Judith V.M.G. Bovée M.D., Ph.D., research
Research authored by Dr. Bovée
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List of Publications via PubMed
(NIH National Library of Medicine)
Dr. Bovée is one of the team members of EuroBoNet pathologist specialised in the pathology of bone and soft tissue tumours.
She is part of the bone tumour research group. The main emphasis of her research is focused on enchondromas,
osteochondromas and chondrosarcomas.
Press Release 2 / 13 / 08
Multiple osteochondromas
Judith V.M.G. Bovée
Orphanet Journal of Rare Diseases 2008, 3:3 (13 February 2008)
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2009 Conference abstract
On the Clinical Manifestation and the Genetics of Ollier Disease

T.C. Pansuriya, S.H.M. Verdegaal, P.C.W. Hogendoorn, A.H.M. Taminiau, and J.V.M.G. Bovee
Leiden University Medical Center, P.O. 9600, 2300 RC Leiden, The Netherlands

Enchondromatosis is a non-hereditary disease, characterised by the presence of multiple enchondromas with a marked unilateral
predominance mainly affecting medulla of the metaphyses and diaphyses of short and long tubular bones of the limbs, especially
the hands and feet. The risk of malignant transformation is suggested to be up to 35%. Due to the rarity of these diseases,
systematic studies on clinical behaviour providing information how to treat patients are lacking. Also, studies to the genetic
cause of Ollier disease are sparse and hampered by low numbers. PTHR1 mutations can be found in only a small proportion (so
far 5 of 62) of cases.

We performed a descriptive retrospective EMSOS (European Musculoskeletal oncology Society)-study in which 12 institutes in
eight countries participated. 118 patients with Ollier Disease and 15 patients with Maffucci Syndrome were included. Unilateral
localization of disease was found in 60% of Ollier patients and 40% of patients with Maffucci Syndrome. One of the predictive
factors for developing chondrosarcoma is the location of the enchondromas; the risk increases especially when enchondromas
are located in the scapula (33%), humerus (18%), pelvis (26%) or femur (15%). For the phalanges, this risk is 14% in the hand
and 16% in the feet. The decision whether or not to perform extensive surgery is difficult, especially in patients who suffer
multiple chondrosarcomas. Malignant transformation was found in forty-four patients with Ollier Disease (37%) and eight
patients with Maffucci Syndrome (53%). Dedifferentiated chondrosarcoma was not found. Multiple synchronous or metachronous
chondrosarcomas were found in 15 patients. Nine patients died (range 21-54 yrs). Seven of them died disease related due to
pulmonary metastasis (2 humerus, 2 pelvis, 3 femur). Two patients died from glioma of the brain.

To study the genetic background of Ollier disease we performed SNP analysis using Affymetrix SNP6.0 on 15 enchondromas and
24 chondrosarcomas of different grades from 30 Ollier patients and normal DNA from 12 Ollier patients for paired comparison.
We studied tumour tissue since we hypothesized that Ollier disease is a mosaic condition, since it affects multiple bones with an
often unilateral predominance. All samples were divided into three groups: normals, enchondromas and chondrosarcomas. The
number of numerical genomic changes in the chromosomes were not different for the enchondromas (p=0.36) while large
genomic aberrations were seen in chondrosarcomas as compared to normals (p=0.01). Results are analyzed using R, Partek and
Nexus. No common region of Loss of Heterozygosity (LOH) was shared between all enchondromas. LOH at 6p, 9q and 13q is
shared by a proportion of chondrosarcomas. A list with candidate genes was generated combining the SNP data with expression
profiles generated using Illumina Bead Array and these genes are currently being validated. Enchondromas located in the
phalangeal bones of the hands were genetically different from enchondromas located in the long bones. In summary the absence
of common copy number variations or loss of heterozygosity suggests that instead point mutations or epigenetic mechanisms
seem to play a role in the origin of Olllier disease. Mutation analysis revealed absence of the reported G121E, A122T, R150C and
R255H variations in PTHR1 in our series. In addition, mutations in NDST1, the first modification enzyme of the HS polymer which
was recently suggested to compete with EXT1 for binding to EXT2, were also absent.
2009 Conference abstract
Osteochondroma Formation: Haploinsufficiency or Two Hits?

Christianne MA Reijnders 1, Cathelijn JF Waaijer1, Andrew Hamilton7, Sander Dijkstra2, John Ham5, Egbert Bakker3, Karoly
Szuhai4, Marcel Karperien6, Pancras CW Hogendoorn1, Sally E Stringer7,
Judith VMG Bovée1
Departments of 1Pathology, 2Orthopedic Surgery, 3Human and Clinical Genetics, and 4Molecular Cell Biology, Leiden University
Medical Center, Leiden, The Netherlands; 5Department of Orthopedics, OLVG, Amsterdam, The Netherlands; 6Department of
Tissue Regeneration, University of Twente, Enschede, The Netherlands; 7Cardiovascular Group, School of Clinical and Laboratory
Sciences, Faculty of Human and Medical Sciences, University of Manchester, Manchester, United Kingdom

Multiple osteochondromas (MO) is an autosomal dominant disorder caused by germline mutations in EXT1 and/or EXT2, whereas
solitary osteochondroma is a non-hereditary lesion. EXT is involved in heparan sulfate biosynthesis. We investigated the
controversial issue whether osteochondromas arise via the classical two-hit model for tumor suppressor genes or via

An in vitro 3D chondrogenic pellet model was used to compare heterozygous mesenchymal stem cells (MSCs)(EXTwt/-) of MO
patients with normal MSCs and the corresponding tumor specimens (presumed EXT-/-). EXT mutations and mRNA expression
levels were assessed. HS chain length and structure of normal and heterozygous MSCs in monolayer culture was determined.
Immunohistochemistry was performed on heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs)(SDC2-4, perlecan,
CD44v3), and HS dependent signaling pathways: TGFbeta/BMP (phosphosmad-1, phosphosmad-2, PAI-1), Wnt (beta-catenin)
and PTHLH (PTHR1, bcl2).

Germline EXT1 and EXT2 mutations were present in MO patients (6/8). We demonstrated a second hit in the EXT genes in 5 out
of 8 osteochondromas (both solitary and hereditary). MSCs with a heterozygous EXT mutation are identical to wildtype MSCs
with regard to HS chain length and structure, in vitro chondrogenesis and the expression of EXT and EXT downstream signaling

In conclusion, since I) a heterozygous EXT mutation does not affect chondrogenesis, heparan sulfate and downstream signaling
pathways and II) we show a second hit in the majority of osteochondromas our results refute the haploinsufficiency theory and
strongly support the two-hit model for osteochondroma formation.

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