Ollier's Disease Research Articles

Genetics and genomics of ovarian sex cord-stromal tumors.

Ovarian sex cord-stromal tumors (SCST) represent approximately 8% of malignant ovarian tumors. The most common are granulosa cell tumors (GCT) which account for approximately 90% of malignant SCST. Recent studies have unraveled the key genomic and genetic events contributing to their pathogenesis. SCST are found in the hereditary syndromes: Peutz-Jeghers syndrome, Ollier disease and Maffucci syndrome, and DICER1 syndrome. Genomic studies have largely been limited to GCT where a number of recurring chromosomal abnormalities (monsomy and trisomy) have been identified although their contribution to pathogenesis remains unclear. In addition to the recurrent DICER1 mutations reported in non-hereditary cases of Sertoli cell and Sertoli-Leydig cell tumors, recurrent somatic mutations in both the juvenile (j) and adult (a) forms of GCT have been reported. Approximately 30% of jGCT contain a somatic mutation, the gsp oncogene, while a further 60% have an activating mutation in the AKT gene. In the case of aGCT, a well characterized mutation in the FOXL2 transcription factor (FOXL2 C134W) is found in almost all cases, which arguably defines the disease, although the molecular events that determine the stage, behavior and prognosis of aGCT remain to be determined.

Limb lengthening in pediatric patients with ollier's disease

Background: Ollier's disease is a non-hereditary skeletal disorder. Orthopedic management of limb length discrepancy could be complex given the nature of bone pathology, the significant amount of length discrepancy and the difficulty to predict it. The goal of the study is to identify the outcomes and complications associated with surgical management of limb length discrepancy. Methods: This is an IRB approved, retrospective review of patients with Ollier's disease who had limb lengthening. The age at the time of surgery, amount of total length discrepancy and discrepancy for each individual bone, amount of lengthening and as a ratio to the length of the bone itself, type of fixator, duration of the fixator, complications are recorded. Unpaired T-tests evaluated the effect of simultaneous versus single-bone lengthening and tibia vs. femur being lengthened on the external fixator index. One-way ANOVA test was used to evaluate the effect of osteotomy location on mean External Fixator Index (EFI). Results: 14 patients with 40 segmental limb lengthening procedures are identified. The mean LLD was 7.1 cm and mean amount of length gained was 7.8 cm. Follow up was minimum 2 years and maximum 18 years 2 months. The average fixator duration was 178.6 days. The average percent of lengthening through each bone was 19.2. The average EFI was 36.5 days/cm. There was no difference between tibia vs. femur and between simultaneous vs. single bone on EFI. There was no difference among osteotomy type. There were 3 cases of nonunion, one delayed union, 5 cases of premature consolidation. One case had fixation failure. There were 7 cases of knee stiffness of which 3 cases required surgery. Conclusions: Our study shows that Enchondromal bone appears to respond to lengthening with a structurally proper regenerate. Premature consolidation needs to be always kept in mind and appropriate adjustment should be made in the rate of lengthening.

Encondromatosis múltiple, enfermedad de Ollier

Multiple enchondromatosis (Ollier's disease) is a rare disease characterized by widespread enchondromas with a unilateral predominance, especially in fingers in early childhood. In general, the short tubular bones of the hand are involved, with progressive lesions resulting in cosmetic problems and functional deformities. Herein, we, describe two cases of Ollier's disease diagnosed on X-ray of hands followed by MRI. There was no evidence of cortical disruption or periosteal reaction associated in either case. The bone lesions revealed cartilaginous matrix. MRI using conventional T1W and T2W sequences and STIR showed expansile lesions within the metacarpals and phalanges of both hands with cartilaginous matrix.

Anaplastic Oligodendroglioma with IDH Mutation and 1p/19q Co-Deletion in a Patient with Ollier Disease (P3.271)

Anaplastic Oligodendroglioma with IDH Mutation and 1p/19q Co-Deletion in a Patient with Ollier Disease (P3.271)

Characteristics of gliomas in patients with somatic IDH mosaicism.

IDH mutations are found in the majority of adult, diffuse, low-grade and anaplastic gliomas and are also frequently found in cartilaginous tumors. Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to post-zygotic acquisition of IDH mutations. In addition to skeletal tumors, enchondromatosis patients sometimes develop gliomas. The aim of the present study was to determine whether gliomas in enchondromatosis patients might also result from somatic IDH mosaicism and whether their characteristics are similar to those of sporadic IDH-mutated gliomas. For this purpose, we analyzed the characteristics of 6 newly diagnosed and 32 previously reported cases of enchondromatosis patients who developed gliomas and compared them to those of a consecutive series of 159 patients with sporadic IDH-mutated gliomas. As was the case with sporadic IDH mutated gliomas, enchondromatosis gliomas were frequently located in the frontal lobe (54 %) and consisted of diffuse low-grade (73 %) or anaplastic gliomas (21 %). However, they were diagnosed at an earlier age (25.6 years versus 44 years, p < 0.001) and were more frequently multicentric (32 % versus 1 %, p < 0.001) and more frequently located within the brainstem than sporadic IDH mutated gliomas (21 % versus 1 %, p < 0.001). Their molecular profile was characterized by IDH mutations and loss of ATRX expression. In two patients, the same IDH mutation was demonstrated in the glioma and in a cartilaginous tumor. In contrast to sporadic IDH mutated gliomas, no enchondromatosis glioma harbored a 1p/19q co-deletion (0/6 versus 59/123, p = 0.03). The characteristics of gliomas in patients with enchondromatosis suggest that these tumors, as cartilaginous tumors, result from somatic IDH mosaicism and that the timing of IDH mutation acquisition might affect the location and molecular characteristics of gliomas. Early acquisition of IDH mutations could shift gliomagenesis towards the brainstem thereby mimicking the regional preference of histone mutated gliomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0302-y) contains supplementary material, which is available to authorized users.

Multiple enchondromas and skin angiomas: Maffucci syndrome

A 52-year-old man presented to our dermatology clinic for evaluation of several bluish nodules of the right hand and wrist (fi gure) that had gradually increased in number over the previous 31 years. The lesions were asymptomatic but had been causing the patient embarrassment and had started aff ecting his social interactions. No one in his family had a history of similar lesions. During adolescence he had had surgical excision of several painful enchondromas involving the proximal phalanx of the right fi fth fi nger and three chondrosarcomas of the metacarpo-phalangeal joints of the right hand, but at the time he had no evidence of cutaneous lesions and therefore had been diagnosed as having Ollier disease (enchondromatosis). On examination he had several hard, painless, compressible, angiomatous, subcutaneous nodules on the fi ngers of the right hand, consistent with a diagnosis of enchondromas, which was confi rmed on radiography (fi gure). Histology of one of the skin lesions showed typical features of cavernous haemangioma—ie, large blood-fi lled spaces lined by tumour endothelial cells separated by fi brous tissue. Human herpesvirus type 8 and D2-40 immunohistochemical stains were negative. On the basis of clinical and histological fi ndings we made a diagnosis of Maff ucci syndrome. We referred the patient to our plastic surgery department for excision of the largest angiomas, and he has follow-up every 6 months to assess new or changing lesions and check for possible chondrosarcomas. Maff ucci syndrome is a rare, sporadic genodermatosis aff ecting both males and females, which is associated with postzygotic somatic mutations in isocitrate dehydrogenase 1 and 2 genes. Although cases of late-onset Maff ucci syndrome have been reported, it usually manifests around age 4–5 years, aff ecting the hands or feet in a unilateral or asymmetrical fashion. Clinically, it is characterised by the combination of benign enlargements of cartilage (enchondromas) and multiple angiomatous skin lesions— usually cavernous haemangiomas, but patients can also present with lymphangiomas and spindle cell haemangioendotheliomas. Treatment is usually necessary only for aesthetic or functional problems. Surgery is the most common therapeutic approach for both cartilaginous and cutaneous lesions. Possible complications include spontaneous fractures, malignant transformation of angiomatous lesions, and sarcomatous degeneration of enchondromas—with a lifetime risk of about 100%. Prompt identifi cation of Maff ucci syndrome can help to identify and treat possible chondrosarcomas in a timely fashion. The principal diff erential diagnoses are KlippelTrenaunay syndrome, Kaposi sarcoma, glomuvenous malformations, Proteus syndrome, blue rubber bleb naevus syndrome, and Ollier disease, which is frequently confused with Maff ucci syndrome. Ollier disease does not present with angiomatous lesions but only enchondromas, which have a much lower risk of malignant transformation (about 25% of cases) compared with patients who have Maff ucci syndrome.

External fixation reconstruction of the residual problems of benign bone tumours.

The mechanical features of and biologic response to using distraction osteogenesis with the circular external fixator are the unique aspects of Ilizarov’s contribution that allows deformity correction and reconstruction of bone defects. We present a retrospective study of 20 patients who suffered from a variety of benign tumours for which external fixators (EF) were used to treat deformity, bone loss, and limb-length discrepancy. A total of 26 bony segments in twenty patients (10 males, 10 females; mean age 17 years; range 7–58 years) were treated with EF for residual problems from the tumour itself (primary treatment) in 8 patients and for complications related to the primary surgery (secondary treatment) in 12 patients. Histological diagnoses were Ollier’s disease (n = 4), Fibrous Dysplasia (n = 5), Congenital multiple exostosis (n = 5), giant cell tumour (n = 2) and one case for chondromyxoid fibroma, desmoid fibroma, chondroma and unicameral bone cyst. Various types of external fixators used to treat these problems. These were Ilizarov, unilateral fixator, multiaxial correction frame (Biomet, Parsippany, NJ), Taylor spatial frame (Memphis, TN) and smart correction multiaxial frame. The mean follow-up time was 69.5 months (range 35–108 months). The mean external fixation time was 159.5 days (range 27–300 days). The mean external fixation index was 67.4 days/cm (12–610) in 26 limbs who underwent distraction osteogenesis. The mean length of distraction was 4.9 cm (range 0.2–14 cm). At final follow-up, all patients had returned to normal activities. Complications were in the form of knee arthrodesis in one patient, pin tract infection in six and residual shortening in eight patients. The use of EF and the principles of distraction osteogenesis, in the management of problems associated with benign bone tumours and related surgery yields successful results especially in young patients. With this approach, the risk for recurrence of shortening and deformity may be minimized with overcorrection or over-lengthening as dictated by preoperative planning.

Ollier disease with anaplastic astrocytoma: A review of the literature and a unique case.

Background:Ollier disease is a rare, nonfamilial disorder that primary affects the long bones and cartilage of joints with multiple enchondromas. It is associated with a higher risk of central nervous system (CNS) malignancies; although the incidence is unknown.Case Description:Here, we present the case of a 55-year-old woman who developed an anaplastic astrocytoma with a known diagnosis of Ollier disease with a survival time of over 3 years.Conclusion:This report draws attention to the rarity of this disease and the paucity of information regarding CNS involvement in Ollier disease, as well as reviews the current literature.

NGTS-02CHARACTERISTICS OF GLIOMAS IN PATIENTS WITH ENCHONDROMATOSIS

BACKGROUND: Enchondromatosis (Ollier disease and Maffucci syndrome) are rare non-hereditary skeletal disorders which were recently shown to be due to somatic mosaic mutations of IDH1 or IDH2. Enchondromatosis patients are at increased risk of developing gliomas. The aim of the present study was to describe the characteristics of gliomas occurring in these patients in comparison to the characteristics of sporadic IDH mutated gliomas. METHODS: The clinical, histological and radiological characteristics of 39 enchondromatosis patients with gliomas (present series n = 7, previously reported cases n = 32) were analyzed and compared to the characteristics of 159 patients with sporadic IDH mutated gliomas. RESULTS: Gliomas occurring in patients with enchondromatosis were diffuse low-grade (73%) or anaplastic gliomas (21%). They were, most frequently located in the frontal lobe (53%) or in the brainstem (23%). An IDH mutation was present in 7 out of the 8 patients in whom it was assessed. Median age at diagnosis was 28 years [range 6-46]. Twelve patients (30.8%) had multicentric gliomas and 2 patients a gliomatosis cerebri. Compared to sporadic IDH mutated gliomas, enchondromatosis gliomas were diagnosed at an earlier age (28 versus 44 years, p < 0.001), were more frequently multicentric (30.8% versus 1.3%, p < 0.001) and were more frequently located within the brainstem (22.5% versus 0.6%, p < 0.001). CONCLUSION: The histological and molecular characteristics of gliomas observed in patients with enchondromatosis as well as their high rate of multicentricity are in agreement with the hypothesis of an underlying mosaicism of the IDH mutation. The differences between the characteristics of enchondromatosis and sporadic IDH mutated gliomas (earlier age at diagnosis, more frequent brainstem involvement) suggest that the characteristics of IDH related gliomagenesis could vary according to the age at which the mutation is acquired.

Segmental Hemihyperplasia-Related Macrodactyly with Congenital Renal Agenesis: A Hand Surgeon's Point of View.

Segmental Hemihyperplasia-Related Macrodactyly with Congenital Renal Agenesis: A Hand Surgeon's Point of View.

Ollier Disease With Sole Chest Wall Involvement

Ollier Disease With Sole Chest Wall Involvement

Ollier Disease: Pathogenesis, Diagnosis, and Management.

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.

Limb reconstruction in Ollier's disease.

We present our experience of lengthening and correction of complex deformities in the management of patients with Ollier’s dysplasia (multiple enchondromatosis) from 1985 and 2002. All patients were under 18 years with a minimum follow-up time of 2 years (mean 9.6 years, range 2–15 years). There were a total of ten patients of which seven were male and three female. The mean age at presentation was 10.7 years (range 5–17 years; SD 3.7 years). The total length gain was 42.3 mm (range 30–110 mm; SD 28.9 mm). The number of days in external fixation was 164.8 days (range 76–244 days; SD 42.9 days). The bone healing index was 32.5 days/cm (18–50 days/cm; SD 10.3 days/cm). Patients with Ollier’s disease have limb length inequality and angular deformities and require multiple reconstructive procedures owing to a high incidence of recurrence. We identified a tendency for the osteotomy to prematurely consolidate and advise the latency period after surgery to be 4–5 days and for distraction to proceed at a faster rate.

Detection of Unknown sites of multiple enchondroma (Ollier′s Disease) mimicking like metastasis using bone scintigraphy

Ollier's disease characterized by multiple skeletal enchondroma is a rare noninherited disease of unknown etiology. Majority of the skeletal enchondroma are present in the metaphyses and diaphysis of tubular limb bones. Ollier's disease has a predilection for unilateral distribution. Malignant changes in Ollier's disease may occur in adult patients. Radionuclide bone scanning is one method used to assess lesions depicted on radiographs or magnetic resonance images that are presumed to be enchondromas. Furthermore, a bone scan may give a clue to the multifocality of the disease. We report a case of right first phalangeal enchondroma in a 23-year-old male, who underwent bone scintigraphy detected multifocal asymmetric right side involvement of radius, humerus, femur, and tibia which confirm a diagnosis of Ollier's disease.

Digitial endochondroma

A patient with Ollier disease presenting with onycholysis and nail dystrophy related to a subungual enchondroma is presented.

EG-08 * IDH MUTATIONS IN GLIOMAS ASSOCIATED WITH ENCHONDROMATOSIS

The enchondromatoses, Ollier's disease and Maffucci syndrome, are non-heritable developmental disorders characterized by multiple enchondromas (Olllier's) in association with hemangiomas (Maffucci). Glial neoplasms are reported in both disorders but a pathogenic mechanism underlying this association has not been identified. We report a case of anaplastic astrocytoma in a 23 year old man with Maffucci syndrome whose tumor carried a substitution mutation of arginine for cysteine at position 132 (R132C) of the isocitrate dehydrogenase 1 (IDH1) protein. This mutation, commonly found in Maffucci-associated enchondromas and hemangiomas, was not detected on routine immunohistochemical (IHC) analysis of the astrocytoma using the R132H mutation-specific antibody, commonly applied in clinical laboratories. The R132C mutation was detected by polymerase chain reaction (PCR) and subsequently confirmed using a SNaPshot assay. Because somatic mosaic IDH mutations are associated with enchondromas and hemangiomas in Maffucci syndrome, we looked for the R132C mutation in a hemangioma, peripheral blood mononuclear cells (PBMNC) and histologically normal brain surrounding the tumor from this patient. The mutation was present in the hemangioma, absent in PBMNC, and present in 2% of alleles in ‘normal’ brain. The low level in surrounding brain tissue is consistent with tumor cell infiltration, not mosaicism, as a S173T p53 mutation in the tumor showed similar results. Using IHC, we further demonstrated that the mutant IDH1 protein in this glioma functions as an oncometabolite. Two repressive histone trimethylation marks were strongly positive in the tumor, supporting a role for 2-hydroxyglutarate in the inhibition of histone demethylation. Together, these data demonstrate that an IDH1 mutation common in enchodromatoses underlies the association of glial tumors reported in both Ollier's disease and Maffucci syndrome.

Benign cartilage tumors. What should I do with incidental findings?

The majority of benign bone tumors are cartilage tumors. Most common are enchondroma and osteochondroma. Often they represent incidental findings in radiological diagnostics. Thus, the incidence of cartilage tumors is unknown, as most of them are never diagnosed due to the absence of any symptoms. This article describes the diagnostic and therapeutic approach of benign cartilage tumors, focusing on incidental findings. The current knowledge and our own experience in the diagnostics and treatment of benign condroid tumors are presented. As enchondroma represent most often the classic incidental finding without any symptoms or clinical findings, osteochondroma are often diagnosed in young patients by clinical examination showing a painless swelling that can increase in size according to skeletal growth. Most of these asymptomatic enchondroma and osteochondroma are so called "leave me alone lesions" and do not need any treatment, while other benign tumors (e.g., atypical cartilage tumors, chondroblastoma, chondromyxoidfibroma or osteochondroma with a cartilage cap of over 2cm) need surgical treatment. These active or local aggressive tumors must be differentiated from the "leave me alone lesions". Additionally, patients with syndromes like Ollier disease (enchondromatosis), Maffucci syndrome or hereditary multiple exostosis must be examined and checked carefully as malignant degradation is possible. As most cartilage tumors are benign and remain benign, inappropriate diagnostics or operative treatment just to provide security is obsolete. Plain X-ray is often enough for follow-up and other modalities only become necessary when symptoms occur.

Growth hormone deficiency and multiple Enchondromatosis (Ollier disease) in a boy with short stature

We present a boy diagnosed and treated with growth hormone (GH) for isolated GH deficiency. During 2 year follow up he did not catch up in both height and weight. Although there was no skeletal disproportionality, nor any other complaints, his walk began changing and lower limbs deformity appeared (genua vara). Extensive skeletal radiological survey found multiple enchondromatosis (knees, iliac bones) and Ollier disease was diagnosed. There is no specific treatment for this condition, but its presence questions future GH therapy. The poor response to growth hormone treatment and the risk of developing malignant transformation in the future raises the important questions of the real benefits and the possible harms of its maintenance.

Ollier Disease With Digital Enchondromatosis

Ollier disease is a rare skeletal disorder characterized by multiple enchondromas at metaphyseal regions of the bones. The disease is nonhereditary and usually the result of postzygote mutations during development. We present the features of digital enchondromatosis on bone scintigraphy, PET/CT, radiographs, and MRI in a patient, with a childhood diagnosis of Ollier disease.

Medial canthal lesions in a man with a scarred wrist: Subcutaneous lymphangiomas in association with Maffucci’s syndrome

Maffucci syndrome is characterized by multiple soft tissue hemangiomas and multiple enchondromas. Ollier disease includes enchondromatosis without hemangiomas and these two conditions are now thought to represent a spectrum of congenital mesenchymal dysplasia. We present a case of a 49 year-old male affected by multiple enchondromas, who was reclassified as a Maffucci lymphangioma syndrome after two periocular lymphangiomas were surgically excised.