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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 -
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 -
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 -
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 -
Archives of Pathology & Laboratory... Jan 2020Cartilaginous tumors represent one of the most common tumors of bone. Management of these tumors includes observation, curettage, and surgical excision or resection,... (Review)
Review
CONTEXT.—
Cartilaginous tumors represent one of the most common tumors of bone. Management of these tumors includes observation, curettage, and surgical excision or resection, depending on their locations and whether they are benign or malignant. They can be diagnostically challenging, particularly in small biopsies. In rare cases, benign tumors may undergo malignant transformation.
OBJECTIVE.—
To review common cartilaginous tumors, including in patients with multiple hereditary exostosis, Ollier disease, and Maffucci syndrome, and to discuss problems in the interpretation of well-differentiated cartilaginous neoplasms of bone. Additionally, the concept of atypical cartilaginous tumor/chondrosarcoma grade 1 will be discussed and its use clarified.
DATA SOURCES.—
PubMed (US National Library of Medicine, Bethesda, Maryland) literature review, case review of archival cases at the Massachusetts General Hospital, and personal experience of the authors.
CONCLUSIONS.—
This review has examined primary well-differentiated cartilaginous lesions of bone, including their differential diagnosis and approach to management. Because of the frequent overlap in histologic features, particularly between low-grade chondrosarcoma and enchondroma, evaluation of well-differentiated cartilaginous lesions should be undertaken in conjunction with thorough review of the imaging studies.
Topics: Bone Neoplasms; Chondroblastoma; Chondroma; Chondrosarcoma; Diagnosis, Differential; Humans
PubMed: 31877083
DOI: 10.5858/arpa.2019-0441-RA -
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 -
Anatolian Journal of Cardiology Apr 2022
Topics: Cardiology; Cardiovascular System; Hospitals; Humans; India; Italy
PubMed: 35435846
DOI: 10.5152/AnatolJCardiol.2021.960 -
Experimental and Therapeutic Medicine Sep 2023Maffucci syndrome is an extremely rare disease which can manifest symptoms as early as childhood. It is estimated that there have been <300 cases reported globally;...
Maffucci syndrome is an extremely rare disease which can manifest symptoms as early as childhood. It is estimated that there have been <300 cases reported globally; however, this number is likely to be an underestimate. Maffucci syndrome is characterized by multiple enchondromas and soft tissue hemangiomas, which can cause growth and developmental malformations. In addition to bone deformities, pathological fractures and a loss of mobility, patients with Maffucci syndrome may develop secondary central chondrosarcoma and have a higher risk of developing non-skeletal malignant tumors, such as gliomas and mesenchymal ovarian tumors. The present study provides information for clinicians about this disease through the use of imaging, physical examinations, clinical manifestations and the treatment strategy used. There is need to summarize the existing cases of this disease around the world and produce an effective framework for the diagnosis, treatment and prevention of Maffucci syndrome, in order to better understand this disease. The present study reports on a 15-year-old male diagnosed with Maffucci syndrome. . Due to the risk of malignant tumor development in the absence of effective treatment, regular and careful observation through monitoring of tumor markers and imaging studies is important for patients with Maffucci syndrome. As cases of this disease are rare and case data is limited, it is difficult to create a clear treatment plan. There is an urgent need to establish a case database of Maffucci syndrome patients and explore its pathogenesis for early diagnosis, treatment and prevention of disease.
PubMed: 37602309
DOI: 10.3892/etm.2023.12134 -
Radiology Case Reports Oct 2022Maffucci syndrome is a non-hereditary congenital condition that affects the skin and skeleton. Enchondromas (benign cartilage enlargements), bone abnormalities, and...
Maffucci syndrome is a non-hereditary congenital condition that affects the skin and skeleton. Enchondromas (benign cartilage enlargements), bone abnormalities, and venous anomalies (hemangiomas) are all symptoms. Enchondromas occur as a result of mesodermal dysplasia and have the potential to become cancerous. They are most commonly found on the phalanges and long bones. Venous abnormalities commonly manifest themselves as soft lumps or tumors on the distal extremities. A 19-year-old boy presented with swellings on his fingers and left foot since the age of 5, along with a few bluish soft tissue swellings on his left heel. Multiple expansile lytic lesions and soft tissue swellings with phleboliths were seen on X-ray. Histology confirmed the diagnosis of hemangiomas and enchondromas. Soft tissue swellings were found to have hyper echoic areas, as well as modest marginal blood flow on Doppler, which could indicate hemangiomas. Maffucci syndrome was identified, and treatment with a multidisciplinary approach was initiated. Maffucci syndrome is a rare genetic illness reported in the literature less than 200 times. The enchondromas and hemangiomas have a strong link to malignant changes, with chondrosarcomas accounting for 30% of the associated malignancies. On X-ray, enchondromas are easily identified as osteolytic lesions with cortex thinning and endosteal scalloping while color Doppler ultrasound detects the presence of hemangiomas. Phleboliths are easily identified as small calcifications on X-rays. Radiographic examinations should be considered in patients presenting with bone or soft tissue swellings for an early diagnosis of Maffucci syndrome.
PubMed: 35936883
DOI: 10.1016/j.radcr.2022.07.008 -
Indian Journal of Otolaryngology and... Oct 2019Maffucci syndrome is an extremely rare sporadic disease, characterized by multiple enchondromas and associated with multiple hemangiomas and/or lymphangiomas. First case...
Maffucci syndrome is an extremely rare sporadic disease, characterized by multiple enchondromas and associated with multiple hemangiomas and/or lymphangiomas. First case was reported in 1881, and fewer than 200 case have been reported to date. Potential sarcomatous malignant transformation have been noticed in previous cases. This report describes the case of 21 years-old male complain of right sided nasal obstruction for 10 months, and right sided aural fullness. Examination revealed multiple asymptomatic nodules in both hands since childhood, that have not been investigated and a large nasopharyngeal mass. Computed tomography, showed a 36 mm in 30 mm diameter lesion extending from the inferior aspect of the clivus and basisphenoid into the nasopharynx, which did not seems to be highly vascular with angiogram. Incidental radiological findings of multiple bubbly lytic bony lesions. Endoscopic sinus surgery and clival lesion excision was performed. Pathology confirmed diagnosis of clival enchondroma with clinical and radiological features consistent with Maffucci syndrome. Clear etiology have not been established yet. Mutations in gene encoding parathyroid hormone receptor 1 found in 10% of enchondromatosis. Mutations in gene encoding isocitrate dehydrogenase 1 and 2 (IDH 1&2) occur in some enchondromas and spindle cell hemangiomas. Maffucci syndrome usually presents with asymmetrical distribution of multiple enchondromas. Malignant transformation is the most concerning potential sequel. Many studies have shown sarcomatous degeneration of enchondromas to chondrosarcomas in average of 25% of cases. Patient counselling and education are crucial in the management. Surgical excision usually for symptomatic patients and suspicious lesions. Nevertheless, all patient of Maffucci syndrome will require a long term follow up and surveillance for the lifelong risk of malignant transformation. Maffucci syndrome diagnosis based on clinical presentation, radiological and histopathological findings. Surgical excision offered for symptomatic patients and for suspicious lesions. Lifelong risk of sarcomatous malignant transformation necessitate a long term surveillance.
PubMed: 31742037
DOI: 10.1007/s12070-018-1463-8