Introduction 

Maffucci Syndrome is a rare genetic disorder characterised by the presence of multiple enchondromas (non-cancerous [benign] cartilage tumours) and hemangiomas (benign blood vessel tumours). Enchondromas can cause skeletal deformities, and variation in limb length, and potentially transform into cancerous (malignant) tumours, most commonly chondrosarcomas (bone cancer). Hemangiomas typically occur in the skin and soft tissues but can also be found in internal organs. The syndrome usually manifests in early childhood, with these tumours developing throughout life​.^1,2

Maffucci Syndrome is extremely rare, with fewer than 200 cases reported worldwide. This rarity makes it a significant focus of study due to its complex pathology and the high risk of associated malignancies. The syndrome is usually sporadic, meaning it occurs by chance and is not inherited. Individuals with Maffucci Syndrome are at an increased risk of developing other types of malignancies, including gliomas and other sarcomas, due to somatic mutations in the IDH1 and IDH2 genes, which are also implicated in several different tumour types​.^1,2 

The rarity and severity of the disease underscore the importance of regular monitoring and early detection of malignant transformations. Advanced imaging techniques, such as MRI and CT scans, are recommended for thorough evaluation and follow-up of patients to manage the condition effectively and mitigate complications arising from malignant tumours​.^1,2

Clinical characteristics

Description of enchondromas

Enchondromas are benign cartilage tumours typically found in the limb bones (such as the femur, tibia, and phalanges), skull, ribs, and vertebrae. They develop close to the growth plate cartilage and are often asymmetrically distributed, frequently affecting one side of the body more than the other.^2,3

Enchondromas can lead to several complications, including:^2,3 

• Bone Deformities– Irregular bone growth can cause significant skeletal deformities
• Limb Shortening– As the tumours interfere with normal bone growth, they can result in shorter limbs
• Fractures– The weakened bone structure due to the presence of enchondromas makes bones more susceptible to fractures

Presentation of hemangiomas and lymphangiomas

Maffucci Syndrome is distinct from Ollier Disease primarily due to multiple hemangiomas, lymphangiomas, and enchondromas. Ollier Disease involves only enchondromas without the vascular component. This distinction is crucial for diagnosis and management, as Maffucci Syndrome carries a higher risk of malignant transformation compared to Ollier Disease.^2,4 

Age of onset and progression

Symptoms of Maffucci Syndrome usually manifest in early childhood. The first signs are often visible as bony masses or limb deformities and can be detected through physical examination or radiographic imaging by the first decade of life.^3,4

The formation of new enchondromas typically ceases after early adulthood. However, existing enchondromas can still cause complications or undergo malignant transformation, necessitating ongoing monitoring throughout the patient's life.⁴

Physical appearance and lifespan

Individuals with Maffucci Syndrome often exhibit short stature due to bone deformities and limb shortening caused by enchondromas. Despite these skeletal issues, muscle development is usually not significantly affected. Patients may have a normal range of muscle strength and function unless complications arise from the bone deformities​.⁴

Intelligence in individuals with Maffucci Syndrome is typically normal, with no direct impact on cognitive development. The lifespan can be normal as well, provided that the complications, particularly the risk of malignant transformation, are effectively managed through regular medical follow-up and appropriate interventions.⁴

Genetic basis 

IDH1 and IDH2 gene mutations

Isocitrate dehydrogenase (IDH) enzymes, specifically IDH1 and IDH2, play a crucial role in cellular metabolism. They speed up the conversion of isocitrate to alpha-ketoglutarate, a key step in the Krebs cycle, which is essential for cellular energy production.^5,6

Mutations in IDH1 and IDH2 genes lead to a gain of function that produces an oncometabolite, 2-hydroxyglutarate (2-HG).¹¹ This oncometabolite interferes with cellular differentiation and promotes tumorigenesis. In Maffucci Syndrome, these mutations are primarily found in enchondromas and spindle cell hemangiomas, contributing to their development​.^5,6

Mosaicism in maffucci syndrome

Maffucci Syndrome is characterised by somatic mosaicism, meaning that mutations in IDH1 and IDH2 occur in some but not all body cells. These mutations arise during early embryonic development, leading to a mosaic pattern of affected and unaffected cells throughout the body​.⁶

The disease is not inherited in a Mendelian fashion. This lack of inheritance is because the mutations are not present in the germline (sperm or egg cells) but occur post-zygotically in somatic cells. As a result, the condition is not passed from parents to offspring.⁶

Other potential genetic factors

While IDH1 and IDH2 mutations are prominent in Maffucci Syndrome, other genetic factors might also contribute to the disease. Ongoing research aims to identify additional mutations and pathways involved. The genetic landscape of Maffucci Syndrome is complex, and further studies are necessary to uncover the full spectrum of genetic alterations that may play a role.^5,6

Pathophysiology 

Development of enchondromas

Enchondromas are benign cartilage tumours that typically develop near the growth plates of bones. Growth plates are areas of developing cartilage tissue near the ends of long bones in children and adolescents. These tumours usually appear in the small bones of the hands and feet and the long bones like the femur and tibia.⁷

Enchondromas can lead to several pathological changes and complications in the bones. They cause bone deformities due to their irregular growth patterns. Over time, these tumours can cause limb shortening and increase the risk of fractures because the affected bones become weaker and more brittle.^7,8

Hemangiomas and lymphangiomas formation 

Hemangiomas are benign tumours formed by an abnormal buildup of blood vessels, while lymphangiomas are benign tumours formed by an abnormal growth of lymphatic vessels. In Maffucci Syndrome, these tumours often appear as bluish nodules on the skin and can also affect internal organs. The tumours are formed due to dysregulated angiogenesis and lymphangiogenesis, processes involved in the formation of blood and lymphatic vessels.⁸

Risk of malignant transformation

Patients with Maffucci Syndrome have a higher risk of developing malignant tumours, most commonly chondrosarcomas, which are cancers of the cartilage. Additionally, they have an increased risk of other cancers such as ovarian and liver cancers. The malignant transformation typically occurs in the pre-existing enchondromas or hemangiomas.⁸

The risk of malignant transformation in Maffucci Syndrome is linked to genetic mutations, particularly in the IDH1 and IDH2 genes, which lead to abnormal cellular processes and tumorigenesis. The production of the oncometabolite 2-hydroxyglutarate by mutated IDH enzymes disrupts normal cell differentiation and promotes cancer development. This genetic instability increases the likelihood of various tumours developing from the benign lesions characteristic of the syndrome.^7,11

Diagnosis 

Clinical evaluation and imaging

The diagnosis of Maffucci Syndrome involves detailed clinical evaluation and imaging techniques. Radiological assessments, including X-rays, CT scans, and MRIs, are essential for identifying and monitoring the multiple enchondromas and hemangiomas characteristic of the syndrome. X-rays can reveal the typical locations and patterns of enchondromas, while MRIs provide detailed images of the tumours' structure and any associated complications, such as bone deformities​.^9,10

When there is suspicion of malignant transformation, histological analysis is performed. A biopsy of the suspicious lesion is taken and examined under a microscope to identify cellular abnormalities indicative of malignancy. This process is crucial for diagnosing chondrosarcomas or other cancers that may develop from benign enchondromas.^9,10

Differential diagnosis

Differential diagnosis is necessary to distinguish Maffucci Syndrome from other conditions like Ollier Disease and other forms of enchondromatosis. The key difference is the presence of hemangiomas in Maffucci Syndrome, which is not found in Ollier Disease. Ollier Disease is characterised solely by multiple enchondromas without any vascular anomalies. This distinction is vital as it influences the management and monitoring strategies for the patient.¹⁰

Summary

Maffucci Syndrome is a rare genetic disorder marked by multiple benign cartilage tumours (enchondromas) and blood vessel tumours (hemangiomas). These tumours often lead to bone deformities, and limb length discrepancies, and can turn malignant, particularly into chondrosarcomas. The syndrome typically appears in early childhood and is characterised by somatic mutations in the IDH1 and IDH2 genes, which disrupt normal cellular functions. Unlike Ollier Disease, Maffucci Syndrome includes vascular tumours, increasing the risk of various malignancies. Regular monitoring with advanced imaging techniques is crucial for early detection and management of potential complications.

Future research aims to understand the genetic landscape of Maffucci Syndrome further, identifying additional mutations and pathways involved. This could lead to better diagnostic tools and targeted therapies. Advances in imaging and biopsy techniques will enhance the early detection of malignant transformations, improving patient outcomes. There is also a need to develop standardised treatment protocols and long-term monitoring strategies to manage this condition’s risk of malignancy. Ongoing studies are expected to provide deeper insights into the molecular mechanisms driving the disease, paving the way for novel therapeutic approaches.

FAQs

How is the maffucci syndrome inherited?

Maffucci syndrome is not inherited in a Mendelian fashion. This lack of inheritance is because the mutations are not present in the germline (sperm or egg cells) but occur post-zygotically in somatic cells. As a result, the condition is not passed from parents to offspring.⁶

What is the gene for maffucci syndrome?

Mutations in IDH1 and IDH2 genes lead to a gain of function that produces an oncometabolite, 2-hydroxyglutarate (2-HG).¹¹ This oncometabolite interferes with cellular differentiation and promotes tumorigenesis. In Maffucci Syndrome, these mutations are primarily found in enchondromas and spindle cell hemangiomas, contributing to their development​.^5,6

What is the cause of the maffucci syndrome?

Maffucci Syndrome is characterised by somatic mosaicism, meaning that mutations in IDH1 and IDH2 occur in some but not all body cells. These mutations arise during early embryonic development, leading to a mosaic pattern of affected and unaffected cells throughout the body​.⁶

What is the pathophysiology of enchondromas?

Enchondromas are benign cartilage tumours that typically develop near the growth plates of bones. Growth plates are areas of developing cartilage tissue near the ends of long bones in children and adolescents. These tumours usually appear in the small bones of the hands and feet and the long bones like the femur and tibia.⁷ Enchondromas cause bone deformities due to their irregular growth patterns. Over time, these tumours can cause limb shortening and increase the risk of fractures because the affected bones become weaker and more brittle.^7,8