Certain types of malignant tumor have a risk of being associated with Maffucci syndrome, according to previously published case reports (3,4). The present study analyzed Maffucci syndrome according to case reports published in the Web of Science Core Collection database (webofscience.com/wos/woscc/basic-search; accessed July 20, 2022). The keywords used in the literature search were ‘Maffucci’ and ‘case’.

The VOSviewer (version 1.6.17) software was used for constructing and visualizing bibliometric networks (vosviewer.com). Based on literature search results, Maffucci syndrome was reported in 248 case reports in 45 countries, with the highest number of reports conducted in Italy (n=66) and the USA (n=63). The majority of the top 10 countries that reported cases of Maffucci syndrome in the literature review were located in Europe and the USA, which may indicate that Maffucci syndrome is more likely to occur in Caucasian populations in these countries (Table I, Fig. 4). However, the publication of case reports can be related to the economic status and scientific research expertise of the region. Therefore, the absence of reports of Maffucci syndrome in certain regions does not mean there is no incidence of disease in these regions, as case studies require a large amount of data to support publication. The present study used VOSviewer to analyze the frequency of keywords used by previous case studies reporting Maffucci syndrome The high-frequency subject terms were extracted using the Bibliographic Items Co-occurrence Matrix Builder (BICOMB), and a core subject term co-occurrence matrix was established. Through VOSviewer statistics of keywords in the field of Maffucci syndrome to form a co-word network diagram composed of core subject terms (Fig. 5). Meanwhile the article lists the first 10 high-frequency keywords (Table II).

Maffucci syndrome is a rare mesodermal dysplastic disease characterized by multiple enchondromas and vascular malformations, particularly fusiform cell hemangiomas. Growth and developmental problems can result from vascular and bone malformations as early as childhood (1). Enchondroma is a common benign bone tumor in the distal extremities, characterized by chondrocyte involvement in the development of the long bones, limb shortening, pelvic tilt and scoliosis. Typically, enchondroma appears as solitary lesions, but Maffucci syndrome can cause the occurrence of multiple lesions. Enchondroma tends to be recurrent, which can lead to local bone destruction, pain and fractures, amongst other complications. Vascular lesions in patients with Maffucci syndrome are located in the subcutaneous tissue, usually distal to the extremities and demonstrate a lateral distribution, but can also involve mucosal tissues, such as the oral cavity (5). Additionally, these patients may develop secondary central chondrosarcomas and are more likely to develop non-skeletal malignancies in addition to bony masses, bone deformities and pathological fractures. In addition to causing the malignant transformation of visceral chondromas and hemangiomas, Maffucci syndrome has been reported to be linked to brain and ovarian tumors, leukemia and oral squamous cell carcinoma (1,5-7).

The pathogenesis of Maffucci syndrome is currently unclear, but it is generally believed to be caused by non-hereditary mutations in IDH1 and IDH2 (1,7,8). Amary et al (1) and Pansuriya et al (8) reported that Maffucci syndrome is caused by somatic mosaic IDH1/2 mutations, which can also be related to cases of isolated enchondroma and chondrosarcoma. >70% of reported Maffucci syndrome cases have a IDH1/2 mutation, which strongly suggests that these mutations are responsible for its pathogenesis (9). In addition, IDH1/2 mutations can cause a range of cancers, such as glioma, cholangiocarcinoma, chondrosarcoma, and acute myeloid leukemia (4). Mutations in IDH1/2 causes production of the tumor metabolite 2-hydroxyglutaric acid, which restricts cell differentiation by inhibiting the activity of chromatin-modified histones and DNA demethylation (5). Moreover, previous studies have reported mutations in the parathyroid hormone receptor 1 (PTH1R) gene in patients with multiple endophytic chondromatosis (10,11). It has been reported that a small number of patients with multiple endochondromatosis have mutations in PTH1R and these mutations lead to a decline in receptor function, which may also be a cause of Maffucci syndrome (12,13).

Currently, there are no unified criteria for the diagnosis of Maffucci syndrome; however, there are a number of clinical features that can be useful for diagnosis. The development of specific diagnostic criteria need to be verified using data from a large number of case studies. The first step towards diagnosis should analyze clinical features of disease combined with patient imaging results. The clinical features were described previously in this study. When combined with imaging results, indicated that there were spots, longitudinal strips and honeycomb in the center, or side, of the bone in addition to cystic transparent areas, either presenting alone or mixed. In multiple enchondromas, it is possible to see spots of calcification in the transparent area, sometimes radial dense stripes, and often long tubular bone shortening. Small hemangiomas are difficult to observe through imaging studies, as they may only exhibit increased local soft tissue density on X-ray films, while larger multiple hemangiomas exhibit irregular thickening or nodular protrusions of soft tissue, and there are often venous stones of different sizes present, which may suggest Maffucci syndrome (14,15). In addition, it is possible to locally remove an isolated mass for pathological analysis. Pathological examinations found mainly endophytic chondroma and cavernous angioma, with or without thrombosis (3). However, performing a biopsy of diseased tissue may be unsafe and cause serious complications, such as severe bleeding, so the decision to remove diseased tissue for pathological examination should be based on the clinical situation (3,16). Molecular detection methods are used to analyze peripheral blood and tumor tissue to detect mutations in IDH1, IDH2, ELKS/RAB6-interacting/CAST family member 2 (ERC2) gene or PTH1R. For example, as an alternative diagnostic method to tissue biopsy, detection of cell-free DNA (cfDNA) can provide a highly accurate diagnostic method for Maffucci syndrome and can avoid the complications associated with tissue biopsy procedures (13). It has previously been reported that low-frequency somatic IDH1p.Arg132Cys mutations are consistently detected in hemangioma tissues and cystic blood-derived (13). Therefore, it has been suggested that genetic diagnosis of Maffucci syndrome may be improved with cfDNA sequencing, a reliable and sensitive diagnostic approach (1,8,16,17).

A Maffucci syndrome diagnosis typically occurs for a patient during adolescence (2), as a result of the clinical manifestations of disease coupled with imaging results, as demonstrated by the patient in the present study. Combining the results from imaging studies, pathological analysis and molecular analysis, indicated that the provisional diagnosis of Maffucci syndrome was likely, however, a differential diagnosis was still required (18,19). It is important to distinguish endophytic chondroma from bone cysts, giant cell tumors of the bone, bone fibrous dysplasia and other conditions with a comparable imaging presentation. Enchondromatosis can be a symptom of either Maffucci syndrome or Ollier disease, which is also caused by IDH gene mutation (17,18). Compared with Maffucci syndrome, Ollier disease lacks the clinical manifestation of hemangioma and typically presents unilaterally. Imaging studies of patients with Ollier disease have demonstrated that there is generally no venous stone in the hemangioma and previously published studies reported that the probability of chondroma malignant transformation in Ollier disease was low (20,21). Furthermore, Maffucci syndrome needs to be distinguished from other diseases characterized by similar vascular malformations, such as blue rubber bleb nevus syndrome, Klippel-Trenaunay syndrome and glomuvenous malformations.

Currently, there is no standard treatment plan for Maffucci syndrome; however, specific inhibitors of IDH1/2 have demonstrated to be beneficial for the treatment of specific malignant tumor (16). Acute myeloblastic leukemia can be effectively treated using ivosidenib or enasidenib, which inhibit IDH1 and IDH2 protein expression (22). Current research into treatments for Maffucci syndrome has been initiated by the discovery of IDH1/2 inhibitors, an important step forward for treatment of this disease, particularly for patients suffering from severe symptoms such as rapid tumor progression, dysfunction of blood system and motor system and malignant tumors (16).

At present, there is no effective treatment available for vascular lesions of Maffucci syndrome. Sirolimus, a mTOR inhibitor, can effectively treat various vascular anomalies, but further research must be performed to determine its full effectiveness (23). In general, hemangiomas should be treated to prevent patient pain, swelling and dysfunction of blood system and motor system. Currently, sclerosing agents, surgical resection, radiotherapy, embolization and chemical therapy are the most common treatments (24). Enchondromatosis could cause skeletal deformity and dysfunction, which may require orthopedic surgery, therefore malignant tumors should be resected as soon as possible (25).

To conclude, Maffucci syndrome is relatively rare, presents with diverse clinical features and has an unknown pathogenesis, therefore individual institutions are unlikely to have sufficient resources to study this disease. Therefore, there is an urgent need to summarize the existing cases around the world and produce a set of effective guidelines for the diagnosis, treatment and prevention of Maffucci syndrome, in order to gain a better understanding of this disease.