Genetic mutations, Clinical Manifestations and Management Strategies in Maffucci Syndrome: A Review

Authors: Mohddiya Masmoum¹*, Jabr Asmew², Rasheed Awad¹

Affiliations

1. Alfaisal University, College of Medicine, Riyadh, Saudi Arabia

2. University of Benghazi, Faculty of Medicine, Benghazi, Libya

JERMS

doi: 10.5281/zenodo.14017789

Oct/2024. Journal of Empirical Reviews in Multisystem Syndromes

Volume: 1(1):1-8

*corresponding author

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Abstract

Maffucci syndrome is a rare, congenital and non-hereditary disorder characterized by the presence of multiple enchondromas and soft tissue hemangiomas. Patients mainly present with abnormalities in the long bones, due to increased risk of fractures, deformities and malignant transformation of enchondromas into chondrosarcoma along with other vascular abnormalities, further complicating its diagnosis and management. The aim of this review is to highlight current literature, knowledge and understandings of Maffucci's syndrome pathogenesis, clinical manifestations and current management strategies. It also explores the genetic component of this syndrome and the role of the somatic mutations in the IDH1 and IDH2 genes, which have been implicated in the development of both enchondromas and hemangiomas and involved in other conditions like Ollier disease. Diagnosing Maffucci syndrome is remains mainly clinical, but imaging options like radiography, MRI, and CT scans are still very important and useful in identifying the extent of the disease involvement and directing the management plan. In addition, advances in molecular genetics offer promising avenues for more definitive diagnosis and risk stratification and better prognosis. The cornerstone of Maffucci syndrome treatment is with surgical interventions for skeletal deformities and complications resulting from malignant transformation, while it remains largely symptomatic management. It is of clear significance that multidisciplinary care by orthopedic surgeons, oncologists, and geneticists directly optimizes patient outcome and challenges in long-term surveillance, given the lifelong risk of malignancy and potential for new lesions to develop. Further research into this rare and complex syndrome is of basic interest for a further understanding of its full pathogenesis and for the development of targeted therapies that could improve morbidity and quality of life for affected patients.

Introduction & background

Maffucci syndrome is a very rare, non-inherited mesodermal dysplastic disorder characterized by the presence of multiple enchondromas with soft tissue hemangiomas and was first described by Angelo Maffucci in 1881 [1]. Enchondroma is a benign cartilage bone tumor, predominantly found in the long bones in Maffucci syndrome. Affected patients are predisposed to skeletal deformities, limb-length discrepancies, and an increased tendency for pathological fractures. On the other hand, hemangiomas are benign vascular neoplasms mainly observed in the subcutaneous tissues, particularly of the distal extremities, in association with Maffucci syndrome [1]. The fact that the reported cases are less than 200 suggests that Maffucci syndrome is a highly challenging syndrome to be diagnosed, treated, and followed up [2].

The typical clinical presentation of Maffucci syndrome is in early childhood with development of multiple enchondromas, particularly in the hands and feet with involvement of the long bones, thus, predisposing to functional impairment and pathological fractures [1]. In addition, although benign, the occurrence of hemangiomas in soft tissues causes pain, cosmetic concerns, and occasionally, functional issues depending on their size and location [1]. However, the major factor of concern associated with Maffucci syndrome is the risk for malignancy, occurring in up to 50% of patients diagnosed with this particular syndrome. particularly the malignant transformation of enchondromas into chondrosarcoma, which is a malignant sarcoma of the cartilage, requiring regular monitoring and aggressive surgical intervention and planning [1-3]. Chondrosarcoma is not the only worrisome malignancy in Maffucci syndrome, patients usually have an increased risk of developing other cancers, such as hemangiosarcoma, astrocytoma, and ovarian carcinoma, further necessitating comprehensive vigilant monitoring and complicating their clinical management and plan [2].

The pathophysiological mechanisms of Maffucci syndrome are recently becoming defined—with the discovery of somatic mutations in the isocitrate dehydrogenase genes 1 & 2 (IDH1 and IDH2) among patients diagnosed with the condition [4]. These mutations result in the production of the oncometabolite, 2-hydroxyglutarate, which impairs cellular differentiation, promoting tumorigenesis [5]. Discovery of these mutations in both enchondromas and hemangiomas produced much-needed insight into the molecular mechanisms of this syndrome and opened up potential avenues for directed therapeutic approaches [4]. The diagnosis of the Maffucci syndrome is primarily based on clinical observation, while imaging studies are requisite in assessing the extent of skeletal and vascular involvement in such a condition [1]. Radiography, MRI, and CT scans are the means to determine the distribution and characteristics of enchondromas and hemangiomas and to assess the risk of malignancy and formulate a surgical-medical plan [4]. Recent advances in molecular genetics have opened up avenues for greater diagnostic accuracy and risk stratification, most notably by the detection of IDH1/2 mutations [5]. The treatment of Maffucci syndrome is still extremely challenging because of its complexity and variability. Skeletal deformities and other complications stemming from malignant transformation often mandate surgical interventions [1]. While systemic therapies currently remain limited, continued investigations into targeted therapies, especially investigations focusing on IDH1/2 mutations, give future therapeutic alternatives promise [5-7]. Given the complexity of this condition, such an integrative approach—through orthopedic surgeons, oncologists, geneticists, radiologists—is highly necessary to improve patient outcomes and ensure properly detailed care for patients diagnosed with Maffucci syndrome [1].

Maffucci syndrome represents a complex disorder that presents a host of clinical challenges. New insights and potential therapeutic avenues have been generated for the molecular pathogenesis of this disorder, mainly in regard to the role of the IDH1/2 mutations. An integrated approach that takes into account the diversity of manifestations of this rare disorder is needed for its effective treatment [1,5]. To conducting this narrative review, we searched relevant literature using databases such as PubMed, Scopus, and Google Scholar. We utilized specific keywords related to Maffucci syndrome, including "Maffucci syndrome," "enchondromas," and "hemangiomas," to identify peer-reviewed articles, case reports, and clinical studies. The selection process involved reviewing abstracts and full texts to ensure relevance. Data were extracted and synthesized to provide a comprehensive overview of the current understanding of this rare disorder.

Review

Clinical features

Maffucci syndrome is a disorder characterized by an association between multiple enchondromas and hemangiomas, which affect the skeletal and vascular systems [1]. Enchondromas are benign cartilaginous tumors, which present mainly in long bones with a marked propensity for the hands and feet, causing deformity, limb length discrepancy, and predisposing the patient to an increased risk of pathological fractures [1]. These deformities result in serious functional disability and often lead to surgical interventions [2]. Soft tissue hemangiomas, which are most common in the distal extremities, may lead to some cosmetic problems, and, in certain instances, may also result in pain and ulceration [1]. While hemangiomas are benign neoplasm, its presence in visceral organs like the liver or the gastrointestinal system may result in life-threatening complications such as hemorrhage and anemia [4].

One of the most concerning aspects of Maffucci syndrome is that lesions bear an increased risk of malignant transformation. Enchondromas are benign cartilaginous tumors, but it is estimated to progress to a more aggressive malignant form, chondrosarcomas, in 20-50% of patients with this syndrome, which is a major point of attention [1]. This generally occurs during adulthood and is often heralded by increased pain or radiographic changes in the pre-existing enchondromas, in which the bone lesion appears to be taking on more aggressive features [1]. Additionally, patients with Maffucci syndrome are at an increased risk for other malignancies, including hemangiosarcoma, astrocytoma, and ovarian carcinoma [2]. The occurrence of these malignancies significantly impacts the prognosis and requires vigilant long-term monitoring [2,3].

It should, however, be noted that the clinical signs and symptoms associated with Maffucci syndrome are not restricted or confined to only the skeletal and vascular systems. Many patients diagnosed with this syndrome are also known to exhibit a wide range of neurological symptoms [8]. Neurological manifestations of the syndrome include seizures, for example, whereby some patients may experience focal neurological deficits which further complicate their case [5,8,9]. This involvement of the central nervous system is generally linked to the development of intracranial hemangiomas or astrocytomas; both of which can increase morbidity and health complications [9,10]. Provided that Maffucci syndrome is able to manifest such a wide and diverse spectrum of symptoms and clinical manifestations involving different systems, performing an adequate comprehensive and full-scale clinical evaluation in patients could lead to early diagnosis and effective management of their disease [1].

Genetic insights

Recent molecular genetic advances have shed much light on the underlying pathogenesis of the complex process behind Maffucci syndrome. The elucidation of somatic mutations which occur in the isocitrate dehydrogenase genes (IDH1 and IDH2) in affected individuals is not only crucial because of etiologic reasons but also because of its implication for related disorders; the same mutational pattern is found in Ollier disease, another rare disorder of endochromatosis. The IDH1 and IDH2 genes encode enzymes involved in the catalysis of the reaction from isocitrate to alpha-ketoglutarate in the tricarboxylic acid cycle. Somatically acquired mutations in these genes result in a neomorphic enzyme activity that produces the oncometabolite 2-hydroxyglutarate (2-HG). Elevated levels of 2-HG disrupt normal cellular differentiation and promote tumorigenesis through inhibition of the histone demethylases and the ten-eleven translocation (TET) family of 5-methylcytosine hydroxylases, therefore interfering with epigenetic control. Such specific mutations observed both in enchondromas and hemangiomas suggests that there could be a shared pathogenetic mechanism underlying the two principal characteristics associated with Maffucci syndrome [5]. IDH1 and IDH2 mutations identified as associated with Maffucci Syndrome are generally classified as somatic mutations. This supports the concept of genetic mosaicism as a paramount factor in this disorder [11]. This mosaicism is responsible for the distinctly segmental distribution of lesions, as well as that unique non-Mendelian pattern of inheritance that may be observed in the disorder [11]. Further, these mutations are likely to occur relatively early in embryogenesis or post-zygotic development, leading to localized proliferation of mutant cells that give rise to the enchondromas and hemangiomas that are characteristic of the disease.

While IDH1 and IDH2 mutations are the most prominent genetic alterations identified in Maffucci Syndrome, other genetic factors may also contribute to its pathogenesis. For instance, mutations in the PTHR1 gene, which encodes the parathyroid hormone receptor 1, have been investigated, however, these mutations are more strongly associated with Ollier disease than Maffucci Syndrome. The IDH1/2 mutations have also helped in improving our understanding of the mechanism of the disease, leading to new targeted therapeutic strategies [6,7]. Targeting of mutant IDH1/2 is currently under evaluation in many types of cancers and is expected to show effectiveness for the management of the neoplastic features seen in Maffucci syndrome. Moreover, the identification of these mutations helps in a more precise diagnostic and prognostic assessment, especially for the differentiation of Maffucci syndrome from other diseases that also present similar clinical features, such as Ollier disease [12]. Genetic testing for IDH1/2 mutations may further be useful for the early identification of patients at higher risk for malignant transformation and thus assure better surveillance and preventive strategies [7,12,13]. We need further studies for the discovery of other genetic alterations that would have an impact on the pathogenesis of Maffucci syndrome and look at the chances of individualized therapeutic options [13].

Management strategies

The management of Maffucci syndrome is complex and requires a multidisciplinary approach to manage diverse clinical features and minimize complications [8,14,15]. Essentially, the therapeutic interventions aim at symptomatic management of skeletal deformities and preventing the development of fractures [1]. Surgery, in the form of corrective osteotomies, limb lengthening procedures, and excision of symptomatic enchondromas, is often necessary to maintain functionality and improve the quality of life [1,16]. Where malignant transformation of enchondromas into chondrosarcomas is present, wide surgical resection is invariably indicated to ensure local control and to avoid metastasis. The management plan for hemangiomas in patients with Maffucci syndrome follows generally a more conservative approach, since most of them are asymptomatic and require no treatment [1]. Large symptomatic hemangiomas or those posing cosmetic issues can be managed with sclerotherapy, laser treatment, or surgical excision [3,17,18]. In addition, If located in visceral organs and poses a risk of hemorrhage, embolization or more extensive surgical interventions may be necessary [17,18].

Given the increased malignant changes in patients with Maffucci syndrome, follow-up and continuous monitoring from different medical disciplines are important for early detection of cancer [3,19]. This surveillance can often be done with conventional radiological studies; MRI or CT scanning can be used to keep track of the number and activity of enchondromas and hemangiomas [11]. When IDH1/2 mutations are detected, molecular follow-up may become indicated in detecting malignant changes at an early stage [4]. Furthermore, genetic counseling for the patients and their families is recommended in order to discuss the risks and implications of the disease, particularly if several members within the family are affected [20].

There are limited systemic treatment options in Maffucci syndrome at present, but the future is promising as more research studies on targeted therapies are in progress [6,20,21]. IDH1/2 inhibitors, along with other new agents targeting discrete molecular pathways in the disease process, are under investigation and may offer new treatment options for patients diagnosed with Maffucci syndrome. Until these therapies become widely available, the management of Maffucci syndrome will remain supportive with combined surgical, medical, and supportive care to attend to the diverse needs of affected individuals [1,22].

Conclusion

Maffucci syndrome is a rare, complex disorder characterized by the presence of multiple enchondromas and hemangiomas causing significant clinical manifestations and directly involved in management plan, patient outcomes and prognosis. The potential for malignant transformation is also a main important entity if this syndrome which requires prompt diagnosis and continuous monitoring from multidisciplinary care. Mutations of IDH1 and IDH2 are the culprits for which this disease manifests and progresses and the recent identification of these mutations has paved the way for potential targeted therapeutic strategies. Future research should be aimed to understand the pathogenesis of Maffucci syndrome and its genetic implications providing a gateway to develop targeted therapies and management plans that would improve diagnosis and overall outcomes. Although rare, collaborative research efforts, case reports and international registries will play a key role in having a collective understanding of this syndrome's natural history and several treatment plans and strategies used. Most patients and affected individuals present with skeletal deformities, fractures, vascular lesions or malignancies like chondrosarcomas and other cancers and management should be tailored in a multidisciplinary approach with surgical, medical, symptomatic and supportive care to address both the primary and secondary complications of this complex and rare syndrome. In addition, Regular surveillance and genetic counseling are critical components aimed at detecting malignant transformation early and guiding treatment decisions and improving overall prognosis.

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Conflict of Interest:

The authors that there are no conflicts of interest.

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