Maffucci Syndrome And Ollier Disease

Introduction 

A rare disease affects 1 in 2000 people; however, even though they seem infrequent, around 10% of the population is estimated to suffer from them. More than 7000 rare diseases have been identified, and they are challenging to diagnose due to few cases, clinical similarities, and a lack of diagnosis methodology, making treatment challenging.¹

Ollier disease and Maffuci syndrome are rare diseases affecting the musculoskeletal system. The hallmark of both is benign cartilaginous tumours intraosseous called enchondromas.² To differentiate them, we need to look for the presence of vascular lesions that only exist in Maffuci syndrome. Around 1 in 100,000 people have Ollier disease, and less than 400 cases have been reported for Maffucci syndrome.²

People who suffer from these conditions are at a higher risk of cancer, pathological fractures, growth problems, etc. An early diagnosis is vital to receive proper treatment and avoid possible complications in the future. 

Enchondromatosis

Encondromas are benign bone cartilage tumours that grow mainly in the hands and feet.² As they do not present with symptoms, they are usually found as solitary lesions during imaging for other causes.³ It is estimated that 3% of the population presents enchondromas.⁴

When seen as multiple lesions that cause symptoms, they will be called enchondromatosis.⁵ There are eight main types of enchondromatosis, including Ollier disease and Mafucci syndrome. Most of these conditions are hereditary diseases that require genetic counselling. However, Ollier disease and Maffucci syndrome are non-hereditary conditions. Properly distinguishing these conditions will help guide treatment and know the prognosis. Further genetic studies can help identify associated genes that provide insight into possible personalised treatment (Table 1).⁵

Table 1

Adapted from Kumar et. Al^5,6

Pathophysiology

The process of bone formation involves a series of steps that convert cartilage into bones. As humans develop, cartilage will be located in different places; at first, it is in the centre, and then it goes to the ends of the long bones.⁷ Usually, the cartilage growth plate becomes bone during puberty, and the growth process ends.⁴ When the growth plate remains in the medullary space of the bone (centre of the bone), enchondromas are formed.⁴

There are gene mutations found in enchondromas that are:^4,8

• IDH1

• IDH2

• PTHR1

Ollier disease and maffucci syndrome

Ollier disease and Maffucci syndrome are diseases that present with multiple enchondromas, more than three, during the first decade of life. The difference is that Maffucci syndrome also has vascular anomalies.⁹ Also, neither presents familial cases, meaning they are non-hereditary.⁹

Diagnosis 

There are no specific criteria for diagnosing Ollier disease and Maffucci syndrome. Some studies have shown that less than 30% of Maffucci syndrome patients were initially diagnosed with Ollier syndrome.⁹  The diagnosis involves clinical manifestation and imaging.²

Clinical manifestation

Patients usually present symptoms in the first decade of life, and both have different clinical presentations. Enchondromas mainly cause symptoms and have different characteristics depending on the disease.

Symptoms that are present in both diseases:^10,11

• Several lumps on the limbs
• Joint deformities
• Restricted joint movement, potentially leading to loss of function
• Deviation of the spine
• Shortened bones that present as an asymmetric upper or lower limb and asymmetric finger lengths
• Differences in leg length
• Walking difficulties
• Pain in the affected regions
• Fractures

Enchondromas in Ollier disease are:⁹

• Unilaterally
• Asymmetrically
• Have a predilection for the appendicular skeleton

While Maffucci syndrome are:⁹

• Bilaterally
• Asymmetrically
• A predilection for the appendicular skeleton

Enchondromas are present most commonly in:

• Femur
• Tibia
• Humerus

Vascular anomalies are present only in Maffucci syndrome and usually appear in the hand at 4-5 years old. They are generally present as hemangiomas, which look like bluish spots on the skin that turn white when you press on them, with the following features:¹¹

• Unilateral
• Usually found in the upper extremity (mostly in hands)
• Around 16% were in visceral organs
• The presence of spindle cell haemangioendothelioma is pathognomonic of the disease⁵
• Could progress to malignancy

Cancer

In both diseases, there is a higher risk of malignant transformation, which can occur in skeletal or non-skeletal tissue. 

In Ollier disease, around 5-50% of the enchondromas turn into chondrosarcoma. It is likely in long tubular and flat bones and unlikely in hands and feet.^5,11 Also, they are at a higher risk of non-skeletal malignant lesions such as:¹¹

• Ovarian mesenchymal tumours
• Gliomas

In Maffuci syndrome, enchondromas can progress into chondrosarcoma at an average age of 40 years old. Similarly, hemangiomas have a malignant potential to transform into angiosarcoma.¹¹ They are also associated with other cancers, such as:¹¹

• Gliomas
• Astrocytomas 
• Pancreatic adenocarcinoma
• Hepatocarcinoma

Imaging

Radiography

On conventional X-rays, enchondromas appear as:^5,12

• Multiple areas where the centre of the bone tissue has been lost, mainly in extremities
• Lesions that are oval-shaped, linear, or pyramid-like
• Lesions with clear and distinct edges
• Typically found in the middle or end parts of long bones, such as those in the arms and legs
• Sometimes, it is also found in flat bones like the pelvis or skull

Computed tomography

It is essential for detect:¹²

• Seeing the details of bone and tissue changes
• Show enchondromas (a type of bone tumour) as well-defined, lumpy masses that look lighter or darker and slightly brighter with contrast dye
• Very useful for looking at areas hard to see with X-rays, like the pelvis
• Excellent for checking the size of tumours and whether they have soft tissue parts, which helps in diagnosing chondrosarcoma (a type of cancer)

Magnetic resonance

Magnetic resonance (MR) studies show:⁵

• Lobulated lesions (lumpy or segmented in shape)
• Intermediate signal intensity on T1-weighted images (shows up as a medium shade on these types of MR images)
• Predominantly high signal intensity on T2-weighted sequences (shows up brighter on these types of MR images)

When to suspect of cancer¹¹

• Lesions that grow after skeletal maturity
• Associated with pain
• More than 5 cm

Histology

Histologically, enchondromas show:⁵

• Low cellularity with an abundant hyaline cartilage matrix
• Sometimes, extensive calcifications

Genetic tests

Genetic testing can be used to identify and exclude disorders characterised by enchondromas and exostoses, including:⁹

• Metachondromatosis
• Multiple exostoses Types 1 and 2
• Spondyloenchondrodysplasia with immune dysregulation
• Spondylomegaepiphyseal-metaphyseal dysplasia

The genes that should be looked are:⁹

• PTPN11
• EXT1
• EXT2
• ACP5
• NKX3-2
• IDH 1 and 2

Treatment 

Treatment for Maffucci syndrome varies based on the type of lesion (enchondromas and hemangiomas), their location, and the presence of malignancy.

Enchondromatosis

Surgical treatment is advised when symptoms or pathological fractures are present. Other indications for surgery include:^13,14

• Limb-length discrepancies
• Bone deformities that interfere with daily activities
• Gait disturbances
• Suspected malignant transformation
• Cosmetic concerns
• Oversized enchondromas

Vascular lesions

There is no approved treatment for vascular lesions. Surgery is recommended for vascular overgrowths. Some suggested treatments include:¹⁵

• Sirolimus
• Sclerotherapy
• Surgical resection
• Radiotherapy
• Embolization
• Chemical therapy

Follow-up

The follow-up varies based on age, location, and size.

For children,⁹

• Clinical check-ups every 6 to 12 months
• X-rays of the lesions every 2 to 3 years

For adults⁹,

• Clinical check-ups every 12 to 24 months
• X-rays of the lesions every 2 to 3 years
• An annual whole-body MERI scan for over 25 years
• An annual whole-body MRI scan

Summary

To summarize, Ollier disease and Maffucci syndrome, though rare, present significant clinical challenges due to their association with multiple enchondromas and potential complications such as malignant transformation and skeletal deformities. Proper differentiation between the two conditions is crucial, as Maffucci syndrome uniquely involves vascular anomalies. Early diagnosis, regular monitoring, and tailored treatment strategies, including surgical intervention and genetic counselling, are essential to managing these conditions effectively. Further research into the genetic underpinnings may pave the way for personalised treatments, improving outcomes for those affected by these complex diseases.