What is Maffucci Syndrome

Introduction

The cartilage is a firm yet flexible type of connective tissue that is essential to us, as it connects and supports our bones at our joints, throughout the body.¹ However in some people, this cartilage tissue overgrows to form benign (non-harmful) tumours called enchondromas. The presence of these growths characterises an extremely rare disorder called Maffucci Syndrome (MS).² In MS patients, hundreds of enchondromas can arise starting from their early childhood, most frequently found in their hands and feet, which can collectively lead to severe limb fractures and skeletal deformities.² Other characteristics of Maffucci syndrome include abnormal tangles of blood vessels, called haemangiomas, which are typically visible as bluish lumps just under the skin of MS patients.²

MS is a very rare condition. Since it was first described in 1881 by the Italian physician Angelo Maffucci, only around 200 cases worldwide have been reported in medical literature.³

Although both enchondromas and haemangiomas are usually benign, MS patients are more susceptible to developing various cancers due to these defining symptoms.² Hence, it is important to be aware of this syndrome, to prevent potential cancer formation. This article will detail the symptoms and causes of MS, as well as how the disorder is diagnosed and currently managed. 

Symptoms of Maffucci syndrome

The signs and symptoms of MS can vary – from some patients being asymptomatic (having no symptoms at all), to other patients developing life-threatening complications such as cancer.² If symptoms do occur in patients, they usually develop during early childhood (between 4-5 years old being the average age).⁴ In roughly 25% of cases, symptoms start from birth (also known as congenital).⁴ 

Enchondromas

The first characteristic symptom of MS is the formation of enchondromas (overgrowths of cartilage). These benign tumours most commonly occur in the hands and feet of patients, however, they may also be found in the bones of the following body parts:

• Arms
• Ribs
• Legs
• Skull
• Spine⁵

When small, these enchondromas may not cause any pain or additional symptoms. However, as a consequence of the formation of big enchondromas and the space they fill up, the bones surrounding the overgrowths can become weaker and distorted. Due to this, MS patients can also experience the following symptoms:

• Fractures in affected bones
• Bones visibly bulging out
• Bone pain
• Bone destruction, known as osteolysis
• Curved spine
• Pain when walking, due to enchondromas found on the soles of feet⁵

It is also important to note that enchondromas are typically asymmetrically distributed around the body. In fact, some patients only develop these overgrowths on just one side of their body, which is called unilateral distribution.⁶ This uneven distribution of enchondromas can result in the following symptoms:

• Uneven length in arms or legs: one being longer than the other, due to enchondromas stumping and distorting the growth of one of the limbs
• Short stature
• Functional impairment of limbs
• Mobility issues
• Pain and discomfort⁶

Haemangiomas

Haemangiomas (the abnormal entanglement of blood vessels) typically form after the development of enchondromas.⁷ They tend to first manifest just under the skin of patients, as bluish, purple or red spots, and in time they can become hard, bumpy and sometimes warty.⁷ It should be noted thought that haemangiomas do not necessarily form around bones that have already been affected by enchondromas. However, similarly to enchondromas, these entanglements are found asymmetrically and widely distributed around the body. Their most common location is the hand, and they can also be found within the following body parts:

• Eyes
• Tongue
• Trachea: the tube that connects your voice box to your lungs 
• Intestines
• Throat
• Meninges: the membranes that cover and protect the brain and spine⁷

Malignant transformation of enchondromas and haemangiomas

In a significant portion of patients, there is a risk of their enchondromas and haemangiomas becoming cancerous (malignant):

• Enchondromas can turn into chondrosarcomas – In roughly 30% of MS patients, their benign enchondromas can become malignant and turn into chondrosarcoma, which is a type of bone cancer that starts in cartilage cells.⁸ 
• Haemangiomas can turn into vascular cancers (occurs in blood vessels) – In roughly 8.5% of MS cases, these entanglements can become cancerous.⁹  

Other malignancies that MS patients are more susceptible to include the following:

• Pancreatic and hepatic adenocarcinoma 
• Mesenchymal ovarian cancer 
• Glioma 
• Astrocytoma 
• Sarcomas⁸ 

Prognosis and life expectancy of Maffucci syndrome patients

Although MS is a chronic, lifelong condition, some patients are asymptomatic or experience very minor physical limitations.⁸ This means that the disorder does not affect their life expectancy.

However, for patients who have various enchondromas in their spine, this can affect their quality of life due to severe physical restrictions. Moreover, for patients who develop malignancies, this condition can potentially shorten their lifespan.²

Causes of Maffucci syndrome

MS is a genetic disorder, meaning that the disease is caused by a mutation (random change) in specific genes of these patients. The genes responsible for the development of this syndrome are isocitrate dehydrogenase 1 (IDH1) and isocitrate hydrogenase 2 (IDH2), with the former being the most common genetic mutation (found in 98% of patients) compared to the latter (found in 2%).¹⁰ The IDH genes have the role of making enzymes which are essential for many important processes within the body. Mutations within these genes mean that these enzymes will not function as they normally do, leading to the formation of enchondromas.¹⁰

Moreover, in 2021, another gene was discovered to play a role in the development of MS – this gene being the ELKS/RAB6-interacting/CAST family member 2 (ERC2). Mutations in this gene are associated with the formation of haemangiomas in MS patients.¹¹

The genetic mutations responsible for the development of MS are classed as “somatic mutations”. This means that the mutation responsible is not one that has been passed down from familial generation to generation (hereditary), but instead occurs randomly whilst a baby is developing in the womb.¹⁰ 

Diagnosis

A doctor will diagnose MS through clinical evaluations. These physical exams will help the healthcare professional find visible signs of the disorder, as well as allow the patient to discuss their history of symptoms. To further confirm an MS diagnosis, radiological imaging is used (such as X-rays and CT scans), to  take pictures and visualise the bones which may be affected by enchondromas.³

Other potential techniques for diagnosis include the surgical removal of pieces of affected bone and tissue, where a medical expert will then assess such samples under a microscope to confirm the presence of enchondromas and haemangiomas.³ This diagnosis method also helps distinguish whether a patient’s enchondroma has turned malignant (into a chondrosarcoma). 

Differential diagnosis

MS can be often mistaken for other disorders:

• Ollier syndrome – This syndrome is very similar to MS, as both diseases are caused by the same genetic mutations in the IDF gene, and both lead to enchondroma symptoms.  However, the way to distinguish between the two syndromes is through the development of haemangiomas: Ollier syndrome patients do not suffer from them, whereas MS patients do.⁹  

• Blue Rubber Bleb Nevus syndrome (BRBNS) – This syndrome is characterised by the development of bluish spots and lesions, which appear to be very similar to the haemangiomas found in MS. However, BRBNS is caused by a different somatic mutation, hence genetic testing can be done to properly differentiate between the two diseases.¹² 

• Proteus syndrome – This syndrome, similarly to MS, is characterised by benign tumours that are found in the connective tissues between the bones, particularly in the feet. Also just like MS, curvature of the spine can occur in Proteus syndrome patients. However, Proteus syndrome is caused by a different somatic mutation, and hence genetic testing can be carried out to differentiate between the two disorders.¹³ 

Management and treatment for Maffucci syndrome

Although there is no cure for MS, there are various treatments available for patients. The goal of these management options is to be able to alleviate any painful symptoms, fix any broken bones, and also detect any signs of cancer as early as possible.¹⁴

Symptomatic management

If enchondromas lead to severe skeletal issues and limb deformities, treatments to manage these can include:

• Braces to correct abnormal curvatures of the spine
• Casts to fix broken bones
• Shoe lifts to reduce differences in leg length¹⁴

If haemangiomas become painful and bothersome, then a doctor can recommend sclerotherapy. This is a procedure that involves injecting a solution called a sclerosing agent into the body at the location of the haemangiomas, which will hopefully shrink the entanglements.¹⁴ 

Surgical interventions

Surgery is the most effective treatment currently available for MS patients. Specifically, orthopaedic surgeons (who specialise in surgeries relating to bones, muscles and ligaments) can perform a variety of surgical interventions to improve the quality of life of MS patients. Examples include:

• Surgery to correct skeletal deformities
• Surgery to fix broken bones
• Surgery to reduce differences in limb length
• Surgery to remove any enchondromas or chondrosarcomas
• Surgery to remove abnormalities found in the hands¹⁴

Monitoring and surveillance

Radiologists, who are experts in using imaging techniques to diagnose medical conditions, will order regular radiological exams for MS patients over time, to evaluate any changes in the patients’ bones, ligaments, and overall symptoms. This is done due to the elevated risk that MS patients have for developing cancer. With this type of surveillance, the underlying hope is that if any cancer develops, the radiologists can detect it early, and any treatment given will be more effective, increasing the survival chances of the patient.¹⁴

Current research into new treatments

There is a lot of current research taking place worldwide which aims to ameliorate the treatments available for MS patients who have severe symptoms and subsequent malignancies. For example:

• The drug Ivosidenib, known to stop the IDH1 gene from functioning within the body, is showing promise as an effective treatment for MS patients with chondrosarcomas.¹⁵ 
• A drug called Sirolimus is being assessed as a potential treatment for haemangiomas.¹⁶ 

FAQs

How can I prevent Maffucci syndrome?

Experts do not fully understand the genetic mutations behind the development of MS, as they appear to happen randomly. Hence, there are no current strategies to prevent the disorder.

How common is Maffucci syndrome?

This disease is incredibly rare – it is suggested that the syndrome affects less than 1 in every 100,000 people.³ 

Who is at risk of Maffucci syndrome?

There is no group of people more susceptible to developing MS – the disorder occurs in all ethnic groups, one cannot inherit the disease from a parent, and it affects males and females equally.⁴

When should I see a doctor?

If you notice any bulging of your bones around your body (particularly in the hands and feet), as well as any bluish lumps and spots, these could indicate the presence of enchondromas and haemangiomas respectively. You should go to the doctor to get these checked out.

If you are already diagnosed with MS, and your symptoms cause you no pain, then usually it does not need to be treated, and hence you do not need to see a doctor. However, it is vital to have regular checkups with a healthcare professional, to make sure that no malignancies are forming. If your symptoms start to become painful, then you should see your doctor, as they will recommend the best course of treatment. 

Summary

MS is a rare genetic disorder characterised by the formation of benign tumours in the connective tissue called cartilage (enchondromas), as well as the formation of abnormal tangles of blood vessels (haemangiomas). These growths appear during a patient’s early childhood, and symptoms which arise from these overgrowths can vary between patients – some may feel asymptomatic, some may feel pain in their bones and limbs, whereas some can suffer from extreme deformities in their spine and limbs, as well as the development of various cancers. Although there is no current cure for MS, there are various treatments used to alleviate symptoms, the most common being braces and surgeries that can fix any broken bones or deformities. It is imperative for MS patients to regularly get their growths checked, even if the patient is asymptomatic. This is because MS patients are more susceptible to developing cancer, hence regular check-ups will allow doctors to catch any cancer early, therefore further treatment is more effective and improves the prognosis of the patient.