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 radius 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 transformation 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 osteochondromas in a heterozygous individual are thought to be caused by either sporadic loss of heterozygosity because of inactivation of the remaining normal allele of EXT1 or EXT2, or by a second corresponding mutation 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 maturation and differentiation necessary for normal endochondral ossification within the growth plate. The molecules 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 complex paracrine feedback loop exists within the growth plate in which local 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 absence 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 abnormal chondrocyte proliferation at sites of exostosis formation.16 More re- search is required to fully elucidate the mechanism behind exostosis formation 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 lesions 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, the lesions also are frequently found in the vertebral borders of the scapulae, ribs, and iliac crests. Osteochondro- cessation of growth usually occurs at ly, pain associated with snapping or mas have been observed in the tarsal skeletal maturity. Lesions have been popping may occur when a large and carpal bones; however, they are infrequently reported to spontane- muscle repeatedly moves over the top seldom apparent clinically. There is ously regress during the course of of an exostosis (eg, quadriceps over only one reported case of an exosto- childhood and puberty.Recurrence of a distal femoral exostosis during run- sis of the skull and no reported cases an exostosis after surgical excision, al- ning). Restricted range of motion of a lesion arising from the facial though rare, may be attributed to in- (ROM) is a common report of indi- bones,6,8 likely as a result of intramem- complete removal of lesions contig- viduals with severe involvement of branous ossification at these locations. uous with the physis in growing the proximal femur or forearm. Exostoses are initially diagnosed in children or to incomplete removal of Associated soft-tissue problems in- the first decade of life in more than the cartilaginous cap.6,22 clude impingement, entrapment, or 80% of individuals with HME.21 They injury of tendons, nerves, or vessels. are commonly first discovered on the Spinal involvement has been docu- tibia or scapula because those are of- Clinical Manifestations mented in 7% of affected patients; spi- ten the most conspicuous locations. nal cord compression is a rare but HME occasionally is diagnosed at Although exostoses are histological- well-documented complication of birth, but such an early diagnosis is ly benign lesions, they can cause a va- HME.23 Both urinary and intestinal usually the result of a specific search riety of clinical problems. Patients obstruction, although uncommon, in the presence of a positive family with HME most frequently report have been reported as complications history. The size and number of le- pain and cosmetic concerns. Pain may of the presence of osteochondroma. sions vary considerably between af- be the result of a variety of problems Dysphagia secondary to a ventral cer- fected individuals, and patients with associated with the exostoses, such as vical exostosis and spontaneous he- smaller and fewer lesions may never a bursa formation or repeated soft- mothorax as a result of rib exostoses become symptomatic. The lesions tissue trauma over a prominent os- has been described.24,25 Exostoses also tend to enlarge while the physes are teochondroma. In pedunculated os- have been noted to interfere with nor- open at a growth rate proportionate teochondromas, fracture at the base mal birth, leading to a higher rate of to the overall growth of the patient; may occur after local trauma. Final- cesarean sections.9

112 Journal of the American Academy of Orthopaedic Surgeons Jonathan R. Stieber, MD, and John P. Dormans, MD

The most common deformities associated with HME include short stature, limb-length discrepancies, valgus deformities of the knee and ankle, and asymmetry of either the pectoral or pelvic girdles. Osteochondromas in the forearm can result in shortening of the ulna with resultant bowing of the radius with ulnar deviation of the wrist, subluxation of the carpus on the distal radius, and subluxation or dislocation of the radial head9,11,15 (Fig. 3). Less commonly, relative shortening and angular deformities of the metatarsals, metacarpals, and phalanges, as well as scoliosis, coxa valga, and acetabular dysplasia, have been described.14,15,26,27 Patients with HME are frequently of short stature, with most heights 0.5 to 1.0 SD below the mean.3,15 Affect- ed men and women have heights be- 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- low the fifth percentile in 36.8% and ening, and ulnar carpal drift. Anteroposterior (C) and lateral (D) radiographs demonstrating 44.2% of cases, respectively.9 Sitting similar deformities in the left forearm of the same boy. (Reproduced with permission from height is generally less affected than 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.) total height, indicating more exten- sive involvement of the limbs than of the axial skeleton.15 characteristic relative elongation or sus 75%, respectively), equal involve- dorsal subluxation of the distal ulna ment results in more substantial ul- Upper Extremity seen in Madelung’s deformity.15 nar shortening. Second, bones with Involvement Jaffe8 and Porter et al17 suggested a smaller cross-sectional diameter tend that the length of forearm bones cor- to be shortened more considerably Forearm relates inversely with the size of the when affected by HME; this can be Osteochondromas of the upper ex- exostoses. Moreover, lesions with attributed to greater proportionate in- tremities commonly cause forearm sessile rather than pedunculated mor- volvement of the physis. As a result, deformities. The prevalence of such phology have been associated with equal involvement of the two bones deformities is as high as 40% to more notable shortening and defor- preferentially affects the ulna, which 74%.7,8,11,15,28 Disproportionate ulnar mity.5 Thus, the skeletal growth dis- has a diameter of only one fourth that shortening has been frequently de- turbance observed in HME is a local of the radius. Consequently, radial scribed and may be associated with effect; the growth of the osteochon- bowing was thought to be caused by radial bowing. Subluxation or dislo- droma overwhelms and retards the a tethering effect of relative ulnar cation of the radial head has been re- growth of any closely associated phy- shortening.3 Burgess and Cates,4 how- ported in 22% to 33% of patients with sis, resulting in a tethering effect on ever, found that radial bowing was HME.15,28 Dislocation of the radial paired structures. Larger lesions with not correlated with measured ulnar head is associated with loss of prona- greater cortical involvement tend to shortening in their series of 35 patients. tion, enhanced ulnar variance, and influence bone growth more substan- They reported a strong correlation be- functional impairment.29 Disruption tially than do smaller lesions. tween ulnar shortening in excess of of the distal radioulnar joint, ulnar de- The disproportionate shortening of 8% and dislocation of the radial head. viation, and ulnar translocation of the the ulna can be generally attributed The extent of forearm involvement carpal bones are often associated with to two causes. First, because the dis- in patients with HME is strongly as- HME. This complex of deformities tal ulnar physis is responsible for sociated with the general severity of seems to be similar to Madelung’s de- greater longitudinal growth relative the disease. Taniguchi30 classified his formity,but it does not manifest in the to that of the distal radius (85% ver- patients into three groups: (1) those

Vol 13, No 2, March/April 2005 113 Manifestations of Hereditary Multiple Exostoses with no involvement of the distal forearm, (2) those with involvement of the distal radius or ulna without shortening of either bone, and (3) those with involvement of the distal radius or ulna with shortening of either bone. He reported that increasing forearm involvement was associated with an earlier age of diagnosis of HME, a greater number of gener- alized exostoses as well as of exostoses affecting the knee, shorter stature, and increased valgus deformity of the ankle. All of the patients with dislocation of the radial head were categorized in group 3, with shortening of either bone in addition to distal exostoses. Many of the deformities of the forearm are amenable to surgical treatment. Knowledge of the natural history of the disease and timely intervention are the keys to prevent- ing deformity in patients with HME. Although early aggressive surgery is often recommended, it is also contro- versial.4,7,31 Specific indications for surgery include painful lesions, an increasing radial articular angle, progressive ulnar shortening, exces- sive carpal slip, loss of pronation, and increased radial bowing with subluxation or dislocation of the radial head.31 Figure 4 Masada classification of forearm deformities in hereditary multiple exostoses. Type 32 I: Primary exostosis formation is in the distal portion of the ulna, which is relatively short Masada et al classified forearm compared with the radius. Type IIa: In addition to ulnar shortening, the radial head is dis- deformities into three types accord- located secondary to an exostosis at the proximal metaphysis of the radius. Type IIb: The ing to the morphology of the defor- radial head is dislocated without a proximal radial exostosis. Type III: Primary exostosis formation is in the metaphysis of the distal radius, leading to relative shortening of the radius mity (Fig. 4). In type I, the distal ulna compared with the ulna. (Adapted with permission from Masada K, Tsuyuguchi Y, Kawai has the greatest exostosis formation. H, Kawabata H, Noguchi K, Ono K: Operations for forearm deformity caused by multiple The ulna is shortened with bowing osteochondromas. J Bone Joint Surg Br 1989;71:24-29.) of the radius, but the radial head is not affected, and the proximal part of the radius is not dislocated. Tapering metaphysis of the radius. In type IIb, In a study of 18 patients who un- of the ulnar head and ulnar tilt of the radial head dislocation occurs in the derwent surgery for correction of distal radius are both present. This absence of a proximal radial exosto- forearm deformities, Fogel et al31 re- deformity is the most common and sis. In type III, the primary exostosis ported that, although early osteo- is observed in 55% (31/56) to 61% formation is in the metaphysis of the chondroma excision alone can de- (22/36) of forearms.28,32 In type II, the distal radius, with relative shortening crease or halt the progression of radial head is dislocated and the ulna of the radius compared with the ul- forearm deformity, it does not consis- is shortened. Bowing of the radius is na.32 Based on successful outcomes in tently provide full correction. Ulnar less severe than in the type I defor- a limited number of patients with a translocation of the carpal bones on mity, secondary to dislocation of the type I deformity, Masada et al32 rec- the distal radius can be corrected by radial head. In type IIa, the radial ommended exostosis excision, radial ulnar lengthening, but persistent head is dislocated as a result of ex- osteotomy, and immediate ulnar relative ulnar shortening is likely to ostosis formation at the proximal lengthening. recur. For patients with increased

114 Journal of the American Academy of Orthopaedic Surgeons Jonathan R. Stieber, MD, and John P. Dormans, MD radiocarpal angulation or carpal sub- a temporary intraoperative external this type II deformity in skeletally ma- luxation, osteochondroma excision in fixator with long plate fixation (Fig. ture patients, excision of the radial conjunction with distal radial osteot- 5). Eleven patients additionally under- head was recommended in addition omy or hemiepiphyseal stapling re- went distal radial osteotomy and to excision of exostosis, radial osteot- sulted in improved function and cos- achieved stable reduction of abnor- omy, and immediate ulnar lengthen- mesis. The seven forearms that mal radial inclination. Of the surgi- ing.32 Attempts at surgical relocation received all three procedures showed cally treated patients, 85% experienced of the radial head have not consistent- improvement in the degree of ulnar improvement of pronation/supination ly proved to be successful.7 Radial deviation. The mean improvement in (average increase, 39°). Forty percent head position can be gradually cor- the radial articular angle was 20°. The had improved radial/ulnar deviation rected with an Ilizarov fixator to mean range of forearm rotation in the (average increase, 15°). Sixty percent lengthen the ulna and to apply trac- six forearms with available measure- had unchanged radial/ulnar deviation on the radius, either directly ments improved from 78° preopera- tion, but postoperatively their arc of through the interosseous membrane tively to 118° at a minimum 2-year motion improved to a more neutral or indirectly through the carpus by follow-up.31 alignment (average of both radial and distal ulnar fixation or a radioulnar Pritchett33 performed ulnar length- ulnar deviation, 22°). transfixion wire.35 Patients may be left ening in 10 forearms, resulting in im- Complete dislocation of the radial with a painful, stiff, or weak upper proved cosmetic appearance, ROM, head can be a serious sequela of fore- extremity despite surgical treatment. and stability of the radial head. Wa- arm deformity and can result in pain, Controversy exists concerning the ters et al34 performed acute ulnar instability, and decreased motion at necessity of early surgery and wheth- lengthening in 17 patients with HME. the elbow. Early surgical intervention er the outcomes are superior to those They used a long Z-cut osteotomy and should be considered. Historically,for of untreated patients. Stanton and

Figure 5 A, Indications for closing-wedge radial osteotomy to decrease radial inclination and ulnar lengthening for correction of length discrepancy. The radial osteotomy is performed first. B, The ulna is exposed, and the external fixator and the distal end of the plate are applied. A long Z-cut osteotomy is performed. C, The ulna is slowly lengthened until near-neutral ulnar variance is achieved. D, The plate is 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.)

Vol 13, No 2, March/April 2005 115 Manifestations of Hereditary Multiple Exostoses

Hansen29 contend that deformities of gular deformities of the digits, but these as 98% of affected individuals; the the upper extremity in patients with have been reported. Pseudomallet fin- proximal tibia ranges from 70% to 98% HME are well tolerated and result in ger secondary to the presence of an involvement and the fibula, from 30% minimal functional loss when mea- exostosis located on the distal second to 97% of cases.11,15,21,38 As a result, val- sured both subjectively and objective- phalanx has been reported, with suc- gus knee deformities are found in 8% ly. Similarly, Arms et al36 conducted cessful treatment after resection.37 to 33% of patients with HME.10,11,15,38 a telephone survey of 37 skeletally Patellar dislocation is another com- mature patients, who reported satis- plication of valgus knee deformity in faction with both function and cos- Lower Extremity HME.10 mesis despite the presence of defor- Involvement mity. Noonan et al28 reported that Knee untreated patients tended to adapt Limb-length discrepancy is common- Shapiro et al15 and Nawata et al10 well to their differences; only 13% re- ly seen in patients with HME. A clin- suggested that valgus knee deformi- ported appreciable pain or limitation ically notable inequality ≥2cmhas ty was primarily caused by proximal related to job performance. In that been reported in 10% to 50% of affect- tibia changes. In fact, both the distal study, however, 40 of 77 upper ex- ed individuals.11,15,38 Shortening can femur and the proximal tibia tend to tremities were more than 2 SD below occur in the femur and the tibia. The contribute to the deformity.38 Nawa- the mean in at least one area of func- femur is affected approximately twice ta et al10 found the fibula to be short- tional assessment, including grip as commonly as the tibia.15 Surgical ened disproportionately compared strength, pinch strength, ROM, and treatment with appropriately timed with the tibia and contended that the hand function. Additionally, Stanton epiphysiodesis has been satisfactori- disparity was responsible for the con- and Hansen29 reported a prevalence ly performed in growing patients. sistent valgus direction of the defor- of early degenerative joint disease in mity. In the series by Shapiro et al,15 3 of 56 involved upper extremities in Femur 7 of 20 patients with this valgus de- their cohort (average age, 21 years). In addition to limb-length discrep- formity required corrective osteoto- Wood et al7 noted that surgeries of the ancies, several lower extremity defor- my. In another series, 3 of 13 knees distal forearm may result in only mities have been documented. Le- required treatment, including femo- modest functional improvement but sions of the proximal femur have ral opening wedge osteotomy, prox- marked cosmetic benefit. been reported in as few as 30% in imal tibial hemiepiphysiodesis, and some series to as many as 90% in oth- high tibial osteotomy38 (Fig. 6). In the Hand er studies of patients with HME, with same series, 7 of 31 knees had oppos- Hand involvement has been re- coxa valga present in up to 25% of in- ing angular deformities of the distal ported in 30%11 to 79%21 of patients. dividuals with the disorder.11,15,21 Por- femur and proximal tibia, which com- Fogel et al31 observed metacarpal and ter et al39 correlated increasing osteo- pensated to produce acceptable knee phalangeal involvement in approxi- chondroma load with an increasing alignment. These changes were not mately 70% of their patients. In their femoral neck-shaft angle. Femoral an- clinically apparent on physical exam- series of 63 patients, Cates and Bur- teversion and valgus have been as- ination because the normal mechan- gess26 reported that patients with HME sociated with exostoses located in ical axis was maintained by comple- fall into two groups: those with no hand proximity to the lesser trochanter.40 mentary lateral distal femoral angles involvement and those with substan- There have been at least nine report- and medial proximal tibial angles. It tial hand involvement, averaging 11.6 ed cases of acetabular dysplasia in pa- is unclear whether patients with this lesions per hand. The ulnar meta- tients with HME.27,41 Acetabular dys- abnormality in knee geometry are carpals and proximal phalanges were plasia, which is caused by exostoses predisposed to degenerative joint dis- most commonly involved, with the located within or about the acetabu- ease.38 thumb and distal phalanges affected lum or on the medial femoral neck, less frequently.Although exostoses of can lead to femoral lateralization. The Ankle the hand resulted in shortening of the femoral head itself does not appear Exostoses about the ankle can af- metacarpals and phalanges, brachy- to be affected. It is critically impor- fect the growth of the extremity and dactyly also was observed in the ab- tant to recognize this process early may cause pain, decreased ROM, sence of exostoses. Only 4 of 22 pa- and to provide appropriate treatment. weakness, and deformity. Valgus de- tients with hand involvement required Coxa valga may require early varus formity of the ankle is common in pa- surgery.26 In most reports, the major- osteotomy.41 tients with HME and is observed in ity of patients are asymptomatic.15,26 The distal femur is variably in- approximately half of affected pa- Cates and Burgess26 observed no an- volved in as little as 70% to as many tients.3,14,15,38 The deformity can be at-

116 Journal of the American Academy of Orthopaedic Surgeons Jonathan R. Stieber, MD, and John P. Dormans, MD

of the epiphysis may be appropriate. An oblique osteotomy of the distal fibula permits optimal exposure of the tibial exostosis and allows more complete resection.22 In more advanced cases, excision of exostoses alone does not correct the ankle deformity, although it may im- prove preoperative symptoms and cosmesis.22,43 Medial hemiepiphyseal stapling of the tibia in conjunction with excision of the exostoses performed with early ankle deformity can correct a valgus angle ≥15° associated with limited shortening of the fibula.15,43 Fibular lengthening has been used effectively for severe valgus deformity with more significant fibular shortening (ie, when the distal fibular physis is located proximal to the distal tibial physis).43 Supra- malleolar osteotomy of the tibia as well as osteotomy and placement of an Ilizarov device also have been used effectively to treat severe valgus ankle deformity.15,43 In skeletally immature patients, hemiepiphysiodesis or fixation with a transphyseal screw may allow for correction38 (Fig. 7). Such a procedure is indicated when Figure 6 A, Standing anteroposterior radiograph of the lower extremity of a 16-year-old there is a symptomatic or progressive girl demonstrating multiple exostoses and a left femoral valgus deformity. B, Anteroposte- rior radiograph 6 months postoperatively of a left distal femur with the valgus deformity deformity with sufficient remaining corrected by an opening wedge femoral osteotomy. (Reproduced with permission from Pierz growth to allow for adequate correc- KA, Stieber JR, Kusumi K, Dormans JP: Hereditary multiple exostoses: One center’s expe- tion. Growth of exostoses also can re- rience and review of etiology. Clin Orthop 2002;401:49-59.) sult in tibiofibular diastasis, which can be treated by early excision of the lesions. tributed to multiple factors, includ- treated adults (average age, 42 years). ing shortening of the fibula relative Seventy percent of patients with an- to the tibia. Resulting obliquity of the kle involvement reported impairment Neurologic and Vascular distal tibial epiphysis and medial sub- secondary to decreased ROM. Complications luxation of the talus also can be as- Patients with smaller, asympto- sociated with this deformity. Partial matic lesions of the distal tibia and HME can cause both neurologic and compensation may be provided by a fibula can be treated nonsurgically vascular problems throughout the ex- developmental obliquity of the supe- and followed with serial radiographs tremities. Wicklund et al9 reported pe- rior talar articular surface.15 In one se- until skeletal maturity.22 Chin et al22 ripheral nerve compression symptoms ries of 23 adolescents, exostoses of the recommend excision of symptomat- in 22.6% of the 180 patients in their distal tibia were more commonly ic lesions in skeletally mature patients series. Lesions arising from the me- symptomatic than those of the distal as well as in skeletally immature pa- dial aspect of the proximal humeral fibula.22 Lesions in the ankle most of- tients who fail nonsurgical treatment. physis are often symptomatic because ten became symptomatic in the sec- Patients with substantial remaining several important neurovascular struc- ond decade of life. Noonan et al42 growth tend to experience progres- tures may encounter compression found signs of early osteoarthritis in sive deformation; thus, partial or there. Peroneal neuropathy associat- 14 of 75 ankles in their cohort of un- complete resection with preservation ed with exostoses of the proximal fib-

Vol 13, No 2, March/April 2005 117 Manifestations of Hereditary Multiple Exostoses

ability to detect all HME patients without malignant degeneration, thus making it difficult to determine the true denominator.5 More recent studies indicate that the rate of secondary malignancy is <5% per patient.1,11,40,48 The risk of malignant transformation may vary among families, reflecting genetic heterogeneity predisposing to malignant degeneration.11 In their cohort of 217 individuals in 42 French families affected with HME, Francannet et al49 ob- Figure 7 A, Standing anteroposterior radiograph of the ankles of a 7-year-old girl demonstrating left ankle valgus. B, Standing anteroposterior radiograph taken 34 months after sur- served chondrosarcomas in 9 pa- gery. Treatment with a medial transphyseal screw allowed for continued lateral growth to tients, all of which were associated correct the deformity. (Reproduced with permission from Pierz KA, Stieber JR, Kusumi K, with EXT1 mutations. Dormans JP: Hereditary multiple exostoses: One center’s experience and review of etiology. Clin Orthop 2002;401:49-59.) Because of this risk, patients with HME should be followed carefully to detect early sarcomatous transformation. Continuous growth of a lesion ula in children is a recognized com- by a lesion, but they may be either at- after skeletal maturity should raise plication. Cardelia et al44 described the tenuated over the surface or intimate- the suspicion of malignancy,especial- “heel walking extinction test” as be- ly wrapped around the base of an ex- ly when accompanied by pain. Ad- ing helpful in diagnosing peroneal ostosis. Knowledge of the relevant ditionally, in adults, the presence of nerve injury. In this test, the patient anatomy,adequate exposure, and thor- an osteochondroma with a cartilag- is asked to ambulate to fatigue on his ough preoperative planning can fa- inous cap >2 cm has been associated or her heels with both ankles in dor- cilitate successful surgical treatment. with an increased chance of malig- siflexion to determine whether the in- nancy.2 Ultrasound is effective for volved side has a lower threshold for measuring cap thickness on superfi- fatigue. Malignant Transformation cial lesions, but magnetic resonance The prevalence of vascular com- imaging may be better for evaluating pression secondary to exostoses has Malignant transformation of a benign more deeply located lesions. Ideally, been reported to be as high as 11.3%.9 osteochondroma into a chondrosar- skeletally mature patients should be In a series of 97 cases of vascular com- coma is another complication of followed by an orthopaedic oncolo- plications stemming from osteochon- HME. Fortunately, many of the chon- gist. Appropriate patient education is dromas, 71 were from sporadic osteo- drosarcomas in this setting are low crucial for early identification of high- chondromas, and 26 were associated grade and can be treated successful- risk lesions. with HME.45 Pseudoaneurysm, vas- ly with wide excision. Patients with cular compression, arterial thrombo- such lesions usually present with an sis, aneurysm, and venous thrombo- expanding painful mass. Rarely, Summary sis were the most commonly reported nerve compression is the presenting complications. Claudication, acute is- complaint. Ochsner46 reported on 59 HME is an autosomal dominant dis- chemia, and phlebitis were the most patients with HME who had malig- order manifested by multiple lesions commonly associated clinical presen- nant transformation. The mean age at that are frequently associated with tations. Eighty-three percent of vas- diagnosis of malignancy was 31 characteristic skeletal deformities. cular problems were located in the years, with malignant degeneration Linkage analysis has identified two lower extremity, with the popliteal ar- seldom occurring in the first decade genes associated with HME: EXT1 tery most frequently involved.45 or after the fifth decade of life. The and EXT2. The molecules encoded by To address symptomatic neurovas- reported incidence of malignant de- EXT1 and EXT2 are endoplasmic cular involvement, exostosis excision generation is highly variable, ranging reticulum–resident type II transmem- should be performed along with di- from 0.5% to 25%.40,47 This disparity brane glycoproteins that are integral rect nerve or vessel decompression. can be attributed not only to a pos- to HSPG biosynthesis. Mutation of Neurovascular structures are not nec- sible selection bias inherent for a ter- the EXT1 or EXT2 gene causes an er- essarily stretched and pushed aside tiary referral center but also to the in- ror in the regulation of normal chon-

118 Journal of the American Academy of Orthopaedic Surgeons Jonathan R. Stieber, MD, and John P. Dormans, MD drocyte proliferation and maturation formities seen in HME include short with ulnar deviation of the wrist, and that results in abnormal bone stature, limb-length discrepancies, subluxation of the radial head.9,11,21 growth.19,20 Although exostoses are valgus deformities of the knee and For certain characteristic deformities, benign lesions, they often lead to clin- ankle, asymmetry of the pectoral and surgical treatment can prevent pro- ical problems. The most common de- pelvic girdles, bowing of the radius gression and provide correction.

References

1. Black B, Dooley J, Pyper A, Reed M: 15. Shapiro F, Simon S, Glimcher MJ: He- 26. Cates HE, Burgess RC: Incidence of Multiple hereditary exostoses: An epi- reditary multiple exostoses: Anthropo- brachydactyly and hand exostosis in demiologic study of an isolated com- metric, roentgenographic, and clinical hereditary multiple exostosis. J Hand munity in Manitoba. Clin Orthop 1993; aspects. J Bone Joint Surg Am 1979;61: Surg [Am] 1991;16:127-132. 287:212-217. 815-824. 27. Felix NA, Mazur JM, Loveless EA: 2. Unni KK, Dahlin DC: Dahlin’s Bone Tu- 16. Zak BM, Crawford BE, Esko JD: Hered- Acetabular dysplasia associated with mors: General Aspects and Data on 11,087 itary multiple exostoses and heparan hereditary multiple exostoses: A case Cases, ed 5. Philadelphia, PA: Lippincott- sulfate polymerization. Biochim Biophys report. J Bone Joint Surg Br 2000;82: Raven, 1996, vol 4, pp 11-23. Acta 2002;1573:346-355. 555-557. 3. Solomon L: Bone growth in diaphysial 17. Porter DE, Emerton ME, Villanueva- 28. Noonan KJ, Levenda A, Snead J, Fein- aclasis. J Bone Joint Surg Br 1961;43: Lopez F, Simpson AH: Clinical and ra- berg JR, Mih A: Evaluation of the fore- 700-716. diographic analysis of osteochondro- arm in untreated adult subjects with 4. Burgess RC, Cates H: Deformities of the mas and growth disturbance in multiple hereditary osteochondroma- forearm in patients who have multiple hereditary multiple exostoses. J Pediatr tosis. J Bone Joint Surg Am 2002;84: cartilaginous exostosis. J Bone Joint Surg Orthop 2000;20:246-250. 397-403. Am 1993;75:13-18. 18. Hall CR, Cole WG, Haynes R, Hecht JT: 29. Stanton RP, Hansen MO: Function of 5. Carroll KL, Yandow SM, Ward K, Carey Reevaluation of a genetic model for the the upper extremities in hereditary JC: Clinical correlation to genetic vari- development of exostosis in hereditary multiple exostoses. J Bone Joint Surg Am ations of hereditary multiple exostosis. multiple exostosis. Am J Med Genet 1996;78:568-573. J Pediatr Orthop 1999;19:785-791. 2002;112:1-5. 30. Taniguchi K: A practical classification 6. Hennekam RC: Hereditary multiple ex- 19. Duncan G, McCormick C, Tufaro F: The system for multiple cartilaginous exos- ostoses. J Med Genet 1991;28:262-266. link between heparan sulfate and he- tosis in children. J Pediatr Orthop 1995; 7. Wood VE, Sauser D, Mudge D: The reditary bone disease: Finding a func- 15:585-591. treatment of hereditary multiple exos- tion for the EXT family of putative tu- 31. Fogel GR, McElfresh EC, Peterson HA, tosis of the upper extremity. J Hand Surg mor suppressor proteins. J Clin Invest Wicklund PT: Management of deformi- [Am] 1985;10:505-513. 2001;108:511-516. ties of the forearm in multiple heredi- 8. Jaffe H: Hereditary multiple exostosis. 20. Vortkamp A, Lee K, Lanske B, Segre tary osteochondromas. J Bone Joint Surg Arch Pathol Lab Med 1943;36:335-357. GV, Kronenberg HM, Tabin CJ: Regula- Am 1984;66:670-680. 9. Wicklund CL, Pauli RM, Johnston D, tion of rate of cartilage differentiation 32. Masada K, Tsuyuguchi Y, Kawai H, Hecht JT: Natural history study of he- by Indian hedgehog and PTH-related Kawabata H, Noguchi K, Ono K: Oper- reditary multiple exostoses. Am J Med protein. Science 1996;273:613-622. ations for forearm deformity caused by Genet 1995;55:43-46. 21. Solomon L: Hereditary multiple exos- multiple osteochondromas. J Bone Joint 10. Nawata K, Teshima R, Minamizaki T, tosis. J Bone Joint Surg Br 1963;45: Surg Br 1989;71:24-29. Yamamoto K: Knee deformities in mul- 292-304. 33. Pritchett JW: Lengthening the ulna in pa- tiple hereditary exostoses: A longitudi- 22. Chin KR, Kharrazi FD, Miller BS, Man- tients with hereditary multiple exostoses. nal radiographic study. Clin Orthop kin HJ, Gebhardt MC: Osteochondro- J Bone Joint Surg Br 1986;68:561-565. 1995;313:194-199. mas of the distal aspect of the tibia or 34. Waters PM, Van Heest AE, Emans J: 11. Schmale GA, Conrad EU III, Raskind fibula: Natural history and treatment. Acute forearm lengthenings. J Pediatr WH: The natural history of hereditary J Bone Joint Surg Am 2000;82:1269-1278. Orthop 1997;17:444-449. multiple exostoses. J Bone Joint Surg Am 23. Mermer MJ, Gupta MC, Salamon PB, Ben- 35. Dahl MT: The gradual correction of fore- 1994;76:986-992. son DR: Thoracic vertebral body exos- arm deformities in multiple hereditary 12. Krooth RS, Macklin MT, Hilbish TF: Dia- tosis as a cause of myelopathy in a pa- exostoses. Hand Clin 1993;9:707-718. physeal aclasis (multiple exostosis) on tient with hereditary multiple exostoses. 36. Arms DM, Strecker WB, Manske PR, Guam. Am J Hum Genet 1961;13:340-347. J Spinal Disord Tech 2002;15:144-148. Schoenecker PL: Management of fore- 13. Philippe C, Porter DE, Emerton ME, 24. Barros Filho TE, Oliveira RP, Taricco arm deformity in multiple hereditary Wells DE, Simpson AH, Monaco AP: MA, Gonzalez CH: Hereditary multi- osteochondromatosis. J Pediatr Orthop Mutation screening of the EXT1 and ple exostoses and cervical ventral pro- 1997;17:450-454. EXT2 genes in patients with hereditary tuberance causing dysphagia: A case 37. Murase T, Moritomo H, Tada K, Yoshida multiple exostoses. Am J Hum Genet report. Spine 1995;20:1640-1642. T: Pseudomallet finger associated with 1997;61:520-528. 25. Uchida K, Kurihara Y, Sekiguchi S, et exostosis of the phalanx: A report of 2 14. Jahss MH, Olives R: The foot and ankle al: Spontaneous hemothorax caused by cases. J Hand Surg [Am] 2002;27:817-820. in multiple hereditary exostoses. Foot costal exostosis. Eur Respir J 1997;10: 38. Pierz KA, Stieber JR, Kusumi K, Dor- Ankle 1980;1:128-142. 735-736. mans JP: Hereditary multiple exos-

Vol 13, No 2, March/April 2005 119 Manifestations of Hereditary Multiple Exostoses

toses: One center’s experience and re- tosis of the lower extremity and ankle. ostoses and neoplastic degeneration: view of etiology. Clin Orthop 2002;401: J Pediatr Orthop 2002;22:120-124. Review of the literature (author’s 49-59. 43. Snearly WN, Peterson HA: Manage- transl) [German]. Z Orthop Ihre Grenz- 39. Porter DE, Benson MK, Hosney GA: The ment of ankle deformities in multiple geb 1978;116:369-378. hip in hereditary multiple exostoses. hereditary osteochondromata. J Pediatr 47. Garrison RC, Unni KK, McLeod RA, J Bone Joint Surg Br 2001;83:988-995. Orthop 1989;9:427-432. Pritchard DJ, Dahlin DC: Chondrosar- 40. Voutsinas S, Wynne-Davies R: The in- 44. Cardelia JM, Dormans JP, Drummond coma arising in osteochondroma. Can- frequency of malignant disease in dia- DS, Davidson RS, Duhaime C, Sutton L: cer 1982;49:1890-1897. physeal aclasis and neuroﬁbromatosis. Proximal ﬁbular osteochondroma with 48. Gordon SL, Buchanan JR, Ladda RL: He- J Med Genet 1983;20:345-349. associated peroneal nerve palsy: A re- reditary multiple exostoses: Report of a 41. Malagón V: Development of hip dys- view of six cases. J Pediatr Orthop 1995; kindred. J Med Genet 1981;18:428-430. plasia in hereditary multiple exostosis. 15:574-577. 49. Francannet C, Cohen-Tanugi A, Le J Pediatr Orthop 2001;21:205-211. 45. Vasseur MA, Fabre O: Vascular compli- Merrer M, Munnich A, Bonaventure J, 42. Noonan KJ, Feinberg JR, Levenda A, cations of osteochondromas. J Vasc Surg Legeai-Mallet L: Genotype-phenotype Snead J, Wurtz LD: Natural history of 2000;31:532-538. correlation in hereditary multiple exos- multiple hereditary osteochondroma- 46. Ochsner PE: Multiple cartilaginous ex- toses. J Med Genet 2001;38:430-434.

120 Journal of the American Academy of Orthopaedic Surgeons