Maffucci Syndrome: Symptoms, Types, Causes and Treatment

Maffucci syndrome is a rare, complex disorder that intertwines skeletal and vascular abnormalities, often presenting significant challenges for both patients and clinicians. Understanding its symptoms, types, underlying causes, and available treatments is crucial for early recognition and optimal care. In this article, we synthesize the latest evidence to provide a comprehensive overview of Maffucci syndrome, drawing from clinical case reports, genetic studies, and current therapeutic approaches.

Symptoms of Maffucci Syndrome

Maffucci syndrome is primarily recognized for its distinctive combination of bone and vascular abnormalities, but its manifestations can be broad and evolve over time. Early recognition of these symptoms is crucial for timely diagnosis and management, as the disorder carries a significant risk of malignant transformation.

Symptom	Description	Typical Onset	Source(s)
Enchondromas	Benign cartilage tumors in bones	Early childhood	1, 2, 3, 5
Hemangiomas	Vascular malformations, soft tissue lumps	At birth/childhood	1, 2, 3, 4
Skeletal Deformities	Bone abnormalities, asymmetry, fractures	Childhood	1, 2, 3
Pain/Heaviness	Discomfort in affected limbs	Variable	1
Malignant Transformation	Risk of chondrosarcoma or other cancers	Later in course	2, 3, 5, 15

Table 1: Key Symptoms

Enchondromas: The Skeletal Signature

Enchondromas are benign tumors formed from cartilage, usually emerging in the bones of the hands, feet, and long bones such as the femur or tibia. These lesions often present in early childhood and can lead to bone pain, swelling, and visible deformities. As they grow, they may cause:

• Asymmetry of limbs
• Shortening or bowing of affected bones
• Increased risk of fractures, sometimes after minor trauma

Radiographically, enchondromas appear as osteolytic lesions with cortical thinning and endosteal scalloping, making them relatively easy to identify on X-ray 2 3.

Hemangiomas: Vascular Anomalies

Hemangiomas in Maffucci syndrome are not the typical "strawberry marks" seen in infants but are instead venous malformations that can be soft, compressible, and bluish. These vascular lesions often manifest at or soon after birth, usually on the distal extremities (fingers, toes, hands, feet). They may:

• Grow in number and size over time
• Cause pain or a sensation of heaviness in the affected area
• Sometimes contain phleboliths (small calcified nodules), visible on imaging 1 2 4

A special variant, spindle-cell hemangioendothelioma (spindle cell hemangioma), has also been reported in some cases 4.

Skeletal Deformities and Functional Impairment

The combination of multiple enchondromas and hemangiomas leads to progressive skeletal deformities as the child grows. These may include:

• Limb length discrepancies
• Bowing or angular deformities
• Limited range of motion
• Pathological fractures

These musculoskeletal issues can profoundly impact mobility and quality of life 1 3 11.

Pain and Heaviness

Many patients report pain, particularly in areas of active enchondroma growth or vascular lesions. Heaviness and discomfort can also be present, especially in limbs with extensive involvement 1.

Malignant Transformation

A major concern in Maffucci syndrome is the high risk of malignant transformation, particularly into chondrosarcoma (a malignant cartilage tumor). Around 30–40% of patients develop malignancies during their lifetime, most commonly chondrosarcomas, but also other sarcomas and, rarely, non-skeletal tumors 2 3 5 15. Regular monitoring and early intervention are essential.

Types of Maffucci Syndrome

While Maffucci syndrome is classically defined by its hallmark features, variations and overlapping presentations exist. Distinguishing these types can guide diagnosis and management.

Type/Variant	Distinctive Features	Prevalence	Source(s)
Classical	Multiple enchondromas + hemangiomas	Most cases	1, 2, 3
Spindle-Cell Variant	Spindle-cell hemangiomas (SCH)	Less common	4, 7
Overlap Syndromes	Features with Ollier disease or others	Rare	10, 8
Malignant-Transformed	Presence of sarcomas or other cancers	Develops over time	5, 15, 11

Table 2: Types and Variants

Classical Maffucci Syndrome

The classical form consists of multiple enchondromas affecting the bones and soft tissue hemangiomas. Both lesions are often asymmetrical and show a predilection for the distal limbs. There is no sex or racial predilection 1 2 3.

Spindle-Cell Variant

Recent studies have identified a subset of patients in whom the vascular lesions are spindle-cell hemangiomas (SCH), a tumor with both cavernous hemangioma and Kaposi-like features. SCH often arises in the extremities and can recur locally, but rarely metastasizes. This variant suggests the spectrum of vascular tumors in Maffucci syndrome may be broader than previously recognized 4 7.

Overlap Syndromes

Maffucci syndrome shares many features with Ollier disease (multiple enchondromatosis without vascular lesions). Rarely, patients may present with overlapping features or have additional anomalies such as lymphangiomatosis or neurological defects. These cases highlight the mesodermal dysplasia underlying these disorders 10 8.

Malignant-Transformed Type

Some patients are classified based on the development of malignancies, particularly chondrosarcoma. This "malignant-transformed" type is not a separate syndrome but a progression of the classical form, underscoring the need for vigilance in long-term follow-up 5 15 11.

Causes of Maffucci Syndrome

The origins of Maffucci syndrome lie in genetic mutations affecting mesenchymal tissues, though its precise triggers and pathways have only recently been elucidated. Understanding these causes is crucial for accurate diagnosis and exploring potential future therapies.

Cause	Genetic/Pathologic Basis	Heredity	Source(s)
IDH1/IDH2 Mutations	Somatic mosaic mutations (esp. IDH1 R132C)	Non-hereditary	6, 7, 8
ERC2 Mutation	Somatic mutation (L309I) enhances angiogenesis	Non-hereditary	6
Mesodermal Dysplasia	Abnormal development of mesenchyme	Congenital	2, 10, 11
Not PTPN11	Mutations in PTPN11 cause MC, not Maffucci	Non-related	9

Table 3: Genetic and Pathological Causes

IDH1 and IDH2 Mutations: The Molecular Hallmark

The great majority of Maffucci syndrome cases harbor somatic, mosaic mutations in the IDH1 or IDH2 genes (most commonly IDH1 R132C). These genes encode enzymes involved in cellular metabolism, and their mutation leads to abnormal cell proliferation and tumor formation. Importantly:

• The mutations arise after conception (post-zygotic), so the condition is not inherited but occurs sporadically.
• The same mutation is often found in multiple lesions within the same patient, supporting a mosaic pattern.
• IDH1/2 mutations are also seen in Ollier disease, but only Maffucci syndrome patients develop hemangiomas, suggesting additional factors are involved 6 7 8.

ERC2 Mutation and Hemangiomas

A novel somatic mutation in the ERC2 gene (L309I) has been identified in some patients with Maffucci syndrome. This mutation appears to enhance angiogenesis and contributes to the development of hemangiomas specifically, distinguishing Maffucci syndrome from Ollier disease, which lacks this vascular component 6.

Mesodermal Dysplasia

Maffucci syndrome is considered a congenital mesodermal dysplasia, meaning it results from abnormal development of the mesoderm (the embryonic layer that forms bones, cartilage, and blood vessels). This explains the coexistence of skeletal and vascular lesions 2 10 11.

Not Inherited: The Role of Somatic Mosaicism

Unlike some other bone tumor syndromes, Maffucci syndrome is not passed down through families. It results from somatic mutations—genetic changes that occur after fertilization, leading to mosaicism (cells within the same person having different genetic makeups) 6 7 8. Notably, loss-of-function mutations in PTPN11 cause a different syndrome (metachondromatosis) and are not found in Maffucci syndrome 9.

Treatment of Maffucci Syndrome

Managing Maffucci syndrome requires a multidisciplinary approach tailored to the individual’s symptoms, lesion locations, and risk of malignancy. While there is no definitive cure, several strategies can help control symptoms and prevent complications.

Treatment	Purpose/Target	Typical Use	Source(s)
Surgical Excision	Remove enchondromas/hemangiomas	Symptomatic/malignant	1, 11, 12
Sclerotherapy	Treat hemangiomas (injection therapy)	Vascular lesions	1, 14
Compression Therapy	Support for vascular swellings	Adjunct	1
Sirolimus Therapy	Medical treatment for hemangiomas	Experimental	14
Multidisciplinary Care	Coordination of treatment	All patients	2, 3
Cancer Surveillance	Early detection of malignancy	Ongoing	5, 15, 12
Proton Beam Radiosurgery	Targeted treatment for tumors	Cranial/base lesions	12

Table 4: Treatment Options

Surgical Management

Surgical removal is the mainstay for symptomatic enchondromas and hemangiomas, especially when lesions cause pain, deformity, or functional impairment. Surgery is also indicated for malignant transformation, aiming for complete excision with clear margins 1 11 12. However, surgical intervention may be complex, especially in areas involving critical neurovascular structures (e.g., cranial base tumors) 12.

Sclerotherapy and Compression

For hemangiomas, sclerotherapy (injecting agents to shrink the lesions) and compression therapy can help manage symptoms and reduce lesion size. These are especially useful for lesions that are not amenable to surgery or are recurrent 1 14.

Novel Medical Therapies

Emerging therapies such as sirolimus, an mTOR inhibitor, have shown promise in managing spindle cell hemangiomas associated with Maffucci syndrome, particularly when combined with surgical approaches 14.

Multidisciplinary and Supportive Care

Optimal management involves a team approach, including orthopedists, oncologists, radiologists, and geneticists. Supportive therapies may include physiotherapy, pain management, and orthopedic devices to address skeletal deformities and maintain function 2 3.

Cancer Surveillance

Given the high risk of malignant transformation, regular clinical and radiological surveillance is crucial. This includes monitoring for:

• Changes in lesion size or character
• New onset of pain or neurological symptoms
• Signs of rapid growth or invasion

Early detection of malignancy (especially chondrosarcoma) can significantly improve outcomes. However, routine, random X-rays are not always effective for early cancer detection; vigilance for clinical changes is vital 15.

Targeted Radiotherapy

For certain tumors in challenging locations, such as cranial base chondrosarcomas, advanced techniques like proton beam radiosurgery may be considered when surgery is not feasible or as adjunctive therapy 12.

Conclusion

Maffucci syndrome is a rare, non-hereditary disorder that intertwines the skeletal and vascular systems, posing unique diagnostic and therapeutic challenges. Here’s a summary of what we’ve covered:

• Symptoms: Early-onset enchondromas and hemangiomas, leading to pain, deformity, and a significant risk of malignancy, particularly chondrosarcoma.
• Types: Classical, spindle-cell variant, overlap with other syndromes, and malignant-transformed forms.
• Causes: Somatic mosaic mutations—especially in IDH1 and sometimes ERC2—lead to mesodermal dysplasia affecting bones and blood vessels.
• Treatment: Multidisciplinary management, including surgery, sclerotherapy, emerging medical therapies, and vigilant cancer surveillance.

Key takeaways:

• Early recognition and diagnosis are crucial.
• The risk of malignant transformation necessitates lifelong monitoring.
• Advances in genetic understanding and targeted therapies may offer hope for future treatments.
• Personalized, multidisciplinary care is essential for improving quality of life.

Maffucci syndrome remains a challenging condition, but with coordinated care and ongoing research, outcomes for patients continue to improve.