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American Journal of Medical Genetics.... May 2020Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant...
Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey's responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS.
Topics: Adolescent; Adult; Child; Child, Preschool; Chondrosarcoma; Enchondromatosis; Female; Granulosa Cell Tumor; Humans; Infant; Infant, Newborn; Male; Middle Aged; Ovarian Neoplasms; Prognosis; Young Adult
PubMed: 32144835
DOI: 10.1002/ajmg.a.61530 -
Journal of Pediatric Genetics Sep 2015Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes... (Review)
Review
Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes the characteristic features of these overgrowth syndromes, as well as the current understanding of their molecular bases, intellectual outcomes, and cancer predispositions. We review syndromes such as Sotos, Malan, Marshall-Smith, Weaver, Simpson-Golabi-Behmel, Perlman, Bannayan-Riley-Ruvalcaba, PI3K-related, Proteus, Beckwith-Wiedemann, fibrous dysplasia, Klippel-Trenaunay-Weber, and Maffucci.
PubMed: 27617124
DOI: 10.1055/s-0035-1564440 -
BMJ Case Reports Mar 2021Maffucci syndrome is a rare congenital, non-hereditary condition characterised by presence of multiple enchondromas and haemangiomas. Enchondromatous lesions affecting...
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.
Topics: Child; Enchondromatosis; Female; Growth Plate; Humans; Leg Length Inequality; Osteotomy; Quality of Life
PubMed: 33658216
DOI: 10.1136/bcr-2020-239619 -
Eplasty 2014
PubMed: 24917896
DOI: No ID Found -
The Journal of Allergy and Clinical... Apr 2023In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of...
BACKGROUND
In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity.
OBJECTIVE
This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.
METHODS
We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3.
RESULTS
Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate.
CONCLUSION
STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
Topics: Child; Humans; Autoimmunity; Cohort Studies; Gain of Function Mutation; Immune System Diseases; Immunologic Deficiency Syndromes; Mutation; STAT3 Transcription Factor; Cell Proliferation; Lymphocytes
PubMed: 36228738
DOI: 10.1016/j.jaci.2022.09.002 -
Annals of Saudi Medicine 1998
PubMed: 17341988
DOI: 10.5144/0256-4947.1998.275 -
PLoS Genetics Dec 2022Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies,...
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.
Topics: Humans; Enchondromatosis; Chondrosarcoma; Sequence Analysis, DNA; Hypoxia-Inducible Factor 1, alpha Subunit; Vascular Diseases; Bone Neoplasms
PubMed: 36480544
DOI: 10.1371/journal.pgen.1010504 -
Current Osteoporosis Reports Feb 2021Enchondroma is a common cartilage benign tumor that develops from dysregulation of chondrocyte terminal differentiation during growth plate development. Here we provide... (Review)
Review
PURPOSE OF REVIEW
Enchondroma is a common cartilage benign tumor that develops from dysregulation of chondrocyte terminal differentiation during growth plate development. Here we provide an overview of recent progress in understanding causative mutations for enchondroma, dysregulated signaling and metabolic pathways in enchondroma, and the progression from enchondroma to malignant chondrosarcoma.
RECENT FINDINGS
Several signaling pathways that regulate chondrocyte differentiation are dysregulated in enchondromas. Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) are the most common findings in enchondromas. Mechanisms including metabolic regulation, epigenetic regulation, and altered signaling pathways play a role in enchondroma formation and progression. Multiple pathways regulate growth plate development in a coordinated manner. Deregulation of the process can result in chondrocytes failing to undergo differentiation and the development of enchondroma.
Topics: Bone Neoplasms; Cell Differentiation; Chondrosarcoma; Disease Progression; Enchondromatosis; Epigenesis, Genetic; Growth Plate; Humans; Signal Transduction
PubMed: 33306166
DOI: 10.1007/s11914-020-00639-7 -
BMC Research Notes Feb 2016Maffucci syndrome is characterized by the sporadic occurrence of multiple enchondromas together with multiple hemangiomas. Patients with Maffucci syndrome are at... (Review)
Review
BACKGROUND
Maffucci syndrome is characterized by the sporadic occurrence of multiple enchondromas together with multiple hemangiomas. Patients with Maffucci syndrome are at increased risk of developing different kinds of malignant tumors.
CASE PRESENTATION
We report on a 39-year-old woman who was diagnosed with Maffucci syndrome together with intrahepatic cholangiocarcinoma (IHCC). Heterozygous somatic mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes are associated with a number of different tumor types (e.g. IHCC) and also with Maffucci syndrome. For IHCC, mutations in IDH1/IDH2 are associated with higher survival rates. IHCC tissue as well as normal liver tissue and peripheral blood were analyzed for IDH1/IDH2-mutations in our patient. In the tumor sample, we identified a recurrent somatic IDH1-mutation affecting Arg132, while in normal liver tissue and peripheral blood, no variants were detected, as expected.
CONCLUSION
This case report presents the second patient in the literature exhibiting the features of Maffucci syndrome along with cholangiocarcinoma. This supports the hypothesis that IDH1/2-mutations, which can be present in different types of tumor tissue simultaneously, arise during embryonic development in a mosaic pattern; as a result, a more aggressive follow-up is proposed in patients with Maffucci syndrome to exclude neoplasms.
Topics: Adult; Cholangiocarcinoma; Enchondromatosis; Female; Gene Expression; Hemangioma; Humans; Isocitrate Dehydrogenase; Liver Neoplasms; Mutation
PubMed: 26920730
DOI: 10.1186/s13104-016-1913-x -
Indian Pediatrics Feb 2007
Topics: Adolescent; Enchondromatosis; Female; Humans
PubMed: 17351310
DOI: No ID Found