerns. Pain maybe the result of a variety of problemsassociated with the exostoses, such asa bursa formation or repeated soft-tissue trauma over a prominent os-teochondroma. In pedunculated os-teochondromas, fracture at the basemay occur after local trauma. Final-

ly, pain associated with snapping orpopping may occur when a largemuscle repeatedly moves over the topof an exostosis (eg, quadriceps overa distal femoral exostosis during run-ning). Restricted range of motion(ROM) is a common report of indi-viduals with severe involvement ofthe proximal femur or forearm.

Associated soft-tissue problems in-clude impingement, entrapment, orinjury of tendons, nerves, or vessels.Spinal involvement has been docu-mented in 7% of affected patients; spi-nal cord compression is a rare butwell-documented complication ofHME.23 Both urinary and intestinalobstruction, although uncommon,have been reported as complicationsof the presence of osteochondroma.Dysphagia secondary to a ventral cer-vical exostosis and spontaneous he-mothorax as a result of rib exostoseshas been described.24,25 Exostoses alsohave been noted to interfere with nor-mal birth, leading to a higher rate ofcesarean sections.9

Figure 2 A, Anteroposterior radiograph of a pedunculated osteochondroma. B, Anteropos-terior radiograph of a sessile osteochondroma.



The most common deformities as-sociated with HME include short stat-ure, limb-length discrepancies, valgusdeformities of the knee and ankle, andasymmetry of either the pectoral orpelvic girdles. Osteochondromas in theforearm can result in shortening ofthe ulna with resultant bowing of theradius with ulnar deviation of thewrist, subluxation of the carpus onthe distal radius, and subluxation ordislocation of the radial head9,11,15

(Fig. 3). Less commonly, relative short-ening and angular deformities ofthe metatarsals, metacarpals, and pha-langes, as well as scoliosis, coxa valga,and acetabular dysplasia, have beendescribed.14,15,26,27

Patients with HME are frequentlyof short stature, with most heights 0.5to 1.0 SD below the mean.3,15 Affect-ed men and women have heights be-low the fifth percentile in 36.8% and44.2% of cases, respectively.9 Sittingheight is generally less affected thantotal height, indicating more exten-sive involvement of the limbs than ofthe axial skeleton.15

Upper ExtremityInvolvement

ForearmOsteochondromas of the upper ex-

tremities commonly cause forearmdeformities. The prevalence of suchdeformities is as high as 40% to74%.7,8,11,15,28 Disproportionate ulnarshortening has been frequently de-scribed and may be associated withradial bowing. Subluxation or dislo-cation of the radial head has been re-ported in 22% to 33% of patients withHME.15,28 Dislocation of the radialhead is associated with loss of prona-tion, enhanced ulnar variance, andfunctional impairment.29 Disruptionof the distal radioulnar joint, ulnar de-viation, and ulnar translocation of thecarpal bones are often associated withHME. This complex of deformitiesseems to be similar to Madelung’s de-formity, but it does not manifest in the

characteristic relative elongation ordorsal subluxation of the distal ulnaseen in Madelung’s deformity.15

Jaffe8 and Porter et al17 suggestedthat the length of forearm bones cor-relates inversely with the size of theexostoses. Moreover, lesions withsessile rather than pedunculated mor-phology have been associated withmore notable shortening and defor-mity.5 Thus, the skeletal growth dis-turbance observed in HME is a localeffect; the growth of the osteochon-droma overwhelms and retards thegrowth of any closely associated phy-sis, resulting in a tethering effect onpaired structures. Larger lesions withgreater cortical involvement tend toinfluence bone growth more substan-tially than do smaller lesions.

The disproportionate shortening ofthe ulna can be generally attributedto two causes. First, because the dis-tal ulnar physis is responsible forgreater longitudinal growth relativeto that of the distal radius (85% ver-

sus 75%, respectively), equal involve-ment results in more substantial ul-nar shortening. Second, bones witha smaller cross-sectional diameter tendto be shortened more considerablywhen affected by HME; this can beattributed to greater proportionate in-volvement of the physis. As a result,equal involvement of the two bonespreferentially affects the ulna, whichhas a diameter of only one fourth thatof the radius. Consequently, radialbowing was thought to be caused bya tethering effect of relative ulnarshortening.3 Burgess and Cates,4 how-ever, found that radial bowing wasnot correlated with measured ulnarshortening in their series of 35 patients.They reported a strong correlation be-tween ulnar shortening in excess of8% and dislocation of the radial head.

The extent of forearm involvementin patients with HME is strongly as-sociated with the general severity ofthe disease. Taniguchi30 classified hispatients into three groups: (1) those

Figure 3 Anteroposterior (A) and lateral (B) radiographs of the right forearm of a 15-year-old boy with hereditary multiple exostoses demonstrating multiple exostoses, ulnar short-ening, and ulnar carpal drift. Anteroposterior (C) and lateral (D) radiographs demonstratingsimilar deformities in the left forearm of the same boy. (Reproduced with permission fromPierz KA, Stieber JR, Kusumi K, Dormans JP: Hereditary multiple exostoses: One center’sexperience and review of etiology. Clin Orthop 2002;401:49-59.)



with no involvement of the distalforearm, (2) those with involvementof the distal radius or ulna withoutshortening of either bone, and (3)those with involvement of the distalradius or ulna with shortening of ei-ther bone. He reported that increas-ing forearm involvement was associ-ated with an earlier age of diagnosisof HME, a greater number of gener-alized exostoses as well as of exos-toses affecting the knee, shorter stat-ure, and increased valgus deformityof the ankle. All of the patients withdislocation of the radial head werecategorized in group 3, with shorten-ing of either bone in addition to dis-tal exostoses.

Many of the deformities of the fore-arm are amenable to surgical treat-ment. Knowledge of the natural his-tory of the disease and timelyintervention are the keys to prevent-ing deformity in patients with HME.Although early aggressive surgery isoften recommended, it is also contro-versial.4,7,31 Specific indications for sur-gery include painful lesions, an in-creasing radial articular angle,progressive ulnar shortening, exces-sive carpal slip, loss of pronation, andincreased radial bowing with sublux-ation or dislocation of the radial head.31

Masada et al32 classified forearmdeformities into three types accord-ing to the morphology of the defor-mity (Fig. 4). In type I, the distal ulnahas the greatest exostosis formation.The ulna is shortened with bowingof the radius, but the radial head isnot affected, and the proximal part ofthe radius is not dislocated. Taperingof the ulnar head and ulnar tilt of thedistal radius are both present. Thisdeformity is the most common andis observed in 55% (31/56) to 61%(22/36) of forearms.28,32 In type II, theradial head is dislocated and the ulnais shortened. Bowing of the radius isless severe than in the type I defor-mity, secondary to dislocation of theradial head. In type IIa, the radialhead is dislocated as a result of ex-ostosis formation at the proximal

metaphysis of the radius. In type IIb,radial head dislocation occurs in theabsence of a proximal radial exosto-sis. In type III, the primary exostosisformation is in the metaphysis of thedistal radius, with relative shorteningof the radius compared with the ul-na.32 Based on successful outcomes ina limited number of patients with atype I deformity, Masada et al32 rec-ommended exostosis excision, radialosteotomy, and immediate ulnarlengthening.

In a study of 18 patients who un-derwent surgery for correction offorearm deformities, Fogel et al31 re-ported that, although early osteo-chondroma excision alone can de-crease or halt the progression offorearm deformity, it does not consis-tently provide full correction. Ulnartranslocation of the carpal bones onthe distal radius can be corrected byulnar lengthening, but persistentrelative ulnar shortening is likely torecur. For patients with increased

Figure 4 Masada classification of forearm deformities in hereditary multiple exostoses. TypeI: Primary exostosis formation is in the distal portion of the ulna, which is relatively shortcompared with the radius. Type IIa: In addition to ulnar shortening, the radial head is dis-located secondary to an exostosis at the proximal metaphysis of the radius. Type IIb: Theradial head is dislocated without a proximal radial exostosis. Type III: Primary exostosis for-mation is in the metaphysis of the distal radius, leading to relative shortening of the radiuscompared with the ulna. (Adapted with permission from Masada K, Tsuyuguchi Y, KawaiH, Kawabata H, Noguchi K, Ono K: Operations for forearm deformity caused by multipleosteochondromas. J Bone Joint Surg Br 1989;71:24-29.)



radiocarpal angulation or carpal sub-luxation, osteochondroma excision inconjunction with distal radial osteot-omy or hemiepiphyseal stapling re-sulted in improved function and cos-mesis. The seven forearms thatreceived all three procedures showedimprovement in the degree of ulnardeviation. The mean improvement inthe radial articular angle was 20°. Themean range of forearm rotation in thesix forearms with available measure-ments improved from 78° preopera-tively to 118° at a minimum 2-yearfollow-up.31

Pritchett33 performed ulnar length-ening in 10 forearms, resulting in im-proved cosmetic appearance, ROM,and stability of the radial head. Wa-ters et al34 performed acute ulnarlengthening in 17 patients with HME.They used a long Z-cut osteotomy and

a temporary intraoperative externalfixator with long plate fixation (Fig.5). Eleven patients additionally under-went distal radial osteotomy andachieved stable reduction of abnor-mal radial inclination. Of the surgi-cally treated patients, 85% experiencedimprovement of pronation/supination(average increase, 39°). Forty percenthad improved radial/ulnar deviation(average increase, 15°). Sixty percenthad unchanged radial/ulnar devia-tion, but postoperatively their arc ofmotion improved to a more neutralalignment (average of both radial andulnar deviation, 22°).

Complete dislocation of the radialhead can be a serious sequela of fore-arm deformity and can result in pain,instability, and decreased motion atthe elbow. Early surgical interventionshould be considered. Historically, for

this type II deformity in skeletally ma-ture patients, excision of the radialhead was recommended in additionto excision of exostosis, radial osteot-omy, and immediate ulnar lengthen-ing.32 Attempts at surgical relocationof the radial head have not consistent-ly proved to be successful.7 Radialhead position can be gradually cor-rected with an Ilizarov fixator tolengthen the ulna and to apply trac-tion on the radius, either directlythrough the interosseous membraneor indirectly through the carpus bydistal ulnar fixation or a radioulnartransfixion wire.35 Patients may be leftwith a painful, stiff, or weak upperextremity despite surgical treatment.

Controversy exists concerning thenecessity of early surgery and wheth-er the outcomes are superior to thoseof untreated patients. Stanton and

Figure 5 A, Indications for closing-wedge radial osteotomy to decrease radial inclination and ulnar lengthening for correction of lengthdiscrepancy. The radial osteotomy is performed first. B, The ulna is exposed, and the external fixator and the distal end of the plate areapplied. A long Z-cut osteotomy is performed. C, The ulna is slowly lengthened until near-neutral ulnar variance is achieved. D, The plateis fixed, the external fixator is removed, and the bone graft is placed. (Adapted with permission from Waters PM, Van Heest AE, Emans J:Acute forearm lengthenings. J Pediatr Orthop 1997;17:444-449.)



Hansen29 contend that deformities ofthe upper extremity in patients withHME are well tolerated and result inminimal functional loss when mea-sured both subjectively and objective-ly. Similarly, Arms et al36 conducteda telephone survey of 37 skeletallymature patients, who reported satis-faction with both function and cos-mesis despite the presence of defor-mity. Noonan et al28 reported thatuntreated patients tended to adaptwell to their differences; only 13% re-ported appreciable pain or limitationrelated to job performance. In thatstudy, however, 40 of 77 upper ex-tremities were more than 2 SD belowthe mean in at least one area of func-tional assessment, including gripstrength, pinch strength, ROM, andhand function. Additionally, Stantonand Hansen29 reported a prevalenceof early degenerative joint disease in3 of 56 involved upper extremities intheir cohort (average age, 21 years).Wood et al7 noted that surgeries of thedistal forearm may result in onlymodest functional improvement butmarked cosmetic benefit.

HandHand involvement has been re-

ported in 30%11 to 79%21 of patients.Fogel et al31 observed metacarpal andphalangeal involvement in approxi-mately 70% of their patients. In theirseries of 63 patients, Cates and Bur-gess26 reported that patients with HMEfall into two groups: those with no handinvolvement and those with substan-tial hand involvement, averaging 11.6lesions per hand. The ulnar meta-carpals and proximal phalanges weremost commonly involved, with thethumb and distal phalanges affectedless frequently. Although exostoses ofthe hand resulted in shortening of themetacarpals and phalanges, brachy-dactyly also was observed in the ab-sence of exostoses. Only 4 of 22 pa-tients with hand involvement requiredsurgery.26 In most reports, the major-ity of patients are asymptomatic.15,26

Cates and Burgess26 observed no an-

gular deformities of the digits, but thesehave been reported. Pseudomallet fin-ger secondary to the presence of anexostosis located on the distal secondphalanx has been reported, with suc-cessful treatment after resection.37

Lower ExtremityInvolvement

Limb-length discrepancy is common-ly seen in patients with HME. A clin-ically notable inequality ≥2 cm hasbeen reported in 10% to 50% of affect-ed individuals.11,15,38 Shortening canoccur in the femur and the tibia. Thefemur is affected approximately twiceas commonly as the tibia.15 Surgicaltreatment with appropriately timedepiphysiodesis has been satisfactori-ly performed in growing patients.

FemurIn addition to limb-length discrep-

ancies, several lower extremity defor-mities have been documented. Le-sions of the proximal femur havebeen reported in as few as 30% insome series to as many as 90% in oth-er studies of patients with HME, withcoxa valga present in up to 25% of in-dividuals with the disorder.11,15,21 Por-ter et al39 correlated increasing osteo-chondroma load with an increasingfemoral neck-shaft angle. Femoral an-teversion and valgus have been as-sociated with exostoses located inproximity to the lesser trochanter.40

There have been at least nine report-ed cases of acetabular dysplasia in pa-tients with HME.27,41 Acetabular dys-plasia, which is caused by exostoseslocated within or about the acetabu-lum or on the medial femoral neck,can lead to femoral lateralization. Thefemoral head itself does not appearto be affected. It is critically impor-tant to recognize this process earlyand to provide appropriate treatment.Coxa valga may require early varusosteotomy.41

The distal femur is variably in-volved in as little as 70% to as many

as 98% of affected individuals; theproximal tibia ranges from 70% to 98%involvement and the fibula, from 30%to 97% of cases.11,15,21,38 As a result, val-gus knee deformities are found in 8%to 33% of patients with HME.10,11,15,38

Patellar dislocation is another com-plication of valgus knee deformity inHME.10

KneeShapiro et al15 and Nawata et al10

suggested that valgus knee deformi-ty was primarily caused by proximaltibia changes. In fact, both the distalfemur and the proximal tibia tend tocontribute to the deformity.38 Nawa-ta et al10 found the fibula to be short-ened disproportionately comparedwith the tibia and contended that thedisparity was responsible for the con-sistent valgus direction of the defor-mity. In the series by Shapiro et al,15

7 of 20 patients with this valgus de-formity required corrective osteoto-my. In another series, 3 of 13 kneesrequired treatment, including femo-ral opening wedge osteotomy, prox-imal tibial hemiepiphysiodesis, andhigh tibial osteotomy38 (Fig. 6). In thesame series, 7 of 31 knees had oppos-ing angular deformities of the distalfemur and proximal tibia, which com-pensated to produce acceptable kneealignment. These changes were notclinically apparent on physical exam-ination because the normal mechan-ical axis was maintained by comple-mentary lateral distal femoral anglesand medial proximal tibial angles. Itis unclear whether patients with thisabnormality in knee geometry arepredisposed to degenerative joint dis-ease.38

AnkleExostoses about the ankle can af-

fect the growth of the extremity andmay cause pain, decreased ROM,weakness, and deformity. Valgus de-formity of the ankle is common in pa-tients with HME and is observed inapproximately half of affected pa-tients.3,14,15,38 The deformity can be at-



tributed to multiple factors, includ-ing shortening of the fibula relativeto the tibia. Resulting obliquity of thedistal tibial epiphysis and medial sub-luxation of the talus also can be as-sociated with this deformity. Partialcompensation may be provided by adevelopmental obliquity of the supe-rior talar articular surface.15 In one se-ries of 23 adolescents, exostoses of thedistal tibia were more commonlysymptomatic than those of the distalfibula.22 Lesions in the ankle most of-ten became symptomatic in the sec-ond decade of life. Noonan et al42

found signs of early osteoarthritis in14 of 75 ankles in their cohort of un-

treated adults (average age, 42 years).Seventy percent of patients with an-kle involvement reported impairmentsecondary to decreased ROM.

Patients with smaller, asympto-matic lesions of the distal tibia andfibula can be treated nonsurgicallyand followed with serial radiographsuntil skeletal maturity.22 Chin et al22

recommend excision of symptomat-ic lesions in skeletally mature patientsas well as in skeletally immature pa-tients who fail nonsurgical treatment.Patients with substantial remaininggrowth tend to experience progres-sive deformation; thus, partial orcomplete resection with preservation

of the epiphysis may be appropriate.An oblique osteotomy of the distalfibula permits optimal exposure ofthe tibial exostosis and allows morecomplete resection.22

In more advanced cases, excisionof exostoses alone does not correct theankle deformity, although it may im-prove preoperative symptoms andcosmesis.22,43 Medial hemiepiphysealstapling of the tibia in conjunctionwith excision of the exostoses per-formed with early ankle deformitycan correct a valgus angle ≥15° asso-ciated with limited shortening of thefibula.15,43 Fibular lengthening hasbeen used effectively for severe val-gus deformity with more significantfibular shortening (ie, when the dis-tal fibular physis is located proximalto the distal tibial physis).43 Supra-malleolar osteotomy of the tibia aswell as osteotomy and placement ofan Ilizarov device also have been usedeffectively to treat severe valgus an-kle deformity.15,43 In skeletally imma-ture patients, hemiepiphysiodesis orfixation with a transphyseal screwmay allow for correction38 (Fig. 7).Such a procedure is indicated whenthere is a symptomatic or progressivedeformity with sufficient remaininggrowth to allow for adequate correc-tion. Growth of exostoses also can re-sult in tibiofibular diastasis, whichcan be treated by early excision of thelesions.

Neurologic and VascularComplications

HME can cause both neurologic andvascular problems throughout the ex-tremities. Wicklund et al9 reported pe-ripheral nerve compression symptomsin 22.6% of the 180 patients in theirseries. Lesions arising from the me-dial aspect of the proximal humeralphysis are often symptomatic becauseseveral important neurovascular struc-tures may encounter compressionthere. Peroneal neuropathy associat-ed with exostoses of the proximal fib-

Figure 6 A, Standing anteroposterior radiograph of the lower extremity of a 16-year-oldgirl demonstrating multiple exostoses and a left femoral valgus deformity. B, Anteroposte-rior radiograph 6 months postoperatively of a left distal femur with the valgus deformitycorrected by an opening wedge femoral osteotomy. (Reproduced with permission from PierzKA, Stieber JR, Kusumi K, Dormans JP: Hereditary multiple exostoses: One center’s expe-rience and review of etiology. Clin Orthop 2002;401:49-59.)



ula in children is a recognized com-plication. Cardelia et al44 described the“heel walking extinction test” as be-ing helpful in diagnosing peronealnerve injury. In this test, the patientis asked to ambulate to fatigue on hisor her heels with both ankles in dor-siflexion to determine whether the in-volved side has a lower threshold forfatigue.

The prevalence of vascular com-pression secondary to exostoses hasbeen reported to be as high as 11.3%.9

In a series of 97 cases of vascular com-plications stemming from osteochon-dromas, 71 were from sporadic osteo-chondromas, and 26 were associatedwith HME.45 Pseudoaneurysm, vas-cular compression, arterial thrombo-sis, aneurysm, and venous thrombo-sis were the most commonly reportedcomplications. Claudication, acute is-chemia, and phlebitis were the mostcommonly associated clinical presen-tations. Eighty-three percent of vas-cular problems were located in thelower extremity, with the popliteal ar-tery most frequently involved.45

To address symptomatic neurovas-cular involvement, exostosis excisionshould be performed along with di-rect nerve or vessel decompression.Neurovascular structures are not nec-essarily stretched and pushed aside

by a lesion, but they may be either at-tenuated over the surface or intimate-ly wrapped around the base of an ex-ostosis. Knowledge of the relevantanatomy, adequate exposure, and thor-ough preoperative planning can fa-cilitate successful surgical treatment.

Malignant Transformation

Malignant transformation of a benignosteochondroma into a chondrosar-coma is another complication ofHME. Fortunately, many of the chon-drosarcomas in this setting are lowgrade and can be treated successful-ly with wide excision. Patients withsuch lesions usually present with anexpanding painful mass. Rarely,nerve compression is the presentingcomplaint. Ochsner46 reported on 59patients with HME who had malig-nant transformation. The mean age atdiagnosis of malignancy was 31years, with malignant degenerationseldom occurring in the first decadeor after the fifth decade of life. Thereported incidence of malignant de-generation is highly variable, rangingfrom 0.5% to 25%.40,47 This disparitycan be attributed not only to a pos-sible selection bias inherent for a ter-tiary referral center but also to the in-

ability to detect all HME patientswithout malignant degeneration,thus making it difficult to determinethe true denominator.5 More recentstudies indicate that the rate of sec-ondary malignancy is <5% per pa-tient.1,11,40,48 The risk of malignanttransformation may vary among fam-ilies, reflecting genetic heterogeneitypredisposing to malignant degener-ation.11 In their cohort of 217 individ-uals in 42 French families affectedwith HME, Francannet et al49 ob-served chondrosarcomas in 9 pa-tients, all of which were associatedwith EXT1 mutations.

Because of this risk, patients withHME should be followed carefully todetect early sarcomatous transforma-tion. Continuous growth of a lesionafter skeletal maturity should raisethe suspicion of malignancy, especial-ly when accompanied by pain. Ad-ditionally, in adults, the presence ofan osteochondroma with a cartilag-inous cap >2 cm has been associatedwith an increased chance of malig-nancy.2 Ultrasound is effective formeasuring cap thickness on superfi-cial lesions, but magnetic resonanceimaging may be better for evaluatingmore deeply located lesions. Ideally,skeletally mature patients should befollowed by an orthopaedic oncolo-gist. Appropriate patient education iscrucial for early identification of high-risk lesions.

Summary

HME is an autosomal dominant dis-order manifested by multiple lesionsthat are frequently associated withcharacteristic skeletal deformities.Linkage analysis has identified twogenes associated with HME: EXT1and EXT2. The molecules encoded byEXT1 and EXT2 are endoplasmicreticulum–resident type II transmem-brane glycoproteins that are integralto HSPG biosynthesis. Mutation ofthe EXT1 or EXT2 gene causes an er-ror in the regulation of normal chon-

Figure 7 A, Standing anteroposterior radiograph of the ankles of a 7-year-old girl demon-strating left ankle valgus. B, Standing anteroposterior radiograph taken 34 months after sur-gery. Treatment with a medial transphyseal screw allowed for continued lateral growth tocorrect the deformity. (Reproduced with permission from Pierz KA, Stieber JR, Kusumi K,Dormans JP: Hereditary multiple exostoses: One center’s experience and review of etiology.Clin Orthop 2002;401:49-59.)



drocyte proliferation and maturationthat results in abnormal bonegrowth.19,20 Although exostoses arebenign lesions, they often lead to clin-ical problems. The most common de-

formities seen in HME include shortstature, limb-length discrepancies,valgus deformities of the knee andankle, asymmetry of the pectoral andpelvic girdles, bowing of the radius

with ulnar deviation of the wrist, andsubluxation of the radial head.9,11,21

For certain characteristic deformities,surgical treatment can prevent pro-gression and provide correction.

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