What is Maffucci syndrome
Maffucci syndrome is an extremely rare disorder that primarily affects the bones and skin. Maffucci syndrome is characterized by multiple enchondromas, which are noncancerous (benign) overgrowths of cartilage that develop within the bones and venous malformations with or without spindle cell hemangiomas 1. These growths most commonly occur in the limb bones, especially in the bones of the hands and feet; however, they may also occur in the skull, ribs, and bones of the spine (vertebrae). Enchondromas may result in severe bone deformities, shortening of the limbs, and fractures.
Maffucci syndrome is very rare. Since it was first described in 1881, fewer than 200 cases have been reported worldwide 2. Maffucci syndrome occurs in all ethnic groups and equally affects both sexes.
The signs and symptoms of Maffucci syndrome may be detectable at birth, although they generally do not become apparent until around the age of 5. Enchondromas develop near the ends of bones, where normal growth occurs, and they frequently stop forming after affected individuals stop growing in early adulthood. As a result of the bone deformities associated with Maffucci syndrome, people with this disorder generally have short stature and underdeveloped muscles.
Maffucci syndrome is distinguished from a similar disorder that involves enchondromas (Ollier disease) by the presence of red or purplish growths in the skin consisting of tangles of abnormal blood vessels (hemangiomas). In addition to hemangiomas, individuals with Maffucci syndrome occasionally also have lymphangiomas, which are masses made up of the thin tubes that carry lymph fluid (lymphatic vessels). These growths may appear anywhere on the body.
Although the enchondromas associated with Maffucci syndrome start out as benign, they may become cancerous (malignant). In particular, affected individuals may develop bone cancers called chondrosarcomas, especially in the skull. People with Maffucci syndrome also have an increased risk of other cancers, such as ovarian or liver cancer.
People with Maffucci syndrome usually have a normal lifespan, and intelligence is unaffected. The extent of their physical impairment depends on their individual skeletal deformities, but in most cases they have no major limitations in their activities.
Maffucci syndrome causes
In most people with Maffucci syndrome, the disorder is caused by mutations in the IDH1 (common) or IDH2 gene (rare). These genes provide instructions for making enzymes called isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2, respectively. These enzymes convert a compound called isocitrate to another compound called 2-ketoglutarate. This reaction also produces a molecule called NADPH, which is necessary for many cellular processes. IDH1 or IDH2 gene mutations cause the enzyme produced from the respective gene to take on a new, abnormal function. Although these mutations have been found in some cells of enchondromas and hemangiomas in people with Maffucci syndrome, the relationship between the mutations and the signs and symptoms of the disorder is not well understood.
Mutations in other genes may also account for some cases of Maffucci syndrome.
Maffucci syndrome is not inherited. The mutations that cause this disorder are somatic, which means they occur during a person’s lifetime. A somatic mutation occurs in a single cell. As that cell continues to grow and divide, the cells derived from it also have the same mutation. In Maffucci syndrome, the mutation is thought to occur in a cell during early development before birth; cells that arise from that abnormal cell have the mutation, while the body’s other cells do not. This situation is called mosaicism.
Maffucci syndrome symptoms
Maffucci syndrome is not recognizable at birth. Lesions usually develop early in childhood, most often between 1-5 years of age. The severity of the disorder is variable. Some patients have a very benign course, whereas others develop serious complications.
The first sign of Maffucci syndrome is usually finding an enchondroma in a long bone. Enchondromas distort and weaken the affected bones, thus initial presentation with a pathologic fracture is common. These cartilaginous tumors cause bulging of the bones, bowing of the arms and legs, and often disproportionate (asymmetric) growth (different lengths of the arms or legs). The patient may exhibit short stature in adulthood. Enchondromas affect only one side of the body in approximately 40 percent of patients.
Vascular lesions on the skin also usually appear in early childhood (around 4-5 years of age) and are often progressive. These lesions do not necessarily occur near the bones that have enchondromas. These vascular lesions begin as compressible, round, bluish spots. In time, they become firm, knotty, warty, and often contain calcium stones (phleboliths). The hand is the most common location; however vascular lesions can also occur in internal structures, such as the membranes that cover the brain and spinal cord (meninges), the tongue, and the oral mucosa.
These vascular lesions used to be called “cavernous hemangiomas”. Microscopic studies have shown that they are comprised of abnormally-formed veins so that the more modern term is “venous malformation.” A benign vascular tumor, designated as “spindle cell hemangioma,” often arises in these malformed veins.
Patients with Maffucci syndrome are at risk to developing a malignant tumor, particularly a tumor of cartilage known as “chondrosarcoma.” The more enchondromas, the higher the risk of malignancy. The frequency has been estimated to be between 15-40 %; however, some investigators believe that chondrosarcoma in Maffucci syndrome is over-reported. Less frequently, other malignant, non-skeletal connective tissue neoplasms can occur in patients with Maffucci syndrome.
Maffucci syndrome diagnosis
The diagnosis of Maffucci syndrome is made by a detailed history, thorough physical examination and radiologic assessment. Surgical removal and microscopic study of the skeletal lesions confirm the presence of enchondroma and distinguish the tumor from chondrosarcoma.
Maffucci syndrome treatment
Management of Maffucci syndrome is focused on the specific signs/symptoms in the particular affected individual. No intervention is needed for asymptomatic patients.
Treatment requires coordinated efforts of a team of specialists (multidisciplinary care).
The warty (verrucous) vascular lesions can be injected with a drug that shrinks and hardens the area (sclerosing agent); however, often operative removal is also needed. Enchondromas can be surgically removed (resected) if necessary. A specialist in hand surgery is needed to correct the skeletal abnormalities of the hand if there is loss of function or recurrent fracture. An orthopedic surgeon addresses leg length discrepancy, abnormal curvature of the spine (scoliosis) or other skeletal abnormalities.
A patient with Maffucci syndrome should be regularly monitored because of the risk of malignant transformation of an enchondroma or development of a tumor elsewhere.
If a malignancy does not occur, patients with Maffucci syndrome have an otherwise normal life expectancy.
Maffucci syndrome prognosis
Patients with Maffucci syndrome usually lead reasonably normal lives with a normal life expectancy if no malignant transformation occurs.
Cancer (chondrosarcoma) may arise within the enchondromas in about 30% of adult patients.
Although the skeletal malformations can sometimes be crippling, patients have managed to perform activities of daily living rather well.
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