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NORD is very grateful to John B. Mulliken, MD, Co-Director, Vascular Anomalies Center; Director, Craniofacial Center, Boston Children’s Hospital, for assistance in the preparation of this report.
Maffucci syndrome is an extremely rare disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities and skin lesions composed of abnormal blood vessels. Enchondromas arise in bones, most frequently in the hands and feet and less often in the legs and long bones of the arm.
Maffucci syndrome is not seen 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 mild course, whereas others can develop serious complications.
The first sign of Maffucci syndrome is usually the growth of an enchondroma in a long bone. Enchondromas distort and weaken the affected bones, thus 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 only affect one side of the body in approximately 40 per cent 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 per cent; however, some investigators believe that chondrosarcoma in Maffucci is over-reported. Less frequently, other malignant, non-skeletal connective tissue neoplasms can occur in patients with Maffucci syndrome.
In 2011, the cause of Maffucci syndrome was discovered to be a mutation in a gene known as IDH1 (rarely IDH2). The same mutations were found in the related disorder Ollier disease. Since the defect occurs after fertilization (called a somatic mutation), Maffucci syndrome is not considered to be hereditary, that is, it cannot be passed along in a family. The cases occur randomly and there are no known pedigrees of affected family members.
Maffucci syndrome occurs in all ethnic groups and equally affects both sexes.
The following disorders can look similar to Maffucci syndrome; however, they usually can be differentiated by clinical examination.
This is a rare skeletal disorder characterized by abnormal bony development and enchondromas in the absence of cutaneous vascular lesions as seen in Maffucci syndrome. While Ollier disease is present at birth, it may not become apparent until early childhood when skeletal deformities or abnormal growth of a limb occurs. Ollier disease primarily affects the long bones and cartilage of the joints of the arms and legs, specifically where the shaft and head of the long bone meet (metaphysis). The pelvis is also often involved and more rarely, the ribs, breast bone (sternum) and cranium are affected. There disease involves growth of enchondromas from cartilage in the long bones so that the outer layer (cortical bone) becomes thin and fragile. After puberty, these cartilaginous growths stabilize as cartilage is replaced by bone. These enchondromas may undergo malignant degeneration but far less frequently than in Maffucci syndrome. Enchondromas from patients with Ollier disease have been found to have mutations in PTH/PTHR receptor I gene located on chromosome 3, but these mutations are not found in Maffucci syndrome. (For more information on this disorder, choose "Ollier" as your search term in the Rare Disease Database).
Blue Rubber Bleb Nevus Syndrome
The blue vascular lesions of Maffucci syndrome can be mistaken for this rare vascular disorder. It is characterized by multiple, soft, elevated, blue, blue-black or purplish-red swellings (venous malformations). The lesions arise in the skin and internal organs, particularly the gastrointestinal tract. They typically appear on the hands and soles of the feet, but can also arise anywhere on the body, including the face and trunk, and in the liver, lungs, spleen, gallbladder, kidney and skeletal muscles. These internal lesions can cause serious complications. Bleeding from the gastrointestinal tract usually results in chronic anemia that may require blood transfusion. (For more information on this disorder, choose "Blue Rubber Bleb Nevus" as your search term in the Rare Disease Database).
This extremely rare condition may be confused with Maffucci syndrome. It is characterized by cerebriform connective tissue nevi ("moccasin feet"), epidermal nevi, lipomas and disproportionate, relentless, and asymmetrical skeletal overgrowth. Proteus patients are essentially normal at birth, except for the nevi. They also can have capillary malformations and venous malformations. The enlarged veins put them at risk for pulmonary thromboembolism. The cause has recently been shown to be a somatic activating mutation in the gene AKT1 occurring in cells during the early embryonic period. It is not hereditary. (For more information on this disorder, choose "Proteus" as your search term in the Rare Disease Database).
A subset of patients initially diagnosed as having Proteus syndrome have another overgrowth disorder CLOVES caused by mutations in the gene PIK3CA. (For more information on this disorder, choose "CLOVES" as your search term in the Rare Disease Database).
The diagnosis of Maffucci syndrome is made by a detailed history, thorough physical examination and radiologic assessment. Surgical removal and microscopic study of the bony lesions confirm the presence of enchondroma and distinguish the tumor from chondrosarcoma.
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 surgical 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 that cause 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about Maffucci syndrome:
John B. Mulliken, MD,
Co-Director, Vascular Anomalies Center
Director, Craniofacial Centre
Boston Children’s Hospital
300 Longwood Avenue
Boston, MA 02115
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
Biesecker LG. Proteus syndrome. In: Cassidy SB, Allanson JE, editors. Management of Genetic Syndromew. New York, NY: Wiley; 2005: 449-456.
Biesecker L. Proteus Syndrome. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:239.
Pansuriza TC, van Eijk R, D’Amato P, et al. Somatic mosaic IDH1 and IDH2 mutationis are associated with enchondromas and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nature Genet. 2011;43:1256-61.
Amary MF, Damato S, Halai D. Ollier disease and Maffucci syndrome are caused by somatic mutations in IDH1 and IDH1. Nature Genet 2011; 43:1262-65.
Couvineau A, Wouters V, Bertrand G, et al. PTHR1 mutations associated with Ollier disease result in receptor loss of function. Hum Mol Genet. 2008;17:2766-75.
Kuwahara RT, Rasberry R. Maffucci Syndrome. Emedicine. http://emedicine.medscape.com/article/1111804-overview. Updated March 28, 2012. Accessed July 12, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Enchondromatosis, Multiple, Ollier Type. Entry No: 166000. Last Edited April 17, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 12, 2012.
Report last updated: 2012/07/16 00:00:00 GMT+0