Overview

Maffucci syndrome is a very rare, non-inherited, genetic disorder that primarily affects bones and skin. It was first described by Angelo Maffucci in 1881 and is characterised by multiple (more than three) enchondromas (benign overgrowths of cartilage in the bones), bone deformities, and haemangiomas (benign blood vessel tumours). The overgrowths of cartilage in the bones, known as enchondromas, typically appear in the hands or feet but can also develop in the skull, ribs, and spine. 

Although benign, they carry a risk of malignancy, particularly chondrosarcoma, with up to half of affected individuals developing this cancer, especially in the skull. Additionally, individuals with Maffucci syndrome have an increased risk of other cancers such as ovarian or liver cancer. 

The cause of Maffucci syndrome is currently unknown, and it predominantly affects young children. The syndrome is exceptionally rare, with only a few hundred cases documented in medical literature. Genetic research has identified genes related to this disorder, and recent studies have linked mutations in IDH1/2 to its pathogenesis.¹

Affected individuals usually have an average lifespan, and exhibit normal cognitive abilities. The degree of their physical impairment depends on their bone deformities, but in most cases, their activities are not significantly impacted.

The article discusses the symptoms of Maffucci syndrome, its causes, diagnostic tools, and standard therapies.

What are the symptoms of maffucci syndrome?

The symptoms of Maffucci syndrome can vary widely, ranging from mild to severe. They may manifest at birth or emerge during childhood. According to the National Organization for Rare Disorders, children with Maffucci syndrome usually develop abnormal blood vessels in their hands when they are around 4 to 5 years old.² 

The first sign of Maffucci syndrome often involves discovering an enchondroma in a long bone. Enchondromas can weaken bones, often resulting in fractures. Approximately 40% of individuals with Maffucci syndrome experience enchondromas affecting only one side of the body.

The main symptoms of the disorder arise from these enchondromas, which can result in:

• Bone pain
• Bone fractures
• Bowed arms or legs
• Bulging bones
• Curved spine
• Osteolysis (progressive destruction of bone tissue)
• Short stature in adulthood
• Different lengths of the arms or legs (one longer than the other)

Symptoms associated with haemangiomas may include:

• Blood clots
• Lymphangiomas, benign malformations (fluid-filled cysts) of the lymphatic system 
• Red, purple, or blue skin growths (haemangiomas), frequently on the hands, which may become hardened and develop a bumpy texture over time
• Underdeveloped muscles

What causes maffucci syndrome?

 Maffucci syndrome is caused by somatic mosaic mutations, meaning changes in the genetic sequence that occur after fertilisation. The genetic abnormalities that drive the overgrowth of cartilage are found in the genes encoding Isocitrate Dehydrogenase 1 (IDH1) or 2 (IDH2), most frequently in IDH1.³

The IDH genes produce enzymes that are important for various cell processes, such as breaking down nutrients and generating cellular energy. However, scientists are still working to fully understand the precise connection between these enzymes and Maffucci syndrome.

The condition isn’t thought to be hereditary, so it can’t be inherited (passed from one generation to the next).

How is maffucci syndrome diagnosed?

The diagnosis of Maffucci syndrome is made through:

• Physical examination to assess bone and skin abnormalities, and review of symptoms and medical history
• Radiological evaluation such as X-ray and CT scan (computed tomography)
• Surgical removal followed by microscopic examination of skeletal lesions to confirm the presence of enchondroma and distinguish it from chondrosarcoma

What are the standard therapies for maffucci syndrome?

While there is no cure for Maffucci syndrome, management focuses on addressing the specific signs and symptoms in the patient. Individuals who are asymptomatic do not require any intervention.

Treatment involves the collaboration of a multidisciplinary team of specialists, including, geneticists, plastic surgeons, haematologists, and interventional radiologists. Haemangiomas may be treated with injections of a sclerosing agent to reduce their size and harden them. In some cases, surgery may also be necessary to manage the condition effectively.

Enchondromas can be surgically removed if necessary. A hand surgeon is essential for managing skeletal abnormalities in the hand, especially in cases involving loss of function or recurrent fractures.

An orthopaedic surgeon addresses issues related to leg length discrepancy, abnormally curved spine (scoliosis) or other skeletal abnormalities.

Individuals with Maffucci syndrome should receive regular monitoring due to the risk of enchondroma malignant transformation or the formation of tumours in other parts of the body.

If a malignancy does not occur, individuals with Maffucci syndrome usually have a normal lifespan.

What is the prognosis for people with maffucci syndrome?

Maffucci syndrome is a chronic, permanent condition. Some individuals experience minor physical issues with few activity limitations, while others face severe cases with significant bone problems and physical limitations. Intelligence remains unaffected, but the condition can potentially shorten lifespan if cancer develops.

Alternative names of the condition 

• Chondrodysplasia with haemangioma
• Kast syndrome
• Dyschondroplasia and cavernous haemangioma
• Chondroplasia angiomatosis
• Multiple angiomas and enchondromas
• Enchondromatosis with multiple cavernous haemangiomas
• Dyschondrodysplasia with hemangiomas
• Enchondromatosis with hemangiomataHemangiomatosis chondrodystrophicaHemangiomata with dyschondroplasia

Summary

Maffucci syndrome is an extremely rare genetic disorder characterised by multiple enchondromas (benign cartilage tumours) and haemangiomas (benign blood vessel tumours). It primarily affects the bones and skin, often presenting with bone pain, fractures, and skeletal deformities such as bowed limbs or curved spine. These abnormalities are caused by somatic mosaic mutations in the IDH1 or IDH2 genes, which play roles in cellular metabolism. 

Diagnosis involves physical examination, radiologic imaging (X-ray, CT scan), and microscopic evaluation of skeletal lesions to differentiate between benign growths and potential malignancies like chondrosarcoma. 

Management focuses on surgical interventions to remove problematic growths, especially when causing pain or functional impairment. While Maffucci syndrome does not affect intelligence, individuals require regular monitoring due to the risk of cancer development, particularly chondrosarcoma. Despite physical challenges, they generally have a normal lifespan unless cancer develops.