j.berh.2020.101505

Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Rheumatology
journal homepage: www.elsevierhealth.com/berh
Multiple hereditary exostoses and
enchondromatosis
Anne Grethe Jurik
Department of Radiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, Entrance C, location
C118/ reference point C109, 8200, Aarhus N, Denmark
a b s t r a c t
Keywords:
Osteochondromatosis
Multiple exostoses
Diaphyseal aclasis
Enchondromatosis
Ollier disease
Maffucci syndrome
Chondrosarcoma
Multiple hereditary exostoses (MHE) and enchondromatosis are
rare multifocal benign disorders usually causing skeletal deformities appearing already in childhood. MHE is a dominant
autosomal inherited disorder characterized by multiple osteochondromas (exostoses) growing outward from the metaphyses of
long bones as well as from flat bones. They may cause reduced
joint motion and pain due to tendon, muscle, and nerve
compression.
Enchondromatosis (or Ollier's disease) is a noninherited disorder
characterized by the presence of multiple intraosseous enchondromas located asymmetrically in the skeleton and with a wide
variation regarding location, size, and number ranging from the
involvement of a single hand to the involvement of the entire
skeleton. It can occur together with soft-tissue hemangiomas in
Maffucci's syndrome. Clinical problems caused by the enchondromas are mainly related to skeletal deformities causing malalignment and restricted motion of joint.
In both disorders, there is a risk of malignant transformation as
well as secondary degenerative joint changes.
© 2020 Elsevier Ltd. All rights reserved.
Introduction
Multiple cartilage tumors are rare. They may present as multiple enchondromas, so-called
enchondromatosis, seen in Ollier's disease and with accompanying hemangiomas in Maffucci's
E-mail address: [email protected].
https://doi.org/10.1016/j.berh.2020.101505
1521-6942/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
2
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
syndrome, or as multiple osteochondromas/exostoses, also referred to as multiple hereditary exostoses
(MHE), familial osteochondromatosis, and diaphyseal aclasis. The prevalence of enchondromatosis is
estimated to be 1: 100,000 [1], whereas the prevalence of MHE is about 1: 50,000, but may be higher in
demarcated populations [2].
Enchondromatosis and MHE usually appear and are diagnosed in childhood because the cartilage
tumors often cause growth disturbances and skeletal deformations, occasionally needing treatment
[2]. In adults, the deformities can influence joint alignment and joint complaints are frequent, often
due to secondary degenerative changes.
Although the tumors are primarily benign, both tumor forms have a potential for malignant
transformation into chondrosarcoma, which influence the management of patients.
Multiple hereditary exostoses (MHE)
MHE is a dominant autosomal hereditary condition, mainly caused by mutations in two genes:
exostosin-1 (EXT1) and exostosin-2 (EXT2), being present in 70e94% of patients, most frequently EXT1
[3]. There is no sex difference regarding the prevalence of MHE [4,5], but male subjects with EXT1 may
have a more pronounced disease [6], probably related to later physeal closure (prolonging the effects of
the EXT gene) in males than in female subjects or hormonal differences.
The disorder is characterized by the presence of multiple benign exostoses (osteochondromas)
consisting of two components, an osseous stem, which is in continuity with the bone marrow of the
underlying bone, and a thin cartilage cap on the surface. They can be broad-based (sessile) or
pedunculated. Most patients present with six or more osteochondromas, and their location can vary
considerably [7]. Osteochondromas can occur corresponding to all bones developed based on the
hyaline cartilage, but the most frequent location is around the knee, including the distal femur,
proximal tibia, and fibula (Fig. 1A), and the humerus. Osteochondromas are also relatively frequent in
the area of the trunk (e.g., pelvis, spine, and scapula), where they similarly have a central continuity
with the underlying bone marrow, but osteochondromas at carpal and tarsal bones are rare. The
osteochondromas develop and increase in number and size during childhood until the growth plates
close, and pedunculated osteochondromas at peripheral bones characteristically grow away from the
growth plate and the joint (Fig. 1A).
Clinical presentation
There is a wide spectrum of clinical manifestations as the number, size, and location of osteochondromas vary. This variation may be related to genetic factors such as the EXT1 mutation with
manifest or incomplete penetrance and gender differences. However, growth deformities of bones and
short stature are present in a considerable number of patients.
The most common complaints in adults are pain and functional impairment. The pain can be caused
by the compression of tendons and muscles (Fig. 1C), sometimes causing chronic irritation and/or
rupture, nerve compression, the development of bursitis over the cartilage cap, and changes secondary
to joint malalignment. More rarely trauma can result in the fracture of pedunculated exostoses.
Reduced motion of joints is often encountered, e.g., limited knee flexion due to an osteochondroma
in the popliteal region, and the reduced rotation of the forearm caused by osteochondromas between
the radius and ulna. Developmental joint deformities often occur, like coxa valga, seen due to exostoses
near the minor trochanter [8] (Fig. 1B), valgus, or flexion deformity at the knee [7] and valgus angulation at the ankle region due to relative shortening of the fibula and obliquity of the distal tibial
epiphysis [9]. The osseous deformities at the hip, knee, and ankle may lead to the development of
degenerative joint disease at a relatively early age.
Osteochondromas in the spine are mostly located at the posterior part of the vertebrae, but they can
extend into the spinal canal. Although symptomatic compression of the medulla is rare [10], spinal
osteochondromas require careful management to prevent serious disability, especially during skeletal
development [11].
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
3
Fig. 1. Multiple hereditary exostoses. (A) AP radiograph of the knee in a 15-year-old girl with MHE showing a mixture of sessile (*)
and pedunculated osteochondromas (arrows). There are sequels of epiphysiodesis performed to correct a valgus deformation. (B)
Radiograph of the pelvis performed 9 years later (at the age of 24 years) due to hip pain on the left side. There are numerous
osteochondromas, most pronounced in the left hip region in addition to bilateral valgus deformity. (C). Supplementary MRI of the
left hip, coronal (left image), and axial proton fat saturated images show reduced space between a voluminous osteochondroma at
the minor trochanter and the ischium with edema in the interposed obturator muscle (arrows) as a sign of impingement. (D) A
preoperative 3D CT image more clearly shows the extent and location of the multiple osteochondromas.
Risk of malignancy
Malignant transformation of osteochondromas is a rare, but important complication, mainly seen in
adult patients. The reported estimated risk of malignant transformation has varied considerably and
the exact risk has not been established. Thus, secondary chondrosarcoma has been reported to occur in
0e11% of patients, but in two recent reviews it was estimated to occur in 3.7% and 3.9% of MHE patients,
respectively [12,13]. The secondary chondrosarcomas described were predominantly localized to the
pelvis, scapula, proximal femur, and humerus [6,12e15]. The possibility of malignant transformation
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
4
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
demands regular clinical follow-up of adult patients, including appropriate imaging, especially of the
trunk area, including the proximal femur and humerus.
Imaging findings
Radiographically osteochondromas present as osseous protuberances with a smooth contour and
usually a regular internal bone marrow structure (Fig. 1A). They can be broad-based or pedunculated.
Benign-appearing osteochondromas in the appendicular skeleton do not require additional evaluation
by magnetic resonance imaging (MRI) to detect malignant transformation as MRI has no diagnostic
value when compared with radiography in this context [16]. However, MRI can be valuable for visualizing soft tissue alterations caused by osteochondromas in the appendicular skeleton, such as
bursitis, tendinitis, and muscle compression (Fig. 1C), in addition to degenerative joint changes, and
MRI or CT have been reported valuable for assessing osteochondromas in anatomically complex areas
such as the pelvis, spine, and thoracic skeleton [12,17] (Fig. 1D). Roach et al. recommend a full spinal
MRI every second year in children with MHE, to identify intraspinal osteochondromas and potential
medullary affection, to prevent neurological damage [11].
Signs of malignancy by radiography are irregular surface (the best predictor of sarcomatous
degeneration), inhomogeneous mineralization with lytic areas in the bone marrow, and accompanying
soft tissue mass, often containing scattered calcifications [17e19] (Fig. 2). Such changes should always
be evaluated by supplementary MRI or CT. By MRI or CT-scanning, a cartilage cap 2 cm, bone
destruction, and soft tissue alterations are indicative of malignancy [20].
Adult MHE patients are recommended to be followed with MRI of the trunk, proximal femur, and
humerus regularly with intervals of 1e2 years, whereas the peripheral osteochondromas can be
monitored clinically with concomitant radiography when needed [12,13].
Fig. 2. Secondary chondosarcoma in MHE. (A) AP radiograph of the pelvis showing several osteochondromas at both proximal
femora and a huge soft tissue mass with scattered mineralization on the left sides (arrows), indicating a malignant tumor. (B)
Supplementary MRI, coronal STIR (left-sided image), and axial T1-weighted images show a huge edematous tumor (white arrows),
which was seen to originate from a sessile osteochondroma at the inferior pubic rami (black arrow).
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
5
Differential diagnoses
Multiple osteochondromas occur in other inherited conditions, which can be considered as differential diagnoses. Metachondromatosis is a rare inherited autosomal dominant disease characterized
by the occurrence of both multiple enchondromas and multiple osteochondromas, caused by the loss
of function of the PTPN11 gene. The clinical appearance can be like HME [21], but there are typically
lesions in hands and feet (which are rare in MHE) in addition to lesions at long tubular bones and the
pelvis, and the lesions typically regress in adulthood. Besides, there are no deformities due to osteochondromas as seen in MHE. Osteochondromas can also be seen as part of Langer-Giedion syndrome, a
very rare congenital disease caused by gene deletion (chromosome 8q23.3-q24.11). The clinical
manifestations of this syndrome include facial dysmorphism, microcephaly, and mental retardation in
addition to short stature and osteochondromas [22].
Treatment and management
There are no disease-modifying medical therapies, but in the absence of clinical problems, osteochondromas require no therapy. Surgical resection is often necessary when the osteochondromas
cause pain, interfere with joint or muscle function, compress nerves or vessels, or cause deformity
(Fig. 1). To correct deformities, joint malalignment, and limb length inequality, more complex procedures are often necessary, such as osteotomies, bone lengthening, and epiphysiodesis, which are
often performed in childhood (Fig. 1A).
In adults, the surveillance of osteochondromas in the area of the trunk is recommended due to the
risk of malignant transformation [13]. The definite diagnosis and the treatment of sarcomatous changes
should be handled in hospitals with a specialist in sarcoma treatment [18].
Enchondromatosis
Enchondromatosis (Ollier's disease) is a rare noninherited disorder characterized by multiple (three
or more) benign enchondromas in the skeleton, most frequently in the metaphyses and diaphyses of
the long tubular bones around the knee joint and in the hands (phalanges and metacarpals) (Fig. 3). The
development of enchondromas is thought to be due to the derangement of cartilaginous growth,
resulting in the migration of cartilaginous rests from the epiphyseal plate into the metaphyseal regions.
The enchondromas usually appear in childhood and increase in size and number until the growth
plates close (Fig. 3). Their distribution is often asymmetrical, and the number, size, and location of the
enchondromas vary considerably. There may be enchondromas in the entire skeleton, limited to onehalf of the body, or involving only one extremity or a single hand. There is, however, a predilection for
the appendicular skeleton, and the involvement of bones in the trunk area is only seen in severe cases
[23]. Male subjects may be more frequently affected than female subjects [23]. The diagnosis is usually
based on clinical findings and radiographic features and can be confirmed, if necessary, by findings of
gene mutations in cartilage tissue corresponding to the IDH1 or IDH2 gene (isocitrate dehydrogenase-1
and -2 gene) encoding the enzyme isocitrate dehydrogenase [24].
Enchondromatosis with accompanying soft tissue hemangiomas is a rare condition referred to as
Maffucci's syndrome. The enchondromas are mostly like those seen in Ollier's disease. The accompanying hemangiomas can occur anywhere, even in the internal organs unrelated to the enchondromas,
but are most frequently seen in the hands (Fig. 4). The syndrome is related to gene mutations corresponding to the IDH1 or IDH2 gene in both cartilage and blood vessels [24], and the enchondromas as
well as the hemangiomas have a potential for malignant transformation into chondrosarcoma and
angiosarcoma, respectively [25] (Fig. 5).
Clinical presentation
The symptoms are rather variable depending on the age of onset and the location, number, and size
of the enchondromas, which may vary considerably. The patient usually presents with painless multiple swellings at extremities or with skeletal deformity including the unequal length of arms/legs,
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
6
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Fig. 3. Enchondromatosis. (A) AP radiograph of a right hand in an otherwise healthy girl in the age range from 7 to 13 years showing the
gradually increasing size of enchondromas in the second and third finger, especially corresponding to the middle phalangeal bone in the
third finger. (B) Supplementary MRI, coronal STIR (to the left), and T1-weighted images show characteristic intraosseous cartilaginous
masses with high intensity on the STIR image. (C) Illustration of multiple enchondromas in the hip region-causing valgus deformation.
deformed fingers (Figs. 3 and 4), joint malalignment, and reduced joint mobility. The development of
bone angulation occurs when the enchondromas are nonuniformly located in the metaphyses. Also,
broadening of the metaphyses can contribute to deformities, such as genu valgus and cubitus varus.
There may be associated pain due to soft tissue changes, e.g., in relation to joint malalignment, and in
adults, secondary degenerative changes.
Risk of malignancy
The reported estimated risk of malignant transformation has varied considerably from 6.6% to over
50%, highest in patients with Maffucci's syndrome [26e28]. This may be due to different locations of
the disease in study populations. In a retrospective multicenter study involving 144 patients with
Ollier's disease and 17 patients with Maffucci's syndrome, the estimated risk of developing
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
7
Fig. 4. Maffucci's syndrome. (A) Images of the right hand in a 32-year-old woman with increasing soft tissue masses corresponding
to the radial side of the hand including the first and second finger. There is a bluish discoloration of the skin due to soft tissue
hemangiomas. (B) MR images, coronal proton fat saturated (upper images), and T1-weighted images show pronounced edematous
soft tissue hemangiomas with dark dots as signs of phleboliths in addition to scattered small enchondromas in the phalangeal bones
best visualized on the T1-weighted images (arrows). (C) Radiographs of the elbow showing joint malalignment and phleboliths
corresponding to soft tissue hemangioma (arrows).
chondrosarcoma was approximately 40% in Ollier patients with long tubular bone, pelvic, and scapula
enchondromas, while the risk was only approximately 15% in patients with enchondromas restricted to
hands and feet [28]. The risk was estimated to be higher (>50%) in Maffucci patients with long tubular
and flat bone enchondromas. The results of other studies is in accordance with these findings;
chondrosarcoma, predominantly localized to long tubular bone and pelvis occurred in 20e25% of
patients with enchondromatosis [17,26], but only in 6.6% of patients with enchondromas limited to the
hand region [27]. The potential for malignant transformation imply a need for lifelong clinical as well as
imaging follow-up to detect malignancy as early as possible and thereby improve prognosis [18].
Maffucci patients with the greatest risk of malignancy should be checked annually, while it may be
sufficient to monitor Ollier patients every second year [13].
Imaging findings
Radiographically, the enchondromas seen in enchondromatosis present as osteolytic lesions with
well-defined, sclerotic margins and internal longitudinal striated and/or speckled mineralization
corresponding to the content of cartilage in the metaphyseal and diaphyseal regions of long bones
(Fig. 3A,C). There may be accompanying bone deformations and shortening in addition to joint
malalignments, etc. In Maffucci's syndrome, radiographs show bone lesions similar to those seen in
Ollier's disease in addition to signs of soft-tissue hemangiomas usually identified by the presence of
calcified phleboliths corresponding to vascular malformations (Fig. 4C).
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
8
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Fig. 5. Secondary chondosarcoma in enchondromatosis. Radiographs of the hands, AP, and oblique views in a 70-year-old woman
with deformed fingers since childhood and an increasing mass corresponding to the left fifth finger during three months. Multiple
enchondromas are seen, especially located at the fourth and fifth finger, and a manifest lytic area in the middle phalangeal bone of
the left fifth finger accompanied by a soft tissue mass (arrows). This indicates a malignant transformation and biopsy revealed
chondrosarcoma grade 3 causing the amputation of the finger.
MRI is superior to radiography for visualizing enchondromas and can contribute to the differentiation between benign enchondromas and chondrosarcoma [16]. MRI is therefore increasingly used to
diagnose and monitor enchondromatosis in long tubular bones and the trunk area. Enchondromas in
the hands and feet can usually be sufficiently assessed by radiography [29], which can be supplemented by MRI if radiography reveals changes that show signs of malignancy.
Signs indicating a possible malignant transformation are cortical thinning, bone destruction,
cortical remodeling/thickening, bone expansion, and soft tissue involvement [30] (Fig. 5) in addition to
change over time in the form of increasing size, development of poorly defined intraosseous border,
surrounding edema, and increasing excavation of cortical bone [31].
Imaging follow-up of patients with extensive enchondromatosis can be performed by using a
whole-body MRI (WBMRI) providing the visualization of both the skeleton and the soft tissue with
regard to changes of enchondromas as well as hemangiomas. WBMRI should be from vertex to toes [13]
as there is a risk of malignant transformation not only in the trunk area but also in long and small
tubular bones [26]. WBMRI also enables the detection of other malignancies, which can be encountered, especially in Maffucci patients, who are at increased risk of other malignant disorders such as
astrocytoma and pancreatic adenocarcinoma [1]. However, hands, feet, and elbow regions can sometimes be difficult to assess adequately by WBMRI. When necessary, the WBMRI therefore has to be
supplemented by a radiography or a site-specific MRI of these regions.
Maffucci patients with the greatest risk of malignancy should be checked annually, while every
second year may be sufficient in patients with enchondromatosis only [13].
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
9
Differential diagnoses
The differential diagnoses include metachondromatosis (see section about MHE) and sometimes
MHE. Although enchondromas can be distinguished from osteochondromas based on tumor location in
the center of bones whereas osteochondromas are located at bone surfaces, there can be periosteal
enchondromas simulating osteochondromas.
Treatment and management
There are no disease-modifying medical therapies, but in the absence of clinical problems, Ollier's
disease requires no treatment. Surgery is indicated in the case of complications, such as pathological
fractures and growth disturbances. In adults, the surveillance of enchondromas is recommended with
regard to malignant transformation. The definite diagnosis and treatment of sarcomatous changes
should be handled by hospitals that are specialized in sarcoma treatment [18].
Summary
MHE and enchondromatosis are rare benign disorders usually causing skeletal deformities influencing musculoskeletal function. There are no disease-modifying medical therapies. Thus, surgery is
the only therapeutic possibility with regard to the correction of deformation-causing symptoms, e.g.,
because of the compression of tendons, muscles, nerves, and vascular structures or joint malalignment
predisposing to osteoarthritis. However, the most feared complication is a risk of malignant transformation. The exact risk is still unknown and need to be clarified. Malignant transformation has been
estimated to occur in about 4% of patients with MHE, but may depend on the disease severity. The
estimated risk of having enchondromatosis has varied from 6.6% to over 50%, being lowest in patients
with a disease confined to the hands and highest in patients with Maffucci's syndrome. Because of this
risk, life-long surveillance of MHE and enchondromatosis patients is recommended, including regular
MR imaging. In enchondromatosis, there may be a need for whole-body imaging, whereas imaging of
the trunk areas including the proximal femur and humerus seem to be sufficient in MHE patients. The
appropriate interval between screening for malignancy and cost-effectiveness with regard to saving
lives and expenses is currently unknown and need to be evaluated.
Practice points
MHE and enchondromatosis are rare benign disorders often causing skeletal deformities
influencing musculoskeletal function.
Currently, there are no disease-modifying medical therapies, but deformities can often be
corrected by surgery.
There is a risk of malignant transformation in both disorders necessitating life-long
surveillance.
Research agenda
Development of disease-modifying drugs would be highly appreciated
There is a need for further studies regarding the most appropriate follow-up strategy with
regard to malignant transformation.
Studies encompassing large patient populations, e.g., obtained by multicenter studies
are needed to evaluate the real risk for malignant transformation, especially in
enchondromatosis.
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
10
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Funding
None.
Declaration of Competing Interest
None.
References
[1] Pansuriya TC, Kroon HM, Bovee JV. Enchondromatosis: insights on the different subtypes. Int J Clin Exp Pathol 2010;3(6):
557e69.
[2] Schmale GA, Conrad 3rd EU, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Jt Surg Am 1994;
76(7):986e92.
[3] Jennes I, Pedrini E, Zuntini M, et al. Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat 2009;30(12):1620e7.
[4] Porter DE, Lonie L, Fraser M, et al. Severity of disease and risk of malignant change in hereditary multiple exostoses. A
genotype-phenotype study. J Bone Jt Surg Br 2004;86(7):1041e6.
[5] Wicklund CL, Pauli RM, Johnston D, Hecht JT. Natural history study of hereditary multiple exostoses. Am J Med Genet 1995;
55(1):43e6.
[6] Pedrini E, Jennes I, Tremosini M, et al. Genotype-phenotype correlation study in 529 patients with multiple hereditary
exostoses: identification of "protective" and "risk" factors. J Bone Jt Surg Am 2011;93(24):2294e302.
[7] Clement ND, Porter DE. Can deformity of the knee and longitudinal growth of the leg be predicted in patients with hereditary multiple exostoses? A cross-sectional study. Knee 2014;21(1):299e303.
[8] Wang YZ, Park KW, Oh CS, et al. Developmental pattern of the hip in patients with hereditary multiple exostoses. BMC
Muscoskel Disord 2015;16. 54-5015-0514-5.
[9] Noonan KJ, Feinberg JR, Levenda A, et al. Natural history of multiple hereditary osteochondromatosis of the lower extremity and ankle. J Pediatr Orthop 2002;22(1):120e4.
[10] Sciubba DM, Macki M, Bydon M, et al. Long-term outcomes in primary spinal osteochondroma: a multicenter study of 27
patients. J Neurosurg Spine 2015;22(6):582e8.
[11] Roach JW, Klatt JW, Faulkner ND. Involvement of the spine in patients with multiple hereditary exostoses. J Bone Jt Surg
Am 2009;91(8):1942e8.
[12] Fei L, Ngoh C, Porter DE. Chondrosarcoma transformation in hereditary multiple exostoses: a systematic review and
clinical and cost-effectiveness of a proposed screening model. J Bone Oncol 2018;13:114e22.
[13] Jurik AG, Jorgensen PH, Mortensen MM. Whole-body MRI in assessing malignant transformation in multiple hereditary
exostoses and enchondromatosis: audit results and literature review. Skeletal Radiol 2020;49(1):115e24.
[14] Clement ND, Ng CE, Porter DE. Shoulder exostoses in hereditary multiple exostoses: probability of surgery and malignant
change. J Shoulder Elbow Surg 2011;20(2):290e4.
[15] Czajka CM, DiCaprio MR. What is the proportion of patients with multiple hereditary exostoses who undergo malignant
degeneration? Clin Orthop Relat Res 2015;473(7):2355e61.
[16] De Beuckeleer LH, De Schepper AM, Ramon F. Magnetic resonance imaging of cartilaginous tumors: is it useful or
necessary? Skeletal Radiol 1996;25(2):137e41.
[17] Brien EW, Mirra JM, Luck Jr JV. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical
basis with an emphasis on radiology, pathology and clinical biology. II. Juxtacortical cartilage tumors. Skeletal Radiol 1999;
28(1):1e20.
[18] Ahmed AR, Tan TS, Unni KK, et al. Secondary chondrosarcoma in osteochondroma: report of 107 patients. Clin Orthop Relat
Res 2003;411:193e206.
[19] Garrison RC, Unni KK, McLeod RA, et al. Chondrosarcoma arising in osteochondroma. Cancer 1982;49(9):1890e7.
[20] Tsuda Y, Gregory JJ, Fujiwara T, Abudu S. Secondary chondrosarcoma arising from osteochondroma: outcomes and
prognostic factors. Bone Joint Lett J 2019;101-B(10):1313e20.
[21] Fisher TJ, Williams N, Morris L, Cundy PJ. Metachondromatosis: more than just multiple osteochondromas. J Child Orthop
2013;7(6):455e64.
[22] Cappuccio G, Genesio R, Ronga V, et al. Complex chromosomal rearrangements causing Langer-Giedion syndrome atypical
phenotype: genotype-phenotype correlation and literature review. Am J Med Genet 2014;164A(3):753e9.
[23] Kumar A, Jain VK, Bharadwaj M, Arya RK. Ollier disease: pathogenesis, diagnosis, and management. Orthopedics 2015;
38(6):e497e506.
[24] Amary MF, Damato S, Halai D, et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1
and IDH2. Nat Genet 2011;43(12):1262e5.
[25] Maione V, Stinco G, Errichetti E. Multiple enchondromas and skin angiomas: Maffucci syndrome. Lancet 2016;388(10047):
905e6736 (16)00088-X.
[26] Liu J, Hudkins PG, Swee RG, Unni KK. Bone sarcomas associated with Ollier's disease. Cancer 1987;59(7):1376e85.
[27] Altay M, Bayrakci K, Yildiz Y, et al. Secondary chondrosarcoma in cartilage bone tumors: report of 32 patients. J Orthop Sci
2007;12(5):415e23.
[28] Verdegaal SH, Bovee JV, Pansuriya TC, et al. Incidence, predictive factors, and prognosis of chondrosarcoma in patients
with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients. Oncol 2011;16(12):1771e9.
[29] Gajewski DA, Burnette JB, Murphey MD, Temple HT. Differentiating clinical and radiographic features of enchondroma and
secondary chondrosarcoma in the foot. Foot Ankle Int 2006;27(4):240e4.
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505
A.G. Jurik / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
11
[30] Murphey MD, Flemming DJ, Boyea SR, et al. Enchondroma versus chondrosarcoma in the appendicular skeleton: differentiating features. Radiographics 1998;18(5):1213e37. quiz 1244-5.
[31] Brien EW, Mirra JM, Kerr R. Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis
with an emphasis on radiology, pathology and clinical biology. I. The intramedullary cartilage tumors. Skeletal Radiol
1997;26(6):325e53.
Please cite this article as: Jurik AG, Multiple hereditary exostoses and enchondromatosis, Best Practice &
Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2020.101505