An intermediate phenotype in IDH related enchondromatosis spectrum.

Mosaic variants of IDH1 (isocitrate dehydrogenase-1) R132 and IDH2 (isocitrate dehydrogenase-2) R172 loci were detected in most of the bone cysts of Ollier and Maffucci series and in the blood and tissue samples of metaphyseal enchondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) patients. We aimed to report an intermediate phenotype comparing with the reported cases. The proband was a 9-year-old boy with widespread metaphyseal enchondromatosis involving metaphyses of long tubular bones, iliac bones and tubular bones of both hands and feet and sparing spine and flat and short bones. He underwent quad whole exome sequencing (index-both parents-healthy sibling). Sanger sequencing was performed for confirmation and segregation purposes. Heterozygous IDH1 R132H (c.395G > A) variant was detected in his blood via whole exome sequencing and Sanger analysis in mosaic state, 22% of the reads and Sanger signal. He had no D-2-hydroxyglutaric aciduria in urinary organic acid analysis. Our case is unique with the presence of IDH1 R132H variant in blood with metaphyseal enchondromatosis without D-2-hydroxyglutaric aciduria. It was a transitional phenotype. With his phenotype, we expand the IDH1/IDH2 related enchondromatosis phenotypes.

Juvenile granulosa cell tumor associated with Ollier disease.

Prior case reports have described synchronous ovarian juvenile granulosa cell tumor (JGCT) and enchondromatosis in patients with Ollier disease and Maffucci syndrome. We present a case of a juvenile granulosa cell tumor with an IDH1 somatic mutation identified in the ovarian tissue in a 15-year-old female who presented with abnormal vaginal bleeding, several months of irregular menses, and a large multicystic adnexal mass. Multiple mixed lytic and sclerotic lesions were identified in the bones of the pelvis on imaging studies obtained during the work-up of her abdominal mass. Like previous reports in patients with undiagnosed enchondromatosis, these lesions were presumed to represent skeletal metastases; however, biopsy tissue revealed a hyaline cartilage neoplasm. Subspecialty review of the imaging findings revealed imaging features classic for Ollier disease involving the flat bones of the pelvis. It is important for radiologists to be familiar with the association between enchondromatosis and JGCT. When a female patient with enchondromatosis presents with a large, unilateral, mixed solid-cystic ovarian mass, the diagnosis of JGCT can be suggested. Alternatively, when a patient is diagnosed with JGCT, any skeletal lesions should be scrutinized for imaging features that suggest a hyaline cartilage neoplasm to avoid the misdiagnosis of skeletal metastases in a patient with previously undiagnosed Ollier disease or Maffucci syndrome. To our knowledge, this is the second reported confirmed case of an IDH1 somatic mutation identified in the ovarian tissue of a JGCT in a patient with Ollier disease.

Outcomes of intralesional osteotomy and distraction osteogenesis for limb length equalization in Ollier's disease.

Limb length discrepancy and deformities resulting from Ollier's disease are challenging to treat and have increased complications. We aimed to assess the safety of intralesional osteotomy for distraction osteogenesis and report the results of guided growth as a method of deformity correction in such conditions. We retrospectively reviewed 13 patients (eight boys and five girls), 28 segments (12 femora and 16 tibias), treated using Ilizarov circular ring fixator in one center. Nine patients had an oblique plane deformity, whereas four had a coronal plane deformity. Femoral shortening ranged from three to 11 cm. Tibial shortening ranged from 3.5 to 12 cm. Intralesional osteotomy was carried out in all patients, and guided growth (hemiepiphysiodesis) was used in seven segments (25%). The median age was 11 years (6-14 years) at surgery, with a median follow-up of 4.5 years (3-18 years). The median achieved lengthening in the femur was 7 cm (5-11 cm) and in the tibia was 5 cm (3-9 cm). The average Bone Healing Index (BHI) for the femur was 32 days/cm (28-38 days/cm), and for the tibia was 36 days/cm (28-40 days/cm). Before frame removal, the mechanical axis was restored to the knee joint center in all cases. Normal radiographic bone regeneration was evident in all cases. Hemiepiphysiodesis successfully corrected the angular deformities. Intralesional osteotomy for distraction osteogenesis is well-tolerated and reliable in Ollier's disease. Radiological normal bone was formed at the distraction site. Guided growth is also a reproducible method for deformity correction in Ollier's disease, similar to other conditions.

Rare Presentation of Pediatric Multiple Enchondromatosis Limited to Single Ray or Single Nerve Distribution in the Hand: A Multicenter Case Series.

BACKGROUND: Multiple enchondromas in the pediatric hand is a relatively rare occurrence and the literature regarding its incidence and treatment is sparse. Within this rare subset of patients, we identified a unique cohort in which lesions are confined to multiple bones in a single ray or adjacent rays within a single nerve distribution. We review the clinical and pathologic characteristics and describe the indications for and outcomes of treatment in this unique subset of patients as well as offer conjectures about its occurrence. METHODS: Institutional review board (IRB)-approved retrospective multicenter study between 2010 and 2018 identified subjects with isolated multiple enchondromas and minimum 2-year follow-up. Data analyzed included demographics, lesion quantification and localization, symptoms and/or fracture(s), treatment of lesion(s), complications, recurrence, and presence of malignant transformation. RESULTS: Ten patients were evaluated with average age at presentation of 9 years (range: 4 to 16) and mean clinical follow-up of 6 years (range: 2.8 to 8.6). Five subjects had multiple ray involvement in a single nerve distribution and 5 had single ray involvement with an average of 4 lesions noted per subject (range: 2 to 8). All children in the study had histopathologic-proven enchondromas and underwent operative curettage±bone grafting. Indications for surgical intervention included persistent pain, multiple prior pathologic fractures, impending fracture and deformity. During the study period three subjects experienced pathologic fracture treated successfully with immobilization. Recurrence was noted in 40% at an average of 105 weeks postoperatively (range: 24 to 260) and appears higher than that reported in the literature. No case of malignant transformation was observed during the study period. CONCLUSIONS: A rare subset of pediatric patients with multiple enchondromas of the hand is described with lesions limited to a single ray or single nerve distribution. Further awareness of this unique subset of patients may increase our understanding of the disease and improve patient outcomes. LEVEL OF EVIDENCE: Level IV-therapeutic (case series).

Update on the imaging features of the enchondromatosis syndromes.

Ollier disease and Maffucci syndrome are the commonest enchondromatosis subtypes, arising from non-hereditary mutations in the IDH1 and IDH2 genes, presenting in childhood and being characterised by multiple enchondromas. Maffucci syndrome also includes multiple soft tissue haemangiomas. Aside from developing bony masses, osseous deformity and pathological fracture, ~ 40% of these patients develop secondary central chondrosarcoma, and there is increased risk of non-skeletal malignancies such as gliomas and mesenchymal ovarian tumours. In this review, we outline the molecular genetics, pathology and multimodality imaging features of solitary enchondroma, Ollier disease and Maffucci syndrome, along with their associated skeletal complications, in particular secondary chondrosarcoma. Given the lifelong risk of malignancy, imaging follow-up will also be explored. Metachondromatosis, a rare enchondromatosis subtype characterised by enchondromas and exostoses, will also be briefly outlined.

IDH1 R132C and ERC2 L309I Mutations Contribute to the Development of Maffucci's Syndrome.

Background: Maffucci's syndrome is characterized by the coexistence of multiple enchondromas and soft-tissue hemangiomas. It has been clear that somatic mosaic isocitrate dehydrogenase type 1 (IDH1) or isocitrate dehydrogenase type 2 (IDH2) mutations are associated with Maffucci's syndrome and Ollier disease, but the mechanisms underlying hemangiomas of the Maffucci's syndrome is still obscure. This study aimed to determine the mechanism of hemangiomas in Maffucci's syndrome. Methods: We received a 26-year-old female patient with typical Maffucci's syndrome, and exome sequencing was conducted using DNA from her peripheral blood and enchondroma tissues. Somatic mutations were characterized by a comparative analysis of exome sequences and further confirmed by the sequencing of PCR products derived from original blood and tissue samples. The mutations of an additional 69 patients with Ollier disease were further tested. The functional impacts of these somatic mutations on Maffucci's syndrome, especially the development of hemangiomas, were evaluated. Results: We reported a typical case of Maffucci's syndrome, which was confirmed by both imaging findings and pathology. Through exome sequencing of this patient's DNA samples, we identified an R132C mutation in the isocitrate dehydrogenase type 1 (IDH1) gene and an L309I mutation in the ELKS/RAB6-interacting/CAST family member 2 (ERC2) gene in this patient. Approximately 33.3% of the clones were positive for the IDH1 R132C mutation, and 19.0% of the clones were positive for the ECR2 L309I mutation. The IDH1 R132C mutation was detected in most of the patients with Ollier disease (51/69 patients), and the mean frequency of this mutation was 63.3% in total sequence readouts, but the ECR2 L309I mutation was absent in all of the patients with Ollier disease. In vitro experiments confirmed that the IDH1 R132C mutation promotes chondrocyte proliferation, and the ERC2 L309I mutation enhances angiogenesis. Conclusions: Our results suggest that while IDH1 is a known pathogenic gene in enchondromatosis, ERC2 is a novel gene identified in Maffucci's syndrome. The somatic L309I mutation of ERC2 contributes to the pathogenesis of hypervascularization to facilitate the development of hemangiomas in Maffucci's syndrome. The combination of the IDH1 R132C and ERC2 L309I mutations contributes to the development of Maffucci's syndrome, and these results may enable further research on the pathogenesis of Maffucci's syndrome.

A case of Maffucci syndrome with a buccal hemangioma harboring a mutation in IDH1.

Maffucci syndrome, first described in 1881, is a rare, non-hereditary skeletal disorder characterized by multiple enchondromas in combination with soft tissue hemangiomas. Recent studies have implicated somatic mutations in IDH1/2 contributing to the pathogenesis of Maffucci syndrome. This study describes the first case of Maffucci syndrome harboring a mutation in IDH1, which was associated with a hemangioma in the oral mucosa. A 32-year-old man, who was diagnosed with Maffucci syndrome during childhood, was referred to our department in April 2020 due to a mass in the left buccal mucosa. The mass was soft, dome-shaped, had dark red protrusions and well-defined borders, and the dimensions were approximately 15 × 10 mm. Magnetic resonance imaging revealed a mass with a dimension of 13 × 10 mm, which appeared hyperintense on T2-weighted images. The vascular lesion was surgically resected under local anesthesia owing to hemangioma diagnosis. We then analyzed the IDH1/2 sequences using DNA extracted from the excised tumor tissue and peripheral blood. The analysis revealed the presence of a heterozygous mutation in IDH1 in the tumor tissue, corresponding to an R132C substitution. The mutation was not present in peripheral blood DNA. After over one year of resection, the patient is presently free from tumor recurrence and is under follow-up for the early detection of recurrent hemangioma.

Monomelic Maffucci syndrome.

Maffucci syndrome is a rare congenital, non-hereditary condition characterised by presence of multiple enchondromas and haemangiomas. Enchondromatous lesions affecting epiphysial growth plates can lead to angular deformities and leg-length discrepancy in the lower limb. We describe a 12-year-old girl with monomelic Maffucci syndrome affecting her left lower limb. She presented with progressive genu valgus deformity of her left knee. This caused her to limp during her gait and was a cosmetic dissatisfaction. The deformity affected her quality of life. She underwent a supracondylar distal femoral corrective osteotomy with a successful clinical outcome and restoration of her gait and cosmetic deformity.

Co-existence of lung carcinoma metastasis and enchondroma in the femur of a patient with Ollier disease.

Tumour-to-tumour metastasis is very unusual and has been defined as a tumour metastasis into another histologically different tumour. It is extremely rare in bone. We report a case of lung squamous cell carcinoma metastasized to an enchondroma in the femur of a patient with Ollier disease. A 60-year-old female had a history of a poorly differentiated squamous cell carcinoma of the lung. She underwent a video-assisted thoracoscopic lobectomy, and a follow-up MRI scan showed three lesions in the left distal femur and proximal tibia, which were initially interpreted as metastasis on radiology. Resection of the left proximal tibial lesion was performed, and the pathological findings were consistent with enchondroma with no evidence of metastasis. Subsequent curettage of lesions in the distal left femur revealed metastatic poorly differentiated carcinoma with foci of hyaline cartilage, which was most consistent with metastatic carcinoma in a pre-existing enchondroma. The MRI films were re-reviewed. Characteristic MRI features of enchondroma were found in the lesion in the left proximal tibia and one of the lesions in the left distal femur, while the features of the other lesion in the left distal femur included cortical destruction and extensive oedema in surrounding soft tissue, which were consistent with a malignant tumour. In addition, the enchondroma in the lateral condyle showed blurring and irregular inner margin and adjacent bone oedema, which likely represents a co-existing metastatic tumour and enchondroma. The difference in lineage was confirmed by immunohistochemistry. The final diagnosis was metastatic poorly differentiated carcinoma of the lung into a co-existent enchondroma. The diagnosis can be challenging and could be easily overlooked both radiologically and histologically. Thorough clinical and radiological information is critical for the diagnosis, and despite a very unusual event, awareness of the tumour-to-tumour metastasis phenomenon can avoid an inaccurate diagnosis by the pathologist, therefore preventing inappropriate clinical intervention.

Familial Giant Enchondroma of Thoracic Spine: A Rare Manifestation of a Rare Disease.

We present a rare case of spinal enchondromatosis in a 15-year-old boy. The patient presented with spastic paraparesis. He also had multiple bony swellings over the long bones. On inquiry it was found that his father had enchondromatosis. Such a familial form of enchondromatosis has not been previously described in the literature.

A Case of Ollier's Disease with P53 Mutation Positive and IDH1 (R132H) Negative Multicentric Gliomas.

Ollier disease is a rare nonhereditary disorder characterized by multiple enchondromas (enchondromatosis). To report a rare case of Ollier disease with gliomas and its mutation analysis. We hereby report a young lady who presented with seizures. She had a past history of multiple bony swellings in the right foot (operated) and swelling over the anterior chest wall for the past 15 years. MRI brain revealed multiple expansile T2/FLAIR hyperintense lesions in right superior and middle frontal gyri, left basifrontal lobe, and left precuneus in the cortical-subcortical location suggestive of glioma. She underwent biopsy which revealed left basifrontal anaplastic astrocytoma, not otherwise specified, WHO grade III, IDH1 (R132H) negative, P53 mutation positive, and ATRX loss of expression. We hereby report a rare case of Ollier disease with multicentric intracranial glioma-IDH1 (R132H) negative, P53 mutation positive, and ATRX loss of expression.

Multiple hereditary exostoses and enchondromatosis.

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.

Whole-body MRI in assessing malignant transformation in multiple hereditary exostoses and enchondromatosis: audit results and literature review.

OBJECTIVE: To analyze the results of annual screening using whole-body magnetic resonance imaging (WBMRI) in patients with multiple hereditary exostoses (MHE) and enchondromatosis (EC), and estimate the risk for transformation to chondrosarcoma (CS) in these disorders. MATERIALS AND METHODS: A total of 62 patients (57 with MHE and five with EC) screened during a mean follow-up period of 4.6 years (range, 1-10 years) using 253 WBMRIs (median four WBMRIs per patient, range, 1-10) were analyzed retrospectively. The time of WBMRIs was compared with dates for diagnosed CSs. A supplementary literature review was performed focusing on the risk of malignant transformation. RESULTS: Ten patients had CS before being enrolled in the screening program, nine with MHE and one with EC. Three asymptomatic CSs were detected by screening; one in a patient with EC and two in patients with MHE, one of whom had CS previously. During the screening period, there was no occurrence of CS not detected by WBMRI in the study group. Histopathologically, the CSs were predominantly grade 1 and were, except for in two patients, located at the truncus, proximal femur, and shoulder girdle. Based on the current material and literature review, the risk of CS seems to be in the range of 2-3.7% for MHE and up to 50% for EC patients. CONCLUSIONS: MRI may be used as a screening method detecting malignant transformation in MHE and EC patients, but the efficacy has to be confirmed in long-term follow-up studies including cost analysis.

Juvenile granulosa cell tumor associated with Maffucci syndrome in pregnancy: A case report.

Juvenile granulosa cell tumor (JGCT) is an extremely rare ovarian tumor that has been associated with Maffucci syndrome. It both secretes hormone and has been postulated to grow in response to hormone. We present a case of a 33-year-old G1P0 asymptomatic woman with a history of Maffucci syndrome found to have a left adnexal mass on routine ultrasonography at 13 weeks gestation. This case demonstrates the sonographic and magnetic resonance imaging (MRI) features of JGCT, as well as the natural progression of the tumor during pregnancy. A follow-up ultrasound 3 weeks after initial diagnosis demonstrated marked growth in size and vascularity of the tumor, prompting unilateral salpingo-oophorectomy. Histopathological findings confirmed the diagnosis of JGCT.

Skull Base Chondrosarcoma Caused by Ollier Disease: A Case Report and Literature Review.

BACKGROUND: Ollier disease (OD) is a rare, nonhereditary bone disease that is characterized by the presence of multiple enchondromatosis (3 or more) with a typical asymmetric distribution which is mainly confined to the appendicular skeleton. OD's most serious complication is the transformation of an enchondroma into chondrosarcoma. The most common sites for chondrosarcoma are in the pelvic and shoulder bones, the superior metaphyseal and diaphyseal regions of the extremities. However, the cranium is an extremely rare site for chondrosarcoma because of OD. CASE DESCRIPTION: We report the case of a 27-year-old woman who was admitted to our hospital with paroxysmal headaches over 1 month and left ptosis for 2 weeks. Magnetic resonance imaging (MRI) scan revealed a mass was located at the left side of the parasellar area. The mass was surgically removed, and histopathologic examination confirmed chondrosarcoma grade I. During follow-up, more imaging examinations and pathologic examination confirmed the final diagnosis was OD. CONCLUSIONS: Intracranial chondrosarcoma caused by OD is extremely rare but should be considered in the differential diagnosis when primary chondrosarcoma is diagnosed. Preoperative diagnosis is challenging, and definitive diagnosis requires immunohistochemical examination and systematic examination of the body. Surgical resection is the most effective therapy for rapid relief of symptoms. For patients with OD with normal intracranial MRI, long-term follow-up is necessary.

Maffucci syndrome complicated by three different central nervous system tumors sharing an IDH1 R132C mutation: case report.

Maffucci syndrome (MS) and Ollier disease (OD) are nonhereditary congenital diseases characterized by multiple enchondromas and/or chondrosarcomas. Recent studies have implicated somatic mosaic mutations of isocitrate dehydrogenase 1 or 2 (IDH1/2) as contributing to the pathogenesis of MS and OD. Occasionally, patients with these disorders may also present with central nervous system (CNS) tumors; however, detailed genetic analyses are limited. In this article, the authors report on a male patient with MS, harboring three CNS tumors that share a common genetic alteration. Over a 9-year period, three separate tumor resections were conducted for sellar, intraparenchymal brainstem, and osseous clival tumors. The histopathological diagnoses were pituitary adenoma, diffuse astrocytoma, and chondrosarcoma, respectively. Sanger sequencing revealed a common IDH1 R132C mutation among all three CNS tumors but not in blood DNA. Administering chemotherapy (nimustine) and subsequent radiation therapy to the brainstem glioma and the residual lesion in the clivus have kept the patient progression free for 18 months. This is the first report demonstrating an IDH1 mutation shared among three different CNS tumors in a single patient with MS. The findings support the hypothesis that in MS and OD, a single common IDH1 mutation triggers tumorigenesis in cells of different origins and locations in a somatic mosaic fashion.

Molecular profiling of different glioma specimens from an Ollier disease patient suggests a multifocal disease process in the setting of IDH mosaicism.

Ollier disease (OD) and Maffucci syndrome are rare conditions due to a post-zygotic somatic mutation that results in mosaicism. In addition to enchondromas and hemangiomas, some of these patients also develop other unrelated tumors, such as gliomas, that harbor IDH mutations, suggesting that an IDH mutation is a common genetic event in the tumorigenesis in this group of patients. We illustrate an interesting case of multifocal IDH-mutant astrocytomas in an OD patient with 8 years of follow-up. We first demonstrated identical IDH mutations in the brain tumor samples from various locations in this patient, but different 1p,19q results by fluorescent in-situ hybridization, different whole genome copy number profiles by OncoScan analysis, and a discrepant IDH2M131I mutation unique to one tumor, supporting a multifocal disease process in the setting of somatic IDH mosaicism.

Bilateral Forearm Pseudotumors in an Adult with Hemophilia A and Ollier Disease: A Case Report.

CASE: A 29-year-old man with mild hemophilia A and Ollier disease presented with bilateral atraumatic forearm pseudotumors. Both forearm pseudotumors were successfully treated surgically with staged radical extirpation and factor VIII replacement therapy. CONCLUSION: Pseudotumors typically occur in adolescents with severe, poorly controlled hemophilia A. The development of factor VIII replacement therapy has progressively reduced the incidence of pseudotumors in patients in the developed world. No standardized therapy exists for pseudotumors that continue to bleed into the muscles despite nonoperative measures. Persistent masses require surgical removal with careful preoperative planning and a team approach.