Ollier Disease: Pathogenesis, Diagnosis, and Management

See discussions, stats, and author proﬁles for this publication at: https://www.researchgate.net/publication/278787870

Article in Orthopedics · June 2015 DOI: 10.3928/01477447-20150603-58 · Source: PubMed

CITATIONS READS 11 115

4 authors, including:

Vijay K Jain Minakshi Bhardwaj Postgraduate Institute of Medical Education and Research PGIMER ,Dr. Ram Manohar Lohia Hospital,New Delhi,India 24 PUBLICATIONS 161 CITATIONS 122 PUBLICATIONS 301 CITATIONS

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Rare tumour of salivary gland View project

PUBLICATION View project

All content following this page was uploaded by Minakshi Bhardwaj on 02 February 2016.

The user has requested enhancement of the downloaded ﬁle. n Feature Article

Ollier Disease: Pathogenesis, Diagnosis, and Management

Avinash Kumar, MS; Vijay Kumar Jain, MS; Minakshi Bharadwaj, MD; Rajendra Kumar Arya, MS

abstract

Ollier disease (Spranger type I) is a rare bone disease that is characterized by multiple enchondromatosis with a typical asymmetrical distribution and confined to the appendicular skeleton. The pathogenesis of enchondromatosis is not clearly understood. Recently, heterozygous mutations of PTHR1, IDH1 (most common), and/or IDH2 genes have been suggested by various authors as genetic aberrations. Genomic copy number alterations and mutations controlling many vital pathways are responsible for the pathogenesis of Ollier disease. A comprehensive description of all genetic events in Ollier disease is presented in this article. Clinically, Ollier disease has a wide variety of presentations. This article describes the plethora of clinical features, both common and rare, associated with Ollier disease. Multiple enchondromas are most commonly seen in phalanges and metacarpals. Radiologically, Ollier disease presents with asymmetrical osteolytic lesions with well-defined, sclerotic margins. In this article, various radiological features of Ollier disease, including radiographs, computed tomography, and magnetic resonance imaging, are also discussed. Gross pathology, cytological, and histological features of both Ollier disease and its malignant transformation are outlined. Although treatment is conservative in most cases, different possible treatment options for difficult cases are discussed. In the literature, there is a paucity of data about the disease, including diagnosis, management, prognostication, and rehabilitation, necessitating a comprehensive review to further define all of the possible domains related to this disease. Orthopedics.[ 2015; 38(6):e497-e506.]

The authors are from the Department of Orthopedics (AK, VKJ, RKA) and the Department of Pathol- ogy (MB), PGIMER, Ram Manohar Lohia Hospital, New Delhi, India. The authors have no relevant financial relationships to disclose. Correspondence should be addressed to: Vijay Kumar Jain, MS, Department of Orthopedics, PGIMER, Ram Manohar Lohia Hospital, New Delhi, India 110001 ([email protected]). Received: January 12, 2014; Accepted: August 4, 2014. doi: 10.3928/01477447-20150603-58

JUNE 2015 | Volume 38 • Number 6 e497 n Feature Article

hondromas are benign, generally asymptomatic tumors of hyaline Table 1 cartilage that are most commonly C Historical Contributions to the Evolution of Ollier Disease located in the phalanges of the hand. They are called enchondromas when they arise Year Author(s) Contribution 8,9 from the medullary canal. Rarely, they 1898 Ollier Coined dyschondroplasie (described as a unilateral lesion) arise on the surface of the bone and are 1923 Bentzon10 Interpreted as a typical reaction of the bones to an active hyperemia of the bone tissues, resulting from the anoma- referred to as periosteal chondromas or lies of the sympathetic nervous system juxtacortical chondromas. 1935 Hunter and Wiles11 First to identify the key distinguishing features such as a Enchondromas are the second most lack of heredity, childhood onset, and unilateral involve- common benign cartilaginous tumor af- ment in Ollier disease ter osteochondromas.1 Enchondromato- 1958 Jaffe12 Defined as the presence of either circumscribed foci or sis,2 or Ollier disease, is defined by the large masses of cartilage in the interior of bones presence of multiple enchondromas (3 or 1978 Spranger et al5 Classified and termed Ollier disease as multiple enchondromatosis more) and characterized by an asymmetric distribution of cartilaginous lesions that can be extremely variable in terms of their size, number, location, evolution, age of Table 2 onset and diagnosis, and requirement for Classification of Multiple Enchondromatosis surgery. The association of lymphangio- a mas with Ollier disease and Maffucci syn- Condition Clinical Features drome (another enchondromatosis) has Ollier disease (Spranger type I) Multiple enchondromas of tubular and flat bones, predominantly unilateral been described in the literature.3,4 Maffucci syndrome (Spranger type II) Same as Ollier disease, with hemangiomas Epidemiology and Classification Metachondromatosis (Spranger type III) Multiple enchondromas and exostoses The estimated prevalence of Ollier dis- Spondyloenchondrodysplasia (Spranger Multiple enchondromas with severe platyspon- type IV) dyly ease is 1 in 100,000.5-7 The true incidence of Ollier disease may be higher because Enchondromatosis with irregular spinal Multiple enchondromas with dysplasia of ver- lesions (Spranger type V) tebral bodies mild phenotypes without skeletal defor- Cheirospondyloenchondromatosis (for- Multiple enchondromas, severe hand and foot mities are sometimes not detected. Few merly generalized enchondromatosis) involvement, mild platyspondyly, erosion of cases of familial occurrence have been (Spranger type VI) iliac crests reported (Table 1).13-15 Dysspondylochondromatosis Multiple appendicular enchondromas with Spranger et al5 created a comprehen- hemivertebrae, dwarfism, limb-length discrepancy sive classification of enchondromato- Genochondromatosis Medial clavicular enlargement, lucent lesions ses based on radiographic appearance, of long bones anatomic site, and mode of inheritance. aSpranger type IV and genochondromatosis do not involve the hands, whereas other types, They divided enchondromatosis into 6 especially types I, II, III, and VI, do involve the hands. subtypes: type I, Ollier disease; type II, Maffucci syndrome; type III, metachondromatosis; type IV, spondyloenchondrodysplasia; type V, enchondromatosis with mucopolysacchariduria, and enchon- ease is basically an abnormality of devel- with irregular spinal lesions; and type VI, dromatosis with concave vertebral bod- opment of the limb bud, which, in post- cheirospondyloenchondromatosis. Most ies. The modified Spranger classification fetal life, causes the long bones to grow in subtypes are nonhereditary, whereas some system is widely used to address types of diameter but not in length. Table 3 sum- are autosomal dominant or recessive. Ha- enchondromatosis, and the common sub- marizes all the proposed theories regard- lal and Azouz16 later added 3 subtypes to types are listed in Table 2.17 ing the pathogenesis of Ollier disease. this classification system based on case In 1943, Jaffe and Lichtenstein18 pro- reports of enchondromatosis: generalized Pathophysiology posed that enchondromatous lesions are enchondromatosis with irregular vertebral The pathogenesis of enchondromatosis actually the displaced cartilaginous rests lesions, generalized enchondromatosis is still not clearly understood. Ollier dis- of normal physeal cartilage cells. This

theory is still widely accepted regarding the genesis of enchondroma. There are Table 3 formations of intraosseous cartilaginous Proposed Theories for the Pathogenesis of Ollier Disease foci in enchondromas that might result Displaced remnants of normal physeal cartilage cells18 from the abnormalities in signaling path- Hamartomatous growth of cartilage cells19-21 ways controlling the proliferation and dif- Failure of endochondral ossification22 24 ferentiation of chondrocytes. Migration of dysplastic nidus from physeal proliferative zone to primary ossification Heterozygous mutations24,25 and mis- zone in metaphyses23 24 sense mutations in parathyroid-related Failure of terminal differentiation of growth plate chondrocytes24 peptide type 1 receptor (PTHR1) or dys- Heterozygous mutations of PTHR1 gene25 regulation in the Indian hedgehog sig- Heterozygous mutations of IDH1 and/or IDH2 gene26-28 naling pathway (eg, overexpression of Loss of chromosomes (Chr 6 and Chr 3), deletions, amplifications, gains, and other hedgehog transcriptional regulator GLI2 genomic copy number neutral structural changes of subtle genes29,30 or activation of a hedgehog-responsive Familial31 GLI2-luciferase in a PTHR1 mutant25) may cause development of enchondromatous lesions in patients with Ollier disease. Recently, heterozygous mutations in also been reported in early adolescence the isocitrate dehydrogenase (IDH) gene and adulthood.37,38 These lesions usually Table 4 have been related to Ollier disease, mainly appear and grow before puberty but soon IDH1 (98%) and IDH2 (2%).26-28 These remodel into normal bone.6,39 Whereas Clinical Presentations of mutations exhibited a phenomenon of enchondromas occur equally in both sex- Ollier Disease intraneoplastic mosaicism similar to that es, Ollier disease is seen twice as often in Multiple swellings seen in fibrous dysplasia and osteochon- men than in women.40 Cosmetic embarrassment 26 droma. Patients usually present with painless Asymmetric physeal arrest The inheritance pattern of Ollier dis- bony masses (Table 4). Although lesions Madelung deformity ease is unknown but is thought to not be generally occur bilaterally, with a unilat- Angular deformity simply a Mendelian pattern.24,31,32 Hence, eral predominance leading to asymmetric Genu varum it seems that Ollier disease is a manifesta- distribution, bilateral symmetric presenta- Genu valgus tion of heterogeneity of various molecular tion has also been described (Figure 1).41 defects. They have a predilection for the appendic- Cubitus valgus ular skeleton, but the trunk bones can also Coxa vara Clinical Features be involved in severe cases.42 Enchondro- Coxa valga The pathognomonic features of Ollier mas are most commonly seen in phalan- Pelvis involvement 11 disease are as follows : ges and metacarpals and are rarely seen in Obstructed labor 43 1. Onset in early childhood the carpal bones. Ollier disease is also Scoliosis 2. Radiological changes limited to the frequently seen in long bones like the fe- Limb-length discrepancy long ends of the bone with stripping of mur and tibia. The trochanters of the fe- Gait disturbances rarefied areas; secondary involvement of mur are commonly involved, whereas the Pathological fractures epiphysis and appearance of speckling in femoral neck is relatively spared.44 Slongo metaphysis and epiphysis with develop- et al44 reported Ollier disease in the femo- Pain ment of growth ral neck leading to posterior tilting of the Loss of function 3. Histological presence of cartilage in proximal femoral epiphysis mimicking a portion of tissue taken from the radiolu- slipped capital femoral epiphysis. Other cent area shown on radiographs bones that can be involved are the pel- quently involved trunk bone, which can There is a large clinical variability in vis (especially the iliac crest), fibula, and lead to scoliosis.7 the presentation of Ollier disease with humerus, but rarely are the ribs, sternum, The most common presenting symp- respect to size, number, location, and and skull involved7; characteristically the tom is cosmetic deformity due to the age of onset.7,33-35 Ollier disease usually vertebral and craniofacial bones are not presence of multiple swellings on the manifests in first decade of life7,36 but has involved.42,45 The pelvis is the most fre- extremity.46 Rarely, bone shortening is

JUNE 2015 | Volume 38 • Number 6 e499 n Feature Article

mal tibia.57 Chondrosarcomas of the hand resulting from enchondromatosis appear to be rare.57 Muramatsu et al57 and Goto et al61 have reported chondrosarcomas in the hand resulting from Ollier disease, although rare, mainly toward the ulnar side. Pain, increasing lesion size, and thinning of the cortices are typical clinical and radiological signs of transformation to low-grade chondrosarcoma.62 Features Figure 1: Clinical photographs of both hands (A) and feet (B) showing multiple swellings. like size greater than 5 to 6 cm, more than two-thirds’ endosteal scalloping of the cortex, cortical breach, extraosseous the only clinical finding. This shortening age 40 years.57 Malignant transforma- soft tissue mass, marked uptake on bone may be due to the defect in the longitu- tion usually occurs between ages 13 and scan, and periosteal reaction also suggest dinal growth of the bones. These growth 69 years.58 Central chondrosarcomas, malignant transformation.63 The usual be- disturbances are either due to an abnormal located centrally in the medullary cav- havior of secondary chondrosarcomas in epiphyseal plate adjacent to the enchon- ity, may lead to sarcomatous changes in enchondromatosis is local invasion, local dromas or to the tethering of the epiph- underlying enchondromas.59 The risk of recurrence, and distant metastasis, most yseal cartilage by an abnormally thick sarcomatous changes of enchondromas commonly to the lungs.57 Damron et al64 periosteal sleeve formed in reaction to the increases in proportion to the amount reported nonmonomelic, multicentric, enchondromatous lesions.47 Asymmetri- of dysplastic tissue (ie, the number and malignant chondrosarcomas associated cal premature physeal arrest can occur, size of lesions) present in the lesions and with Ollier disease. leading to deformity around the joints. cytogenetic aberrations.51 An interstitial Nonuniform distribution of enchondro- deletion of the short arm of chromosome Investigations mas, mainly involving the metaphysis, 1 [del(1) (p11p31.2)] has been described Radiographs may lead to angular deformity. The con- in a low-grade chondrosarcoma devel- On plain radiographs, enchondromas cavity of the angular deformity is toward oping in a patient with Ollier disease.60 typically appear as osteolytic lesions the extensive enchondromatous region.47 Such deletion has also been noticed in (medullary) with well-defined, sclerotic Widening and broadening of the metaphy- primary chondrosarcomas. There are margins; endosteal erosion; and ground- sis occur as the bone starts growing trans- larger numbers of gains and losses of glass appearance of the matrix (Figure versely. As a result, deformities such as genomic copy numbers and their loss of 2). Channel-like radiolucent areas in the genu valgus and cubitus varus, limitations heterozygosity in chondrosarcomas asso- metaphysis with an “organ pipe” appear- in joint mobility, and leg-length discrep- ciated with Ollier disease than in enchon- ance in long tubular bones are common in ancy may occur.48 Pathological fractures dromas. They are most commonly seen Ollier disease.82 The lesions have punctate may occur due to thinning of the cortical in chromosomes 3p, 5q, 6q, 9p, which calcification typical of the radiographic bone over the growing lesions.49,50 Facial results in increased genetic instabil- appearance of cartilaginous matrix. Dys- asymmetry and cranial nerve palsies may ity.29 These secondary chondrosarcomas trophic calcification within the matrix of also occur.48 Neural compression is less are generally grade I or II.57 There may small cartilage masses or fragments of frequently seen in Ollier disease than in also be a correlation between expression lamellar bone are often described as the hereditary multiple exostosis. of PTHrP, PTHR1, and Bcl2 genes and ring and arc, flocculent, or stippled pattern Various tumors are associated with the grade of malignancy in chondrosar- of calcification commonly appreciated in Ollier disease (Table 5). The reported coma.78-81 There is an increased chance long bones.82 Calcification denotes degen- incidence of malignant transformation of of genetic aberrations and mutations in eration and poor vascularity of the lesions; enchondromas in Ollier disease ranges higher-grade chondrosarcomas than in therefore, densely calcified lesions accu- from 5% to 50%.51-56 Chondrosarcomas lower-grade chondrosarcomas.30 Chon- mulate less tracer on bone scan.83 are the most common malignancy aris- drosarcomas resulting from multiple en- The bones of the hand demonstrate a ing from Ollier disease and are present chondromatosis mainly affect the pelvis, characteristic globular appearance on ra- in approximately 25% of patients by shoulder girdle, distal femur, and proxi- diographs. The radiological appearance of

Table 5 Tumors Associated With Ollier Disease Chondrosarcoma51-64 Osteosarcoma54,65 Central nervous system tumors Chondrosarcoma-like parasellar chondrosarcoma Glioma, glioblastoma multiforme66 Astrocytoma51 High-grade anaplastic astrocytoma65,67 Oligoastrocytoma43 Oligodendroglioma32 Ovarian tumors Juvenile granulosa cell tumor51,68-73 Sertoli-Leydig cell tumor74 Leukemia Chronic myeloid leukemia75 Acute myelogenous leukemia31 Figure 2: Anteroposterior radiographs of both hands (A), fingers (B), wrist (C), leg (D), and feet Breast adenoma74 (E) showing multiple well-defined, expansile lytic lesions involving the metacarpals, metatarsals, Lung tumor phalanges, distal end of the radius and ulna, and lower end of the tibia/fibula. No matrix mineralization is seen. Non–small-cell lung cancer76 Fibromatosis (deep) Extra-abdominal desmoid tumor77

enchondromas occurring in flat or irregular bone may not be diagnostic. No periosteal reaction is seen in uncomplicated enchondromas.82

Computed Tomography Computed tomography (CT) is superior to radiography in detecting matrix mineralization, calcification pattern, lobu- lated lesion margins, and degree and ex- tent of endosteal scalloping (Figure 3A). This is particularly important for lesions occurring in the areas difficult to evalu- ate with radiographs, like the pelvis.84 Computed tomography is also useful in evaluating the size and presence of any soft tissue component, which would favor a diagnosis of chondrosarcoma, although Figure 3: Coronal reconstructed computed tomography scan (A) and T2-weighted magnetic resonance image (B) of the right hand confirming the presence of multiple well-defined cystic le- a soft tissue component in enchondroma sions. No associated soft tissue component is seen. Lesions show hyperintense signal on the may occur in association with a fracture T2-weighted image.

JUNE 2015 | Volume 38 • Number 6 e501 n Feature Article

and hematoma.6 Recently, 3-dimensional reveal intense uptake on bone scans, placed round nuclei and abundant pale cy- reconstructed CT has provided help in whereas long-bone enchondromas show toplasm. surgical planning for patients with Ollier mild to moderate increased radiotracer Binucleation, mild atypia, hypercellu- disease.85 activity in only 21% of cases. In addi- larity, and large pleomorphic nuclei, tion, a heterogeneous pattern of uptake is which would indicate malignancy in a Magnetic Resonance Imaging seen in 63% of long-bone intramedullary solitary cartilaginous tumor, are accept- Magnetic resonance imaging (MRI) chondrosarcomas vs 30% of enchondro- able features for benign enchondromas may be requested in cases of pathological mas.63 Tc-99m (V) DMSA scintigraphy in multiple enchondromatosis.54 It is dif- fracture when lesional characterization is can also be used and may be superior to ficult to differentiate enchondromas from necessary prior to treatment.63 On MRI, the Tc-99m MDP scintigraphy for distin- grade I chondrosarcomas until, in the lat- nonmineralized component of enchondro- guishing benign and malignant chondro- ter, the characteristic bone marrow perme- mas appears as low to intermediate signal genic tumors, as well as being useful in ation with trapping of host lamellar bone intensity lesions on T1-weighted sequenc- predicting malignant transformation of on all sides is seen.94-96 es and intermediate to high signal intensity chondrogenic tumors.89 lesions on T2-weighted sequences (Figure Differential Diagnosis 3B).63,86 Small speckled foci of high signal Pathology Ollier disease must be differentiated intensity, often evident on T1-weighted Macroscopic examination of enchon- from multiple hereditary exostosis. The MRIs, are postulated to be due to the lobu- dromas usually shows multiple oval- most important criterion to distinguish lar growth of enchondromas, which leaves shaped or round cartilaginous nodules, enchondromas from osteochondromas as intervening residual areas of normal yellow limited at their periphery by woven or seen in multiple hereditary exostosis is the bone marrow.63,87 Low signal intensity sep- lamellar bone and separated from each localization of bone lesions: osteochon- ta on T2-weighted MRIs are also evident, other by intertrabecular marrow spaces in dromas are located at the bone surface and corresponding pathologically to enchon- the solid cartilaginous matrix with myxoid enchondromas are located in the center of dral ossification or fibrous septations.63 changes appearing as fraying of the ma- bones, thus allowing radiographic distinc- Following contrast administration, enchon- trix.35,90 Microscopically, there are sharply tion.59 Radiologically, Ollier disease may dromas exhibit central ring and arc en- demarcated lobules of mature, hypocel- mimic osteitis fibrosa cystica.97 hancement and septal and peripheral rims lular hyaline cartilage with few double- of enhancement. This pattern of enhance- nucleated cells without cytologic atypia Treatment ment is also seen in chondrosarcomas. Pre- (Figure 4); however, cellularity of the tu- Treatment of Ollier disease is usually liminary studies performed with dynamic mor may vary with increased mitosis. In- conservative, unless complications occur. MRI have suggested early enhancement of side a network of trabecular bone, islands The lesions can be left untreated because chondrosarcoma as a possible useful differ- of mature, nonvesiculated hyaline carti- functional impairment is usually not severe. entiating feature.63 lage cells of various sizes and shapes are Surgery is performed in cases of deformity, embedded in abnormally dense metachro- limb-length discrepancy, pathological frac- Bone Scintigraphy matic staining extracellular substance. The ture, and malignant transformation. The most common bone scintigraphic matrix does not show any myxoid change. The important goals of the treatment finding is increased uptake in the long Calcification and ossification are common, are as follows98: bone diaphysis or metadiaphysis. Pin- especially at the periphery of cartilage lob- 1. Achieving mechanical alignment hole scintigraphy is helpful in determin- ules. This characteristic pattern is called 2. Achieving equivalent limb length for ing the metabolic profile of the tumor bone encasement.91 normal walking tissue in its different evolutional stages. 3. Relieving pain from a pathological Enchondromas may show high uptake Cytology fracture on fluorodeoxyglucose–positron emis- Needle cytology is instrumental in Treatment is directed toward the more sion tomography (FDG-PET) and can making the diagnosis of Ollier disease.92 extensively involved limb, deformities, sometimes mimic a metastatic lesion in Anshu et al93 reported Papanicolaou and complications. Shapiro47 reported that a patient being screened for metastasis.88 stained smears showing the presence of an angular deformity greater than 25° that Bone scan is also helpful in detecting numerous cartilaginous fragments with is not balanced by reverse deformity is an and screening malignant transformation angular edges. Singly scattered round indication for surgery. like chondrosarcoma because the major- cells were also present, occasionally in Only a few treatment options are avail- ity (82%) of long-bone chondrosarcomas tight clusters. The cells had eccentrically able for Ollier disease, especially for im-

proving appearance. An oft-used modality is intralesional curettage with or without bone grafting and/or artificial bone sub- stitute, various osteotomies, and internal fixations. These treatments do not address the problem of limb-length discrepancy. Adas et al99 showed good results with curettage and cementing in distal femur affected with Ollier disease. Osteotomy has been used, but it must be repeated many times. Also, the presence of weak bones is a problem that makes internal fixation difficult. Other modalities of surgical treatment follow.

Ilizarov Technique The Ilizarov technique is difficult but effective in providing mechanical stabilization in patients with Ollier disease. Dis- traction osteogenesis enhances the con- Figure 4: Cytology of an enchondroma with Giemsa stain (original magnification ×400) (A) and Papanico- version of abnormal cartilage of the lesion laou stain (original magnification ×200) (B) showing amorphous magenta-colored material with embed- 100 into new lamellar bone, without the ded uninucleated chondrocytes. Histopathology of an enchondroma showing lobules of mature hyaline need for intralesional curettage or bone cartilage without nuclear atypia and mitosis (hematoxylin-eosin stain, original magnification ×200 [C] and grafting, which was proved radiographi- ×400 [D]). cally by Jesus-Garcia et al.101 Tellisi et al102 used a multiaxial correction frame for distraction osteogenesis in a humerus medullary nailing with a special motor- because, despite large bony deficits after affected by Ollier disease. ized sliding mechanism. the first resection, bony regrowth can occur More wires and olive wires are re- without the need for bone autograft.111 quired for the stabilization because the Corticoplasty and Diaphysectomy bones are weak and many enchondromas Partial resection of the cortical bone Rehabilitation are present. with curettage of the tumor (corticoplas- Physiotherapy like ultrasound, cryo-

ty) for treating hand deformity in Ollier therapy, CO2 laser with stretching, active Intramedullary Nailing disease has been performed by Kim et mobilization, occupational therapy, and Intramedullary nailing is used in pa- al.85 They concluded that corticoplasty coordination exercises improve the func- tients with limb-length discrepancies. resulted in cosmetic improvement without tional ability of patients with Ollier dis- García-Cimbrelo et al103 used an intra- functional deterioration. ease.112 medullary elongation nail for femoral Total/subtotal diaphysectomy and re- shortening when performing intramedul- construction with structural autografts or Prognosis lary osteotomy (internal osteotomy) fol- allografts are usually performed for the Because widely distributed enchondro- lowed by distraction followed by intra- treatment of extensive enchondromas in- mas may pose fewer problems than local- medullary nailing. This allows a shorter volving the fingers.106-108 ized ones (eg, limb shortening, asymme- treatment time and early removal of the try), it is difficult to assess the prognosis external fixator to prevent pin-tract infec- Amputation/Limb Salvage of Ollier disease (Table 6). Multiple en- tions and intramedullary infections; it also Although ray amputation109,110 can be chondromas in Ollier disease have an in- prevents complications like refracture, de- performed for Ollier disease of the hand creased rate of recurrence after surgery, so formity, shortening, and nonunion arising depending on the severity of involvement aggressive follow-up should be performed from premature removal of the external (eg, when destruction of cortical bone and in these cases.113 fixator.103,104 Baumgart et al105 described larger lesions are present), limb salvage can Annual surveillance of patients with good results in 12 patients using intra- be performed in a severely affected hand Ollier disease, both children and adults,

JUNE 2015 | Volume 38 • Number 6 e503 n Feature Article

of Tumours: Pathology and Genetics of Tu- 1951; 63:861-865. mours of Soft Tissue and Bone. Table 6 Lyon, France: 21. Margolis J. Ollier’s disease. Arch Intern Med. IARC Press; 2002. Poor Prognostic Factors 1959; 103:279-284. 3. Auyeung J, Mohanty K, Tayton K. Maffucci 22. Aegerter E, Kirkpatrick TAS. Orthopedic of Ollier Disease lymphangioma syndrome: an unusual variant Diseases: Physiology, Pathology, Radiol- of Ollier’s disease. A case report and a review ogy. 4th ed. Philadelphia, PA: WB Saunders; Age of onset (early age) J Pediatr Orthop B of the literature. . 2003; 1975. Malignant transformation 12(2):147-150. 23. Brien EW, Mirra JM, Kerr R. Benign and Gross asymmetrical distribution 4. Suringa DWR, Ackerman AB. Cutane- malignant cartilage tumors of bone and ous lymphangiomas with dyschondropla- joint: their anatomic and theoretical basis Repeated surgeries Arch Dermatol sia (Maffucci’s syndrome). . with an emphasis on radiology, pathology 1970; 101:472-474. and clinical biology: I. The intramedullary 5. Spranger J, Kemperdieck H, Bakowski H, cartilage tumors. Skeletal Radiol. 1997; Opitz JM. Two peculiar types of enchondro- 26:325-353. Pediatr Radiol. is recommended. Periodic surveillance matosis. 1978; 7:215-219. 24. Couvineau A, Wouters V, Bertrand G, et al. of the brain and abdomen for occult le- 6. Khoo RN, Peh WC, Guglielmi G. Clinics in PTHR1 mutations associated with Ollier dis- diagnostic imaging (124): multiple enchon- ease result in receptor loss of function. Hum sions should also be performed in these dromatosis in Ollier disease. Singapore Med Mol Genet. 2008; 17:2766-2775. J patients. . 2008; 49(10):841-845. 25. Hopyan S, Gokgoz N, Poon R, et al. A mu- 7. Silve C, Juppner H. Ollier disease. Orphanet tant PTH/PTHrP type I receptor in enchon- Conclusion J Rare Dis. 2006; 1:37. dromatosis. Nat Genet. 2002; 30:306-310. Ollier disease is a rare disorder char- 8. Ollier L. Exostoses ost’eogeniques multiples. 26. Pansuriya TC, van Eijk R, d’Adamo P, et Lyon Medical. 1898; 88:484-486. al. Somatic mosaic IDH1 and IDH2 muta- acterized by asymmetrical and bilateral 9. Ollier L. Dyschondroplasie. Lyon Medical. tions are associated with enchondroma and painless bony lesions mainly confined to 1900; 93:23-25. spindle cell hemangioma in Ollier disease the appendicular skeleton. The disorder and Maffucci syndrome. Nat Genet. 2011; 10. Bentzon PKG. Roentgenological and ex- 43(12):1256-1261. commonly presents with cosmetic defor- perimental studies on the pathogenesis of the 27. Bathla G, Gupta S, Ong CK. Multifocal in- mity, limb-length discrepancy, and patho- dyschondroplasia (Ollier’s disease). Acta Ra- diol. 1924; 3:8a. tracranial astrocytoma in a pediatric patient logical fractures, and it is associated with with Ollier disease. Indian J Radiol Imaging. 11. Hunter D, Wiles P. Dyschondroplasia (Olli- 2012; 22(1):58-62. various tumors, especially chondrosar- er’s disease): with report of a case. Br J Surg. 1935; 22:507-519. 28. Amary MF, Damato S, Halal D, et al. Ollier comas. Ollier disease must be differenti- disease and Maffucci syndrome are caused ated from other causes of multiple bony 12 Jaffe HL. Tumors and Tumorous Conditions by somatic mosaic mutations of IDH1 and swellings. Given the hypercellularity of of the Bones and Joints. Philadelphia, PA: IDH2. Nat Genet. 2011; 43(12):1262-1265. Lea & Febiger; 1958. enchondromas in Ollier disease, histologi- 29. Pansuriya TC, Oosting J, Krenács T, et al. 13. Rossberg A. Heredity of osteochondromas Genome-wide analysis of Ollier disease: is it cal distinction between benign and malig- [in German]. Fortschr Geb Rontgenstr Nuk- all in the genes? Orphanet J Rare Dis. 2011; nant tumors may be difficult; therefore, learmed. 1959; 90:138-139. 6:2. in suspected malignant transformation, 14. Carbonell JM, Vineta TJ. A further case of 30. Rozeman LB, Szuhai K, Schrage YM, et al. dynamic MRI and bone scan may help the congenital generalized dyschondrotheosis, Array-comparative genomic hybridization of Ollier type [in Spanish]. Rev Esp Pediatr. central chondrosarcoma: identification of ri- diagnosis, in addition to commonly used 1962; 18:91-99. bosomal protein S6 and cyclin-dependent ki- investigations like radiographs and CT. 15. Lamy M, Aussannaire M, Jammet ML, Ne- nase 4 as candidate target genes for genomic The treatment of Ollier disease is usually zelof C. Three cases of Ollier’s disease in one aberrations. Cancer. 2006; 107(2):380-388. family [in French]. Bull Mem Soc Med Hop conservative; however, in some compli- 31. White MS, Martin PL, McLean TW. Acute Paris. 1954; 70:62-70. myelogenous leukemia associated with Ol- cated cases, reconstructive surgery after 16. Halal F, Azouz EM. Generalized enchondro- lier disease. Pediatr Blood Cancer. 2008; excision to amputation can be performed. matosis in a boy with only platyspondyly in 50:645-646. The overall prognosis of Ollier disease is the father. Am J Med Genet. 1991; 38:588-592. 32. Chang S, Prados MD. Identical twins with Ollier’s disease and intracranial gliomas: favorable, but annual surveillance in chil- 17. Ghatan A, Scharschmidt T, Conrad E. Ex- treme enchondromatosis: a report of two cas- case report. Neurosurgery. 1994; 34:903- dren and adults is recommended. es and review of the literature. J Bone Joint 906. Surg Am. 2010; 92:2336-2343. 33. Lucas DR, Bridge JA. Chondromas: enchon- References 18. Jaffe HL, Lichtenstein L. Solitary benign droma, periosteal chondroma, and enchondromatosis. In: Fletcher CDM, Unni KK, 1. Lewis RJ, Ketcham AS. Maffucci’s syn- enchondroma of bone. Arch Surg. 1943; 46:480-493. Mertens F, eds. World Health Organization drome: functional and neoplastic sig- Classification of Tumours: Pathology and nificance. Case report and review of the 19. Kaplan RP, Wang JT, Amron DM, Kaplan L. Genetics of Tumours of Soft Tissue and Bone. literature. J Bone Joint Surg Am. 1973; Maffucci’s syndrome: two case reports with a Lyon, France: IARC Press; 2002:237-240. 55(7):1465-1479. literature review. J Am Acad Dermatol. 1993; 29:894-899. 34. Mertens F, Unni KK. Enchondromatosis: 2. Fletcher CDM, Unni KK, Mertens F, eds. Ollier disease and Maffucci syndrome. In: World Health Organization Classification 20. Heckman JA. Ollier’s disease. Arch Surg. Fletcher CDM, Unni KK, Mertens F, eds.

World Health Organization Classification 29:894-899. 64. Damron TA, Sim FH, Unni KK. Multicentric of Tumours: Pathology and Genetics of Tu- chondrosarcomas. Clin Orthop Relat Res. 50. Wu KK, Frost HM, Guise EE. A chondro- mours of Soft Tissue and Bone. 1996; 328:211-219. Lyon, France: sarcoma of the hand arising from an asymp- IARC Press; 2002:356-357. tomatic benign solitary enchondroma of 40 65. Braddock GT, Hadlow VD. Osteosarcoma 35. Unni KK. Cartilaginous lesions of bone. J years duration. J Hand Surg. 1983; 8:317- in enchondromatosis (Ollier’s disease): re- Orthop Sci. 2001; 6: 457-472. 319. port of a case. J Bone Joint Surg Br. 1966; 48(1):145-149. 36. Schwarz W, Hardes J, Schulte M. Multiple 51. Schwartz HS, Zimmerman NB, Simon MA, enchondromatosis: Ollier’s disease [in Ger- Wroble RR, Millar EA, Bonfiglio M. The 66. Ranger A, Szymczak A. The association be- man]. Unfallchirurg. 2002; 105(12):1139- malignant potential of enchondromatosis. J tween intracranial tumours and multiple dys- 1142. Bone Joint Surg Am. 1987; 69:269-274. chondroplasia (Ollier’s disease/Maffucci’s syndrome): do children and adults differ? J 37. Miyawaki T, Kinoshita Y, Lizuka T. A case of 52. Schaison F, Anract P, Coste F, De PG, For- Neurooncol. 2009; 95(2):165-173. Ollier’s disease of the hand. Ann Plast Surg. est M, Tomeno B. Chondrosarcoma second- 1997; 38:77-80. ary to multiple cartilage diseases: study of 29 67. Rawlings CE, Bullard DE, Burger PC, Fried- man AH. A case of Ollier’s disease associated 38. Bessler W, Brauer W, Allemann J. Case re- clinical cases and review of the literature [in Rev Chir Orthop Reparatrice Appar with two intracranial gliomas. Neurosurgery. port 726: enchondromatosis of the left femur French]. Mot 1987; 21(3):400-403. and hemipelvis (Ollier’s disease). Skeletal . 1999; 85:834-845. Radiol. 1992; 21:201-204. 53. Rozeman LB, Hogendoorn PCW, Bovée 68. Rietveld L, Nieboer TE, Kluivers KB, Schreuder HW, Bulten J, Massuger LF. First 39. Ko odziej L, Kolban M, Zacha S, Chmiel- JVMG. Diagnosis and prognosis of chon- Expert Rev Mol Diagn case of juvenile granulosa cell tumor in an nicki M. The use of the Ilizarov technique in drosarcoma of bone. . adult with Ollier disease. Int J Gynecol theļ treatment of upper limb deformity in pa- 2002; 2:461-472. Pathol. 2009; 28:464-467. tients with Ollier’s disease. J Pediatr Orthop. 54. Liu J, Hudkins PJ, Swee RG, Unni KK. Bone 2005; 25:202-205. sarcomas associated with Ollier’s disease. 69. Leyva-Carmona M, Vazquez-Lopez MA, Cancer Lendinez-Molinos F. Ovarian juvenile granu- 40. Morris CD, Lee FY, Gebhardt MC. Benign . 1987; 59:1376-1385. losa cell tumors in infants. J Pediatr Hematol bone tumors. In: Chapman MW, ed. Chap- 55. Bukte Y, Necmioglu S, Nazaroglu H, Kilinc Oncol. 2009; 31:304-306. man’s Orthopaedic Surgery. 3rd ed. Phila- N, Yilmaz F. A case of multiple chondrosar- delphia, PA: Lippincott Williams & Wilkins; comas secondary to severe multiple sym- 70. Vaz RM, Turner C. Ollier disease (enchon- 2001:3402-3405. metrical enchondromatosis (Ollier’s disease) dromatosis) associated with ovarian juvenile Clin Radiol granulosa cell tumor and precocious pseudo- 41. Ly JQ, Beall DP. A rare case of infantile Olli- at an early age. . 2005; 60:1306- puberty. J Pediatr. 1986; 108:945-947. er disease demonstrating bilaterally symmet- 1310. ric extremity involvement. Skeletal Radiol. 56. Bovée JV, Graadt van Roggen JF, Cleton- 71. Tamimi HK, Bolen JW. Enchondromatosis 2003; 32:227-230. Jansen AM, et al. Malignant progression in (Ollier’s disease) and ovarian juvenile granulosa cell tumor. Cancer. 1984; 53:1605- 42. Dorfman HD, Czerniak B. Benign carti- multiple enchondromatosis (Ollier’s dis- 1608. lage lesions. In: Dorfman HD, Czerniak B, ease): an autopsy-based molecular genetic Hum Pathol eds. Bone Tumors. St Louis, MO: Mosby; study. . 2000; 31:1299-1303. 72. Le Gall C, Bouvier R, Chappuis JP, Herm- 1998:253-352. 57. Muramatsu K, Kawakami Y, Tani Y, Taguchi ier M. Ollier’s disease and juvenile ovarian granulosa tumor [in French]. Arch Fr Pediatr. 43. Filiz K. Ollier disease anaplastic mixed oli- T. Malignant transformation of multiple en- J Hand 1991; 48:115-118. goastrocytoma: a rare association with brain chondromas in the hand: case report. Surg Am. tumors. Neurosurg Q. 2006; 16:195-197. 2011; 36(2):304-307. 73. Gell JS, Stannard MW, Ramnani DM, Brad- shaw KD. Juvenile granulosa cell tumor in a 44. Slongo T, Schmittenbecher PP, Ganz R. 58. Pfleiderer AG, Thomson P, Milroy CM. View 13-year-old girl with enchondromatosis (Ol- Slippage of the proximal femoral epiphysis from beneath: pathology in focus. ENT pre- J Laryngol Otol. lier’s disease): a case report. J Pediatr Ado- related to multiple enchondromatosis: treat- sentation of Ollier’s disease. lesc Gynecol. 1998; 11:147-150. ment with staged surgical dislocation and 1991; 105:148-150. epiphyseal realignment. A case report at sev- 59. Pannier S, Legeai-Mallet L. Hereditary mul- 74. Weyl-Ben Arush M, Oslander L. Ollier’s dis- en years follow up. Eur J Pediatr Surg. 2011; tiple exostoses and enchondromatosis. Best ease associated with ovarian Sertoli-Leydig 21(2):131-134. Pract Res Clin Rheumatol. 2008; 22(1):45- cell tumor and breast adenoma. Am J Pediatr Hematol Oncol. 1991; 13(1):49-51. 45. Dahlin DC, Salvador AH. Cartilaginous tu- 54. mor of the soft tissues of the hands and feet. 60. Ozisik Y, Meloni AM, Spanier SS, Bush CH, 75. Au WY, Ooi GC, Ma SK, Wan TS, Kwong Mayo Clin Proc. 1974; 49:721-726. Kingsley KL, Sandberg AA. Deletion 1p in YL. Chronic myeloid leukemia in an adolescent with Ollier’s disease after intensive 46. Mitchell ML, Ackerman LV. Case report 405. a low-grade chondrosarcoma in a patient Cancer Genet Cytogenet x-ray exposure. Leuk Lymphoma. 2004; Skeletal Radiol. 1987; 16:61-66. with Ollier disease. . 1998; 105(2):128-133. 45(3):613-616. 47. Shapiro F. Ollier’s disease: an assessment of 76. Sendur OF, Turan Y, Odabasi BB, Berkit angular deformity, shortening, and pathologi- 61. Goto T, Motoi T, Komiya K, et al. Chondro- IK. A case of Ollier disease with non-small cal fracture in twenty-one patients. J Bone sarcoma of the hand secondary to multiple Arch cell lung cancer and review of the literature. Joint Surg Am. 1982; 64:95-103. enchondromatosis: report of two cases. Orthop Trauma Surg. 2003; 123:42-47. Rheumatol Int. 2010; 30:699-703. 48. Frappaz D, Ricci AC, Kohler R, Bret P, Mot- 77. Al-Ismail K, Torreggiani WC, Munk PL. Olli- tolese C. Diffuse brain stem tumor in an 62. Spranger JV, Langer LO, Wiedemann HR. Bone Dysplasias. er’s disease in association with adjacent fibro- adolescent with multiple enchondromatosis Philadelphia, PA: WB matosis. Skeletal Radiol. 2002; 31:479-483. (Ollier’s disease). Childs Nerv Syst. 1999; Saunders; 1974. 15(5):222-225. 63. Murphey MD, Flemming DJ, Boyea SR, 78. Amling M, Pösl M, Hentz MW, Priemel M, Delling G. PTHrP and Bcl-2: essential regu- 49. Kaplan RP, Wang JT, Amron DM, Kaplan L. Bojescul JA, Sweet DE, Temple HT. En- latory molecules in chondrocyte differen- Maffucci’s syndrome: two case reports with a chondroma versus chondrosarcoma in the ap- tiation and chondrogenic tumors. Verh Dtsch literature review. J Am Acad Dermatol. 1993; pendicular skeleton: differentiating features. Radiographics. 1998; 18:1213-1237. Ges Pathol. 1998; 82:160-169.

JUNE 2015 | Volume 38 • Number 6 e505 n Feature Article

79. Bovée JV, van den Broek LJ, Cleton- 90. Maroteaux P, Le Merrer M. Les Maladies Os- in the treatment of patients with Ollier’s dis- Jansen AM, Hogendoorn PC. Upregulation seuses de L’enfant. Paris, France: Médecine- ease. Clin Orthop Relat Res. 2001; 382:82- of PTHrP and Bcl-2 expression characterizes Sciences, Flammarion; 2002. 86. the progression of osteochondroma towards 91. Romeo S, Hogendoorn PC, Dei Tos AP. Be- 102. Tellisi N, Ilizarov S, Fragomen AT, Rozbruch peripheral chondrosarcoma and is a late event nign cartilaginous tumors of bone from mor- SR. Humeral lengthening and deformity cor- Lab Invest in central chondrosarcoma. . 2000; phology to somatic and germ-line genetics. rection in Ollier’s disease: distraction osteo- 80:1925-1934. Adv Anat Pathol. 2009; 16(5):307-315. genesis with a multiaxial correction frame. J Pediatr Orthop B. 80. Kunisada T, Moseley JM, Slavin JL, Martin 92. Azarpira N, Ashraf MJ, Shishegar M, Az- 2008, 17:152-157. TJ, Choong PF. Co-expression of parathyroid arpira MR. Ollier’s disease: cytologic find- 103. García-Cimbrelo E, Curto de la Mano A, hormone-related protein (PTHrP) and PTH/ ings. Cytopathology. 2008; 19:330-332. García-Rey E, Cordero J, Marti-Ciruelos R. PTHrP receptor in cartilaginous tumours: The intramedullary elongation nail for femo- Pathology 93. Anshu MD, Bhiogade Y, Nalinimohan C, a marker for malignancy? . 2002; ral lengthening. J Bone Joint Surg Br. 2002; 34:133-137. Gangane N. Cytodiagnosis of Ollier’s disease: a case report. Diagn Cytopathol. 2009; 84(7):971-977. 81. Pateder DB, Gish MW, O’Keefe RJ, Hicks 37:513-515. 104. Popkov D, Journeau P, Popkov A, Hau- DG, Teot LA, Rosier RN. Parathyroid hor- 94. Kendell SD, Collins MS, Adkins MC, Sunda- mont T, Lascombes P. Ollier’s disease mone-related peptide expression in cartilagi- limb lengthening: should intramedullary nous tumors. Clin Orthop Relat Res. 2002; ram M, Unni KK. Radiographic differentiation of enchondroma from low-grade chon- nailing be combined with circular external (403):198-204. Orthop Traumatol Surg Res. drosarcoma in the fibula.Skeletal Radiol. fixation? 2010; 82. Resnick D. Tumors and tumor-like lesions 2004; 33:458-466. 96(4):348-353. of bone: imaging and pathology specific le- 105. Baumgart R, Betz A, Schweiberer L. A fully sions. In: Diagnosis of Bone and Joint Dis- 95. Weiner SD. Enchondroma and chondrosarcoma of bone: clinical, radiologic, and histo- implantable motorized intramedullary nail orders. Philadelphia, PA: WB Saunders; Clin logic differentiation. Instr Course Lect. 2004; for limb lengthening and bone transport. 1995:3697-3711. Orthop Relat Res 53:645-649. . 1997; 343:135-143. 83. Unni KK, Inwards CY. Chondroma. In: Unni 96 Mirra JM, Gold R, Downs J, Eckhardt JJ. A 106. Miyakawa G. Replacement of the shaft of the KK, Inwards CY, eds. Dahlin’s Bone Tumors. J Bone Joint Surg new histologic approach to the differentia- phalanx with iliac bone. 6th ed. Philadelphia, PA: Lippincott Williams Am. 1961; 43:905-907. & Wilkins; 2010:22-40. tion of enchondroma and chondrosarcoma of the bones: a clinicopathologic analysis of 51 107. Giannikas AC. Treatment of metacarpal en- 84. Lee JKT, Sagel SS, Stanley RJ, et al. Mus- cases. Clin Orthop Relat Res. 1985; 201:214- chondromata: report of three cases. J Bone Computed Body culoskeletal system. In: 237. Joint Surg Br. 1966; 48:333-335. Tomography with MRI Correlation. Phila- delphia, PA: Lippincott Williams & Wilkins; 97. Sanderson GH, Smyth FS. Chondrodysplasia 108. Fatti JF, Mosher JF. Treatment of multiple 2005:1611-1613. (Ollier’s disease): a report of a case resem- enchondromatosis (Ollier’s disease) of the bling osteitis fibrosa cystica.J Bone Joint hand. Orthopedics. 1986; 9:512-518. 85. Kim E, Miyake J, Kataoka T, Oka K, Morito- Surg Am. 1938; 20:61-67. mo H, Murase T. Corticoplasty for improved 109. Ulutas K, Menderes A, Yilmaz M. Enchon- appearance of hands with Ollier disease. J 98. Watanabe K, Tsuchiya H, Sakurakichi K, dromatosis of the hand: severe and mild Hand Surg Am. 2012; 37(11):2294-2299. Yamashiro T, Matsubara H, Tomita K. Treat- forms, and treatment modalities. Ann Plast ment of lower limb deformities and limb- Surg. 2001; 47:214-215. 86. Cohen EK, Kressel HY, Frank TS, et al. length deficiencies with the external fixator 110. Al-Qattan MM, Javed K, Pant R. An unusual Hyaline cartilage origin bone and soft tissue J Orthop Sci in Ollier’s disease. . 2007; case of multiple hand enchondromas. J Hand neoplasms: MR appearance and histologic 12:471-475. correlation. Radiology. 1988; 167:477-481. Surg Eur. 2010; 35:321-322. 99. Adas M, Yurdoglu HC, Tonbul M, Ozbaydar Radiology Review 111. Klausmeyer MA, Cohen MJ, Kulber DA. 87. Dähnert W. Bones. In: MU, Keris I. The results of curettage and Manual. Philadelphia, PA: Lippincott Wil- Reconstruction of Ollier disease in a se- bone cementing for enchondromas of the dis- verely involved hand. Ann Plast Surg. 2013; liams & Wilkins, 2003:70-71. Acta Orthop Trauma- tal femur [in Turkish]. 71(6):646-648. 88. Dobert N, Menzel C, Ludwig R, et al. En- tol Turc. 2007; 41(5):380-386. 112. Formis A, Allegri S, Posteraro L. Rehabilita- chondroma: a benign osseous lesion with 100. Ilizarov GA, Shevtsov VI. Bloodless method high F-18 FDG uptake. Clin Nucl Med. 2002; tion experience in a case of Ollier’s disease. of compression-dystraction osteosynthe- Acta BioMed. 2003; 74(3):151-156. 27:695-697. sis for treatment of pseudoarthrosis of the 89. Kobayashi H, Kotoura Y, Hosono M, et al. humerus [in Russian]. Voen Med Zh. 1974; 113. Sassoon AA, Fitz-Gibbon PD, Harmsen WS, Diagnostic value of Tc-99m (V) DMSA for 6:27-31. Moran SL. Enchondromas of the hand: factors affecting recurrence, healing, motion, chondrogenic tumors with positive Tc-99m 101. Jesus-Garcia R, Bongiovannini JC, Korukian Clin and malignant transformation. J Hand Surg HMDP uptake on bone scintigraphy. M, et al. Use of the Ilizarov external fixator Nucl Med. 1995; 20:361-364. Am. 2012; 37(6):1229-1234.

View publication stats