Maffucci Syndrome Research Articles

Clinical and radiological response of Maffucci related enchondromas to mutant IDH1 inhibitor Ivosidenib

Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.

A rare case report of Maffucci syndrome in a 16-year-old girl

Maffucci syndrome is an extremely rare, sporadic disorder that primarily affects bone and skin. It is characterized by multiple enchondromas, especially in the bones of hands and feet, with cutaneous hemangiomas. Treatment consists of orthopedic and surgical intervention to minimize deformities and for cosmetic purposes. Careful surveillance for both skeletal and non-skeletal malignancies is needed. We report here a case of Maffucci syndrome in a 16-year-old girl.

An osteolytic lesion of the proximal ulna in a patient with Maffucci syndrome: a case report

Maffucci syndrome is a rare, congenital, and nonhereditary syndrome characterized by the occurrence of multiple enchondromas and hemangiomas. According to previous studies, patients diagnosed with Maffucci syndrome have a higher risk of developing malignant tumors, such as ovarian cancer, pancreatic cancer, breast cancer, and central nervous system cancer, in addition to malignant transformations of enchondromas. The authors report a case of a 37-year-old male patient with Maffucci syndrome who presented with multiple enchondromas and hemangiomas. This patient’s presentation and management are discussed, along with a review of the literature. Maffucci syndrome should be expected when encountering a patient with multiple enchondromas and suspected hemangiomas in the limbs. Even if benign lesions such as enchondromas or hemangiomas are diagnosed, regular follow-up is required to monitor for malignant transformations and the development of malignant tumors in other organs.

Síndrome de Maffucci e condrossarcoma

Introduction: Maffucci syndrome is characterized by multiple subcutaneous enchondromas and can be complicated by skull base chondrosarcoma, a rare malignant tumor that produces a cartilaginous matrix that invades the cortical bone and medullary tissue. Objective: To review this syndrome and its correlation with chondrosarcoma. Method: Narrative review based on published information with material for reading and analysis selected from virtual publishers, SciELO, VHL - Virtual Health Library, Pubmed and Scopus. Initially, a search was carried out for descriptors related to the topic, existing in DeCS/MESH using the following terms: “skull base tumor, chondrosarcoma, Maffucci syndrome” with AND or OR search, considering the title and/or summary. Result: After analyzing the relevant articles, 40 articles were selected and included in this review. Conclusion: Skull base lesions should be highly suspected in patients with Maffucci syndrome.

Chondrossarcoma of the skull base incidentally discovered through Maffucci Syndrome

Introdução: A Síndrome de Maffucci (SM) é uma displasia mesodérmica não hereditária congênita associada a malformações venosas cutâneas com discondroplasia. Objetivo: revisar a síndrome de MAffucci e apresentar um caso no qual o condrossarcoma assintomático da base do crânio foi diagnosticado como achado casual e tratado. Resultados: Caracteriza-se por ser uma enfermidade rara com menos de 200 casos descritos pela literatura, não havendo estatísticas sobre sua epidemiologia e prevalência. A Síndrome de Maffucci tem como principal diagnóstico diferencial a Síndrome de Ollier. Outras patologias também devem ser pensadas diante do quadro apresentado, como o sarcoma de kaposi, síndrome de Klippel-Trenaunay-Weber,síndrome de Proteus e doença de Gorham. Conclusão: deve-se ter alto grau de suspeita de lesões da base do crânio em pacientes com síndrome de maffucci.

Therapeutic effect of intramedullary reaming and nailing for long bones lengthening in children with Ollier disease and Maffucci syndrome on enchondromas: multicentric retrospective case series.

Leg length discrepancy (LLD) and malalignment of long bones are frequent orthopedic problems encountered in Maffucci syndrome and Ollier disease (OD). Orthopedic surgeons used historically external fixators to address the deformities. In this multicentric case series, we propose the use of motorized intramedullary nails. We retrospectively reviewed for 9years, in four different centers, patients with OD and Maffucci's syndrome that had lengthening nails for LLD with or without associated deformities. The minimum follow-up period was 24 months. We reported complications, clinical tolerance of lengthening, lengthening rate and target, bone healing index, and EQ-5D-Y functional and visual analog scores (VAS). We also saw on X-rays the whole lengthened bone and its regenerate zone to assess the evolution of the enchondromas. we used the nailing technique in 8 femurs and 2 tibias in 8 patients (mean age: 13.3years, range: 11-16, mean follow-up time: 53.8 months, range: 26-108). The mean correction amount was 6.44cm for the femur over 76.8 days and 3.75cm over 44 days for the tibia with a mean VAS score of 6.63/15 and mean EQ-5D-Y of 81/100. The lengthening goal was achieved in all patients. No mechanical complications were noted. The medullary canal of the operated bones showed improvement and healing in 8 out of 10 segments. Besides achieving the goals of surgery with good functional outcomes, lengthening nails has a therapeutic effect on enchondromas with fewer complications than traditional correction methods.

Defining priorities in the transition from paediatric to adult healthcare for rare bone disease patients: a dialogic approach

The Italian patient association for Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome, Associazione Conto Alla Rovescia-ACAR Aps, conducted a mixed-methods study at its 2023 annual conference. The study included the Open Dialogue Approach and a feedback survey to identify the main priorities in the transitioning process from paediatric to adult healthcare for patients with Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome.The common needs identified by patients, families, caregivers, and healthcare professionals were coordination and continuity of care, patient empowerment and communication, social and practical support, and transition planning and support.This experience fostered a sense of collaboration and cooperation among stakeholders, helping to build trust and create a shared vision for improving the quality of care for these patients. Furthermore, it could be considered a starting point for other patient associations interested in using different approaches to identify the needs of their members and actively involve all stakeholders.

Vascular Malformation? It’s Maffucci Syndrome

Vascular Malformation? It’s Maffucci Syndrome

Intracranial Metastasis of Extracranial Chondrosarcoma: Systematic Review With Illustrative Case.

Cerebral chondrosarcoma metastases are rare and aggressive neoplasms. The rarity of presentation has precluded rigorous analysis of diagnosis, risk factors, treatment, and survival. We analyzed every reported case through exhaustive literature review. We further present the first case with Maffucci syndrome. Three databases, PubMed, Embase, and Google Scholar, and crossed references were queried for cerebral chondrosarcoma metastases. Extracted variables included demographics, risk factors, tumor characteristics, interventions, and outcomes. Univariate and multivariate analyses were performed. Fifty-six patients were included from 1,489 literature results. The average age at brain metastasis was 46.6±17.6 years and occurred at a median of 24±2.8 months from primary diagnosis. Primary tumor histology (dedifferentiated 5.0±1.5 months, mesenchymal 24±3.0 months, conventional 41±7.4 months, p<0.05) and grade (low grade 54±16.7 months vs. high-grade 10±6.4 months, p<0.001) correlated with time interval until brain metastasis. A multiple enchondromatosis syndrome occurred in 13.2% of cases. At time of brain metastases diagnosis, extracranial metastases were identified in 76.2% of cases. Median survival after the development of brain metastasis was 2.0±0.78 months with a 1-year survival of 10.0%. On regression analysis, surgery reduced brain metastasis mortality risk and radiation trended towards reduced mortality risk (surgery: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.064-0.763, p=0.017; radiation: HR 0.31, 95% CI 0.091-1.072, p=0.064). We present a systematic review of cerebral chondrosarcoma metastases. Primary tumor histology and grade correlate with time until cerebral metastasis. Following cerebral metastasis, these tumors have poor prognosis and modestly benefit from surgery.

Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.

Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.

Surgical Resection Combined with Sclerotherapy Treating Maffucci Syndrome's Venous Malformation in Head and Neck Region.

Here, we report our experience treating a patient with Maffucci syndrome and evaluate the outcomes resulting from surgical management combined with sclerotherapy in the treatment of head and neck venous malformations (VMs). A 19-years-old woman with multiple enchondromas and heterauxesis complained of masses in the oral cavity that had gradually increased in size and eventually affected her daily life. A tracheotomy was performed followed by traditional sclerotherapy to treat the oropharyngeal VMs. Next, we surgically excised the VMs of the oral cavity and maxillofacial skin. Magnetic resonance imaging indicated that the oral VMs were nearly eradicated and the oropharyngeal VMs had stabilized. The patient's appearance and normal maxillofacial region function were restored. In summary, local resection combined with sclerotherapy facilitated timely and efficient VMs removal from the head and neck region of a patient with Maffucci syndrome.

Vascular Anomaly Syndromes in the ISSVA Classification System: Imaging Findings and Role of Interventional Radiology in Management.

Vascular anomalies encompass a spectrum of tumors and malformations that can cause significant morbidity and mortality in children and adults. Use of the International Society for the Study of Vascular Anomalies (ISSVA) classification system is strongly recommended for consistency. Vascular anomalies can occur in isolation or in association with clinical syndromes that involve complex multifocal lesions affecting different organ systems. Thus, it is critical to be familiar with the differences and similarities among vascular anomalies to guide selection of the appropriate imaging studies and possible interventions. Syndromes associated with simple vascular malformations include hereditary hemorrhagic telangiectasia, blue rubber bleb nevus syndrome, Gorham-Stout disease, and primary lymphedema. Syndromes categorized as vascular malformations associated with other anomalies include Klippel-Trenaunay-Weber syndrome, Parkes Weber syndrome, Servelle-Martorell syndrome, Maffucci syndrome, macrocephaly-capillary malformation, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis, skeletal, and spinal anomalies) syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome, and CLAPO (capillary malformations of the lower lip, lymphatic malformations of the face and neck, asymmetry of the face and limbs, and partial or generalized overgrowth) syndrome. With PHACES (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects and/or coarctation of the aorta, eye abnormalities, and sternal clefting or supraumbilical raphe) syndrome, infantile hemangiomas associated with other lesions occur. Diagnostic and interventional radiologists have important roles in diagnosing these conditions and administering image-guided therapies-embolization and sclerotherapy, and different ablation procedures in particular. The key imaging features of vascular anomaly syndromes based on the 2018 ISSVA classification system and the role of interventional radiology in the management of these syndromes are reviewed. Online supplemental material is available for this article. ©RSNA, 2022.

Images in Vascular Medicine: Clinical and radiological features of Maffucci syndrome.

Images in Vascular Medicine: Clinical and radiological features of Maffucci syndrome.

Maffucci syndrome complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation: a case report

BackgroundMaffucci syndrome (MS) is a rare, nonhereditary congenital mesodermal dysplasia characterized by multiple enchondromas and hemangiomas, associated with an increased risk of developing malignant tumors. Given their rarity, the pathogenesis of these tumors has not been clarified, and there is no standard treatment.Case presentationWe present a case of a 45-year-old man with MS to supplement the clinical manifestations and explore the molecular mechanism of MS. The patient underwent amputation surgery to inhibit tumor development and was diagnosed with MS with 1–2 grade giant chondrosarcoma in the left ankle. In addition, the whole exon analysis results revealed isocitrate dehydrogenase 1 (IDH1) R132C mutation in chondrosarcoma lesions but not in blood DNA.ConclusionsThis case report showed MS complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation, which is appropriate to monitor the development of MS pathology and other concomitant lesions.

A Case of Chondrosarcoma With Maffucci Syndrome Presenting Adult Onset Otitis Media With Effusion

Maffucci syndrome is a non-hereditary disease, in which benign cartilage tumor called enchondroma occurs throughout the body, causing various symptoms. In particular, when chondrosarcoma occurs in the skull base, various neurologic symptoms can appear. Many of these symptoms have been diagnosed and reported by neurosurgeons. This paper presents a rare case of Maffuci syndrome. The patient is a 34-year-old female who first visited the otolaryngology outpatient department for ear fullness without any other neurological symptoms. The initial diagnosis was adult onset otitis media with effusion (OME), but further examination and biopsy revealed skull base chondrosarcoma. Moreover, the mass was extensively invading the skull base, so surgical treatment would have been dangerous; thus, careful follow-up has been conducted for the patient in the outpatient clinic. This report highlights the importance of nasopharyngoscopy as well as other imaging tests to observe nasopharyngeal masses in OME patients with congenital or acquired diseases, which are known to sporadically develop tumor.

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.

EP251: Vascular anomalies in patients with Maffucci syndrome

Maffucci syndrome (MS) is characterized by multiple enchondromas and spindle cell hemangiomas. However, the full spectrum of vascular anomalies present in these patients have not been well defined. Enchondromas are bilateral in most cases and in ∼13% of cases, MS is noticeable in the first year of age. It can cause joint deformities, mobility limitations, scoliosis, bone shortening, leg-length discrepancy, pathological fractures, pain, and loss of function. Surgery is the only treatment currently available.

Somatic IDH1 variant (p.R132C) in an adult male with Maffucci syndrome

Maffucci syndrome is a rare, highly variable somatic mosaic condition, and well-known cancer-related gain-of-function variants in either the IDH1 or IDH2 genes have been found in the affected tissues of most reported individuals. Features include benign enchondroma and spindle-cell hemangioma, with a recognized increased risk of various malignancies. Fewer than 200 affected individuals have been reported; therefore, accurate estimates of malignancy risk are difficult to quantify and recommended surveillance guidelines are not available. The same gain-of-function IDH1 and IDH2 variants are also implicated in a variety of other benign and malignant tumors. An adult male presented with several soft palpable lesions on the right upper limb. Imaging and histopathology raised the possibility of Maffucci syndrome. DNA was extracted from peripheral blood lymphocytes and tissue surgically resected from a spindle-cell hemangioma. Sanger sequencing and droplet digital polymerase chain reaction (PCR) analysis of the IDH1 gene were performed. We identified a somatic mosaic c.394C > T (p.R132C) variant in exon 5 of IDH1, in DNA derived from hemangioma tissue at ∼17% variant allele fraction. This variant was absent in DNA derived from blood. This variant has been identified in the affected tissue of most reported individuals with Maffucci syndrome. Although this individual has a potentially targetable variant, and there is a recognized risk of malignant transformation in this condition, a decision was made not to intervene with an IDH1 inhibitor. The reasons and prospects for therapy in this condition are discussed.

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.

Ollier disease and neurological complications—a clinical case

Ollier disease, also known as enchondromatosis, is a rare skeletal disease with an estimated prevalence of about 1/100,000. It is characterized by the presence of multiple intraosseous, usually benign cartilage tumors, enchondromas, showing a risk of malignant transformation. The latter is very likely in patients with Maffucci syndrome, where, in addition to enchondromatosis, multiple hemangiomas are observed. Cases of the disease with involvement of the skull bones and intracranial tumor masses have been described in the literature. According to some authors, the treatment of intracranial enchondromes is surgical, aiming at a complete removal. According to others, emphasis should be placed on monitoring, as lesions may remain asymptomatic and surgical resection may lead to additional complications. This article presents the case of a woman with known Ollier disease, hospitalized because of severe headache and blurred vision, presenting with limited mobility of the eyeballs inwards and upwards, with computed tomography data for tumor formation on the right parasellar with multiple cell calcifications interpreted as related to the underlying disease. Some diagnostic and therapeutic challenges in this rare pathology have been discussed.