Introduction

Maffucci syndrome is a rare condition that primarily affects bones and skin. Maffucci syndrome is characterised by growths called enchondromas. These are benign (non-cancerous) masses that originate within the bone cartilage.¹ Other symptoms of Maffucci syndrome include bone deformities and the development of hemangiomas (a type of non-cancerous mass composed of excess blood vessels).²

While the growths associated with Maffucci syndrome are initially non-cancerous, they may become malignant (cancerous) if untreated. In these cases, they can affect more of the skeleton, as well as other parts of the body.

Causes of Maffucci syndrome

Maffucci syndrome is caused by genetic mutations. The IDH1 gene is most commonly mutated in Maffucci syndrome; however, mutations in the IDH2 gene can also cause disease. IDH1 and IDH2 both encode enzymes - IDH1 encodes the enzyme isocitrate dehydrogenase 1, whilst IDH2 encodes isocitrate dehydrogenase 2.³ These enzymes are responsible for the oxidation of substrates in the tricarboxylic acid cycle (TCA cycle), an important part of mitochondrial respiration (cellular energy production).

The genetic mutations responsible for causing Maffucci syndrome are not believed to be hereditary, meaning they cannot be passed down from parents to children. Instead, these mutations are believed to be somatic, meaning the changes within a person’s DNA occur after conception or throughout a person’s development and life.⁴

Skeletal manifestation of Maffucci syndrome

Maffucci syndrome primarily affects the bones, and cause cause issues with posture and bone health.

Enchondromas

Enchondromas are benign cartilage tumours that commonly form within the small bones of the hand and feet, as well as the femur (thigh bone) and humerus (a bone in the upper arm). Cartilage is a tough connective tissue that protects a person’s bones and joints, and provides structural support and attachment sites for muscles.

Typically, enchondromas form during childhood and originate from growth plate cartilage that fails to develop normally during adolescence or adulthood.⁵ Echondromas are typically painless and only cause minor discomfort. However, if there are multiple lesions on single bones, they can become weak and deformed - increasing the chance of bone fractures and enlargement or swelling in the surrounding area.

This can shorten or angulate limbs, depending on the number and size of the lesions.⁶ Large echondromas can be painful or exert pressure on nearby bones. In rare cases, enchondromas may become malignant and develop into bone tumours requiring immediate medical attention. 

Skeletal deformities

Limb length discrepancy 

Limb length discrepancy (LLD) is a common problem in individuals with Maffucci syndrome. LLD is defined as a condition where a person’s limbs form to be different lengths. If more enchondromas form in one limb than the other, they can significantly affect the development of the bone and stunt its growth.⁸

Generally, LLD will occur in the upper and lower extremities of the body. Luckily, discrepancies between 2 and 5 cm be corrected. An LLD in the legs is usually well tolerated below 10 cm, and individuals can live a relatively normal life thanks to the availability of insoles and other treatment options. 

Osteolysis

Osteolysis is defined as the progressive destruction of bone tissue. It can be a side effect of Maffucci syndrome. Osteoclasts (a type of bone cell) are responsible for reabsorbing old or damaged bone matrix (the intracellular substance that makes up most bone mass).¹⁰ This allows for cells called osteoblasts to create new bone tissue, maintaining overall bone homeostasis. 

In osteolysis, osteoclasts are much more active than osteoblasts - resulting in a loss of bone minerals such as calcium and weaker and softer bones.⁹ This increases the risk of bone fractures and other injuries. 

Bony exostoses

Occasionally, bony exostoses may develop on bone tissue. Bony exostoses are benign bone tumours that extend outwards from the bone surface. Exostoses can form on any type of bone, but they are most commonly found on the feet, hips and ear canal. Generally, exostoses do not cause symptoms, but they may cause pain and discomfort depending on where they form. There are several types of exostoses, including:¹¹

• Surfer’s ear: an exostosis that develops within the ear canal. It may affect a person’s hearing and can cause infection
• Haglund’s deformity: an exostosis that forms in the heel bone around the Achilles tendon that connects to the ankle. Can cause heel pain
• Bone spurs: also known as osteophytes, these are a type of exostosis that typically develops near the joints. These are not usually painful and develop gradually over time

Bone cancer

Although enchondromas start as benign, they may become malignant (cancerous) over time. Roughly half of patients with Maffucci syndrome develop a type of bone cancers called chondrosarcoma.¹³ This is a type of cancer that develops in cartilage cells. Most types of chondrosarcoma grow very slowly, but may eventually spread to different parts of the body. Symptoms vary depending on the location of the tumours, but they usually include:

• Bone pain
• Swelling around affected joints
• The appearance of masses 

Individuals with Maffucci syndrome are also more likely to develop other types of cancer, particularly ovarian or breast cancer.¹² Consequently, individuals who have Maffucci syndrome are recommended to undergo regular screening for cancer. If enchondromas do become malignant, they can be treated with surgery or chemotherapy. 

Summary

Maffucci syndrome is a rare disorder that predominantly affects bone and skin. The main characteristics of Maffucci syndrome are the appearance and growth of masses on bones, such as enchondromas and hemangiomas. Enchondromas are generally painless, but they can significantly affect the development of bones and other body parts.

In rare cases, they can result in limb length discrepancy (LLD) and bone cancer. Depending on the severity of their symptoms, individuals with Maffucci syndrome can often live normal lives, with several management strategies available.