RARE DISEASE
Maffucci syndrome
Maffucci syndrome
Maffucci syndrome
Synonyms: Enchondromatosis Spranger type II, Multiple Enchondromatosis type II, Multiple Enchondromatosis, Maffucci Type
Synonyms: Enchondromatosis Spranger type II, Multiple Enchondromatosis type II, Multiple Enchondromatosis, Maffucci Type
Synonyms: Enchondromatosis Spranger type II, Multiple Enchondromatosis type II, Multiple Enchondromatosis, Maffucci Type
Drug discovery
71
papers
On emerging therapies
Overview
Maffucci syndrome is a rare, nonhereditary mesodermal dysplasia characterized by multiple enchondromas (cartilage tumors) and vascular anomalies (hemangiomas/lymphangiomas), typically presenting asymmetrically in early childhood. Caused by somatic IDH1/IDH2 mutations [1][5][17], it carries a 30-50% lifetime risk of malignant transformation (e.g., chondrosarcoma) and elevated susceptibility to gliomas, adenocarcinomas, and other malignancies [2][4][7]. Diagnosis relies on clinical evaluation, imaging (radiography/MRI), and genetic testing [1][6]. Management involves symptom relief, surgical intervention for deformities/fractures, and lifelong malignancy surveillance [3][6][13].
Therapies
Surgical: Debulking of enchondromas, limb-lengthening procedures [8], and hemangioma resection [13].
Medical: Sirolimus for vascular anomalies [13][18], targeted IDH1/2 inhibitors (e.g., ivosidenib) for malignancies [3].
Multidisciplinary care: Orthopedic, dermatologic, and oncologic monitoring for early cancer detection [6][17].
Categories: rare bone diseases, rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare skin diseases
Research Papers
71 drug discovery papers about Maffucci syndrome. Recent publications:
71 drug discovery papers about Maffucci syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-06-23 | ID #683 Clinical and Molecular Features of IDH1-Mutant Astrocytomas in AYA Patients: A 3- year Single-Center Experience
Abstract Background IDH1-mutant astrocytomas are rare in pediatric and adolescent/young adult (AYA) patients, and their biological behavior and optimal management remain poorly defined. While pediatric gliomas are typically low-grade and driven by MAPK pathway alterations, adult diffuse gliomas frequently harbor IDH mutations. AYA patients represent a transitional biological and clinical population, yet treatment strategies are often extrapolated from pediatric or adult paradigms. We describe a single-center experience of IDH1-mutant astrocytomas in pediatric and AYA patients. Methods We retrospectively reviewed 10 consecutive patients aged 12–25 years diagnosed with IDH1-mutant astrocytoma at Bambino Gesù Children’s Hospital between 2022 and 2025. Clinical, radiological, histopathological, and molecular data were analyzed, including next-generation sequencing and germline testing when available. Treatment approaches and outcomes were evaluated. Results The cohort included 8 males and 2 females; one patient had an underlying cancer predisposition syndrome (Ollier/Maffucci). Tumors were located in the cerebral hemispheres (n = 6), pons (n = 3), and cervical medulla (n = 1). Nine tumors were WHO grade 2 and one grade 3. Gross total resection was achieved in four patients, followed by surveillance. Among six patients without gross total resection, four received upfront radiotherapy and two received an IDH1 inhibitor as first-line therapy. At progression, two patients treated initially with radiotherapy received IDH1 inhibitors. Overall, IDH1 inhibitors were administered in five patients. After a median follow-up of 10.2 months (range 6–16), disease stability was observed in all but one patient. Seizure control was satisfactory, and no treatment-related toxicities greater than grade 2 were reported. Conclusions IDH1-mutant astrocytomas in AYA patients appear to represent a distinct biological and clinical entity, supporting the need for age-specific, biology-driven treatment strategies and highlighting the importance of tissue diagnosis to guide targeted therapies.
2026-05-25 | Subclonal IDH1/2 Mutations as a Targetable Vulnerability in Vascular Tumors.
Despite extensive sequencing, the genetic etiology of sporadic angiosarcoma remains poorly defined (1-3). Maffucci syndrome, characterized by vascular tumors and elevated cancer risk, is driven by mosaic gain-of-function mutations in IDH1/2 (4,5), though these have not been reported in sporadic angiosarcoma. We identify recurrent, low-variant allele frequency hotspot mutations in IDH1/2 in over half of sporadic angiosarcomas. Mutations were validated by Sanger sequencing and immunohistochemistry. Mutant IDH1 endothelial cells promote tumorigenesis through non-cell-autonomous mechanisms, secreting 2-hydroxyglutarate (2-HG) to increase growth factor and endothelial-to-mesenchymal transition gene expression, activate pAkt/pERK signaling, induce DNA methylation changes, and promote anchorage-independent growth, which are reversed by the mutant IDH1 inhibitor ivosidenib. Patients with mosaic IDH1 mutations show reduced serum 2-HG and marked tumor regression following ivosidenib treatment. The clinical efficacy of ivosidenib in vascular tumors with subclonal IDH1 mutations suggests that low VAF IDH1/2 mutations may be a targetable vulnerability in sporadic angiosarcoma. (6,7). We identify recurrent, low-VAF IDH1/2 mutations in angiosarcoma and provide evidence that these subclonal mutations promote tumorigenesis through non-cell-autonomous mechanisms. Vascular tumors driven by subclonal IDH1 mutations responded dramatically to ivosidenib, thus revealing a novel treatment for a subset of vascular tumors.
2025-04-21 | Pituitary Complications of Enchondromas Due to Maffucci Syndrome.
Maffucci syndrome (MS) is a congenital disorder caused by a gain-of-function variant in isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) genes on chromosomes 2 and 15, respectively. Common manifestations include the development of multiple enchondromas, chondrosarcomas, and intracranial tumors such as pituitary adenomas. Endocrinological conditions are less frequently associated with MS. We present a patient with MS with complete anterior pituitary insufficiency with central hypothyroidism, adrenal insufficiency, and hypogonadotropic hypogonadism, which may be related to the mass effect of her intracranial enchondromas. With hormonal treatments including thyroid hormone replacement, hydrocortisone, and cabergoline, the patient's symptoms of fatigue and cold intolerance improved. We highlight the importance of endocrinological evaluation in patients with neurological tumors related to MS.
2024-09-28 | Ollier Disease, Acute Myeloid Leukemia, and Brain Glioma: IDH as the Common Denominator.
Ollier disease (OD), acute myeloid leukemia (AML), and brain glioma (BG) are three apparently completely different neoplasms in terms of histopathology, clinic, natural history, and management, but they can affect the same patient. This study aimed to identify the common molecular pathways involved in the pathogenesis of all three diseases and discuss their current and potential role as therapeutic targets. A detailed and comprehensive systematic literature review according to PRISMA guidelines on OD patients harboring BG and/or AML was made. In addition, the unique case of a patient affected by all three considered diseases has been added to our case series. Demographic, pathological, treatment, and outcome data were analyzed and discussed, mainly focusing on the molecular findings. Twenty-eight studies reported thirty-three patients affected by OD and BG, and only one study reported one patient with OD and AML, while only our patient harbored all three pathologies. The IDH R132H mutation was the only genetic alteration shared by all three pathologies and was simultaneously detected in enchondromas and brain glioma in 100% (3/3) of OD patients with BG and also in the neoplastic blood cells of the single patient hosting all three diseases. The IDH1-R132H gene mutation is the etiopathogenetic common denominator among three apparently different tumors coexisting in the same patient. The adoption of mutant-specific IDH1 inhibitor molecules could represent a potential panacea for these conditions in the era of targeted therapies. Further studies with larger clinical series are needed to confirm our results and hypothesis.
2024-08-04 | 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.
oligonucleotides
2022-01-18 | Cell-free DNA from plasma as a promising alternative for detection of gene mutations in patients with Maffucci syndrome
Maffucci syndrome (MS, OMIM 166000) is an extremely unusual, nonhereditary, multisystemic disorder that is characterized with multiple enchondromas and vascular lesions, most of which are spindle cell hemangiomas. Complications of MS, such as bone deformities and dysfunction caused by enchondromas, usually increase during childhood and adolescence. Malignant transformation of enchondromas and other malignancies are the most severe complications. MS is caused by somatic mosaic IDH1/2 mutations, 65% of which are the IDH1 p.Arg132Cys variant. Due to its rarity, there is no international consensus for the most appropriate treatment option of MS.Here, we report a case of a female patient presenting with multiple enchondromas and spindle cell hemangiomas (SCHs) on bilateral hand and feet diagnosed as MS. A detailed clinical, pathological and genetic diagnosis of MS was rendered. Integrative Genomics Viewer (IGV) visualization of next-generation sequencing (NGS) data revealed the consistent detection of the low-frequency somatic IDH1 p.Arg132Cys mutation between SCH tissue and cystic blood-derived cfDNA. This is the first successful molecular diagnosis of MS complicated with SCH utilizing minimally invasive cfDNA techniques. We suggest that cfDNA sequencing could potentially be used as an alternative, reliable and sensitive method to identify molecular information for genetic diagnosis and for future targeted therapies of MS.
small molecules
2026-06-23 | ID #683 Clinical and Molecular Features of IDH1-Mutant Astrocytomas in AYA Patients: A 3- year Single-Center Experience
Abstract Background IDH1-mutant astrocytomas are rare in pediatric and adolescent/young adult (AYA) patients, and their biological behavior and optimal management remain poorly defined. While pediatric gliomas are typically low-grade and driven by MAPK pathway alterations, adult diffuse gliomas frequently harbor IDH mutations. AYA patients represent a transitional biological and clinical population, yet treatment strategies are often extrapolated from pediatric or adult paradigms. We describe a single-center experience of IDH1-mutant astrocytomas in pediatric and AYA patients. Methods We retrospectively reviewed 10 consecutive patients aged 12–25 years diagnosed with IDH1-mutant astrocytoma at Bambino Gesù Children’s Hospital between 2022 and 2025. Clinical, radiological, histopathological, and molecular data were analyzed, including next-generation sequencing and germline testing when available. Treatment approaches and outcomes were evaluated. Results The cohort included 8 males and 2 females; one patient had an underlying cancer predisposition syndrome (Ollier/Maffucci). Tumors were located in the cerebral hemispheres (n = 6), pons (n = 3), and cervical medulla (n = 1). Nine tumors were WHO grade 2 and one grade 3. Gross total resection was achieved in four patients, followed by surveillance. Among six patients without gross total resection, four received upfront radiotherapy and two received an IDH1 inhibitor as first-line therapy. At progression, two patients treated initially with radiotherapy received IDH1 inhibitors. Overall, IDH1 inhibitors were administered in five patients. After a median follow-up of 10.2 months (range 6–16), disease stability was observed in all but one patient. Seizure control was satisfactory, and no treatment-related toxicities greater than grade 2 were reported. Conclusions IDH1-mutant astrocytomas in AYA patients appear to represent a distinct biological and clinical entity, supporting the need for age-specific, biology-driven treatment strategies and highlighting the importance of tissue diagnosis to guide targeted therapies.
2026-05-25 | Subclonal IDH1/2 Mutations as a Targetable Vulnerability in Vascular Tumors.
Despite extensive sequencing, the genetic etiology of sporadic angiosarcoma remains poorly defined (1-3). Maffucci syndrome, characterized by vascular tumors and elevated cancer risk, is driven by mosaic gain-of-function mutations in IDH1/2 (4,5), though these have not been reported in sporadic angiosarcoma. We identify recurrent, low-variant allele frequency hotspot mutations in IDH1/2 in over half of sporadic angiosarcomas. Mutations were validated by Sanger sequencing and immunohistochemistry. Mutant IDH1 endothelial cells promote tumorigenesis through non-cell-autonomous mechanisms, secreting 2-hydroxyglutarate (2-HG) to increase growth factor and endothelial-to-mesenchymal transition gene expression, activate pAkt/pERK signaling, induce DNA methylation changes, and promote anchorage-independent growth, which are reversed by the mutant IDH1 inhibitor ivosidenib. Patients with mosaic IDH1 mutations show reduced serum 2-HG and marked tumor regression following ivosidenib treatment. The clinical efficacy of ivosidenib in vascular tumors with subclonal IDH1 mutations suggests that low VAF IDH1/2 mutations may be a targetable vulnerability in sporadic angiosarcoma. (6,7). We identify recurrent, low-VAF IDH1/2 mutations in angiosarcoma and provide evidence that these subclonal mutations promote tumorigenesis through non-cell-autonomous mechanisms. Vascular tumors driven by subclonal IDH1 mutations responded dramatically to ivosidenib, thus revealing a novel treatment for a subset of vascular tumors.
2025-04-21 | Pituitary Complications of Enchondromas Due to Maffucci Syndrome.
Maffucci syndrome (MS) is a congenital disorder caused by a gain-of-function variant in isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) genes on chromosomes 2 and 15, respectively. Common manifestations include the development of multiple enchondromas, chondrosarcomas, and intracranial tumors such as pituitary adenomas. Endocrinological conditions are less frequently associated with MS. We present a patient with MS with complete anterior pituitary insufficiency with central hypothyroidism, adrenal insufficiency, and hypogonadotropic hypogonadism, which may be related to the mass effect of her intracranial enchondromas. With hormonal treatments including thyroid hormone replacement, hydrocortisone, and cabergoline, the patient's symptoms of fatigue and cold intolerance improved. We highlight the importance of endocrinological evaluation in patients with neurological tumors related to MS.
2024-09-28 | Ollier Disease, Acute Myeloid Leukemia, and Brain Glioma: IDH as the Common Denominator.
Ollier disease (OD), acute myeloid leukemia (AML), and brain glioma (BG) are three apparently completely different neoplasms in terms of histopathology, clinic, natural history, and management, but they can affect the same patient. This study aimed to identify the common molecular pathways involved in the pathogenesis of all three diseases and discuss their current and potential role as therapeutic targets. A detailed and comprehensive systematic literature review according to PRISMA guidelines on OD patients harboring BG and/or AML was made. In addition, the unique case of a patient affected by all three considered diseases has been added to our case series. Demographic, pathological, treatment, and outcome data were analyzed and discussed, mainly focusing on the molecular findings. Twenty-eight studies reported thirty-three patients affected by OD and BG, and only one study reported one patient with OD and AML, while only our patient harbored all three pathologies. The IDH R132H mutation was the only genetic alteration shared by all three pathologies and was simultaneously detected in enchondromas and brain glioma in 100% (3/3) of OD patients with BG and also in the neoplastic blood cells of the single patient hosting all three diseases. The IDH1-R132H gene mutation is the etiopathogenetic common denominator among three apparently different tumors coexisting in the same patient. The adoption of mutant-specific IDH1 inhibitor molecules could represent a potential panacea for these conditions in the era of targeted therapies. Further studies with larger clinical series are needed to confirm our results and hypothesis.
2024-08-04 | 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.
oligonucleotides
2022-01-18 | Cell-free DNA from plasma as a promising alternative for detection of gene mutations in patients with Maffucci syndrome
Maffucci syndrome (MS, OMIM 166000) is an extremely unusual, nonhereditary, multisystemic disorder that is characterized with multiple enchondromas and vascular lesions, most of which are spindle cell hemangiomas. Complications of MS, such as bone deformities and dysfunction caused by enchondromas, usually increase during childhood and adolescence. Malignant transformation of enchondromas and other malignancies are the most severe complications. MS is caused by somatic mosaic IDH1/2 mutations, 65% of which are the IDH1 p.Arg132Cys variant. Due to its rarity, there is no international consensus for the most appropriate treatment option of MS.Here, we report a case of a female patient presenting with multiple enchondromas and spindle cell hemangiomas (SCHs) on bilateral hand and feet diagnosed as MS. A detailed clinical, pathological and genetic diagnosis of MS was rendered. Integrative Genomics Viewer (IGV) visualization of next-generation sequencing (NGS) data revealed the consistent detection of the low-frequency somatic IDH1 p.Arg132Cys mutation between SCH tissue and cystic blood-derived cfDNA. This is the first successful molecular diagnosis of MS complicated with SCH utilizing minimally invasive cfDNA techniques. We suggest that cfDNA sequencing could potentially be used as an alternative, reliable and sensitive method to identify molecular information for genetic diagnosis and for future targeted therapies of MS.
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