Information on the following diseases can be found in the Related Disorders section of this report:

• Ollier Disease
• Klippel-Trenaunay-Weber Syndrome
• Blue Rubber Bleb Nevus Syndrome

Infants with Maffucci syndrome usually do not have obvious symptoms at birth. Symptoms usually develop during early childhood, most often between 1 and 5 years of age. The severity of Maffucci syndrome varies. Some individuals may have a mild course; others may have serious complications.

The first symptom associated with Maffucci syndrome is usually the development of a benign tumor consisting of cartilage (enchondroma). Enchondromas most often occur in certain bones of the hands and feet (phalanges), but can affect any bone preformed from cartilage. The long arms of the arms and legs are also frequently affected.

In approximately 40 percent of cases, enchondromas only affect one side of the body. Enchondromas may cause bulging of affected areas, frequent fractures, bowing of the arms and legs, and may cause irregular, disproportionate (asymmetric) growth (e.g., different lengths of the arms or legs). As affected individuals grow older, they may exhibit short stature.

Abnormalities affecting the blood vessels (vascular malformations) eventually occur by 1 year of age. Tumors consisting of masses of blood vessels (hemangiomas) most commonly affect the skin, especially in the areas near an enchondroma. These lesions often begin as firm, rounded, bluish spots on the skin. The may eventually become knotty, warty (vascular masses) that contain calcium stones (phleboliths). Abnormal widening of the blood vessels (phlebectasia) also occurs. The skin of the hand is most often affected. These benign tumors may also affect internal structures such as the membranes that cover the brain and spinal cord (meninges), the tongue, or the (buccal mucosa).

The blood vessels affected are usually capillaries or veins. The capillaries are tiny blood vessels that connect arteries and veins. Veins are blood vessels that take blood to the heart. Less often, other vessels such as the lymphatic vessels may be affected. Lymph vessels are part of the lymphatic system, the circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body.

Affected individuals may also develop associated malignancies (cancer), especially a tumor consisting of cartilage known as a chondrosarcoma. These malignancies develop from bone and soft-tissue lesions (enchondromas). Some researchers believe that chondrosarcomas are an over-reported finding of Maffucci syndrome; their frequency has been estimated to be between 15 to 34 percent.

Less often, other malignant connective tissue neoplasms including fibrosarcomas, angiosarcomas, lymphangiosarcomas, interstitial tissue cell tumors (gliomas), embryonic tissue cell (mesenchymal) ovarian tumors, and pancreatic adenocarcinomas have also been described.

The exact cause of Maffucci syndrome is unknown. All cases have occurred randomly for no apparent (sporadically). No pedigrees with multiple affected family members have been reported in the medical literature.

Some individuals with enchondromas were found to have a mutation of the PTH/PTHR receptor I gene located on chromosome 3. However, individuals with Maffucci syndrome were tested and found not to have this mutation.

Maffucci syndrome affects males and females in equal numbers. There is no apparent ethnic or racial predilection. The disorder was first described in the medical literature in 1881. One medical textbook published in 2002 stated that approximately 225 cases of Maffucci syndrome have been described at that time.

Symptoms of the following disorders can be similar to those of Maffucci syndrome. Comparisons may be useful for a differential diagnosis.

Ollier disease is a rare skeletal disorder characterized by abnormal bone development (skeletal dysplasia). While this disorder may be present at birth (congenital); it may not become apparent until early childhood when symptoms, such as deformities or improper limb growth, are more obvious. Ollier disease primarily affects the long bones and cartilage of the joints of the arms and legs, specifically the area where the shaft and head of a long bone meet (metaphyses). The pelvis is often involved; and even more rarely, the ribs, breast bone (sternum), and/or skull may also be affected. Ollier disease manifests as greater than normal growth of the cartilage in the long bones of the legs and arms so that growth is abnormal and the outer layer (cortical bone) of the bone becomes thin and more fragile. These masses of cartilage are benign (non-cancerous) tumors known as enchondromas. Enchondromas may occur at anytime. After puberty these growths stabilize as cartilage is replaced by bone. In rare cases, the enchondromas may undergo malignant changes (e.g., chondrosarcomas). The exact cause of Ollier disease is not known. (For more information on this disorder, choose "Ollier" as your search term in the Rare Disease Database.)

Blue rubber bleb nevus is a rare disorder characterized by soft, elevated, blue, blue- black or purplish-red swellings, called hemangiomas or nevus, on the skin or just under the skin. The nodules may be tender, contain blood and be easily compressed. External nevi are usually located on the upper arms or trunk. Internally, nevi may be located in many different sites such as the liver, lungs, spleen, gallbladder, kidney and skeletal muscles. Serious complications may accompany internal growths. When the gastrointestinal tract is affected, uncontrolled bleeding may result in chronic anemia. If nevi are located in the brain, they may cause bleeding and increased intracranial pressure. (For more information on this disorder choose "Blue Rubber Bleb Nevus" as your search term in the Rare Disease Database.)

Proteus syndrome is a rare disorder characterized by overgrowth (hypertrophy) of various tissues of the body. The cause of the disorder is unknown. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random “patchy” pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), and certain skin lesions. In some cases, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism. (For more information on this disorder, choose “Proteus” as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of Maffucci syndrome is made based upon a thorough clinical evaluation, detailed patient history, identification of characteristic findings, and x-ray studies of affected area. X-ray studies or surgical removal and microscopic study (biopsy) of affected areas can identify enchondromas and distinguish these growths from chondrosarcomas.

Treatment
The treatment of Maffucci is directed toward the specific symptoms that are apparent in each individual. Treatment is not necessary for individuals without symptoms (asymptomatic).

Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, specialists who asses and treat skin problems (dermatologists), and other health care professionals may need to systematically and comprehensively plan an affect child’s treatment.

Warty (verrucous) lesions can be inject a drug that hardens the affected tissue (sclerosing agenet), which can then be surgically removed. Enchondromas can be surgically removed (resected) if necessary. If skeletal abnormalities of the hand cause loss of function or recurrent fracture, a hand specialist can be called in. Orthopedic surgery may also be necessary for leg length discrepancies, abnormal curvature of the spine (scoliosis) or other bony abnormalities.

Individuals with Maffucci syndrome should be regularly monitored because of the potential of enchondromas to transform into cancer (malignant transformation).

If no malignant transformation occurs, individuals with Maffucci syndrome have 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
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

TEXTBOOKS
Spitz JL. Genodermatoses. 2nd ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2005:118.

Boon LM, Mulliken JB. Maffucci Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:217-218.

Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:460.

Cohen MMJr, Nori G, Weksberg R. Overgrowth Syndromes. 1st ed. Oxford University Press, New York, NY; 2002:125-127.

Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:518.

JOURNAL ARTICLES
Faik A, Allali F, el Hassani S, Hajjaj-Hassouni N. Maffucci’s syndrome: a case report. Clin Rheum. 2006;25:88-91.

Miyake M, Tateishi U, Maeda T, et al., MR features of angiosarcoma in a patient with Maffucci’s syndrome. Raidat Med. 2005;23:508-12.

Rozeman LB, Sangiorgi L, Briaire-de Bruijn IH, et al., Enchondromatosis (Ollier disease, Maffucci syndrome) is not cause by the PTHR1 mutation p. R150C. Hum Mutat. 24:466-73.

Noel G, Feuvret L, Calugaru V, et al., Chondrosarcomas of the base of the skull in Ollier’s disease or Maffucci’s syndrome – three case reports and review of the literature. Acta Oncol. 2004;43:705-10.

Kaplan RP, Wang JT, Amron DM, et al., Maffucci’syndrome: two case reports and review of the literature. J Am Acad Dermatol. 1993;29:894-9.

FROM THE INTERNET
Kuwahara RT. Maffucci syndrome. Emedicine Journal, April 12 2006. Available at: http://www.emedicine.com/derm/topic256.htm Accessed on: April 22, 2007.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:166000; Last Update:02/15/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=166000 Accessed on: April 22, 2007.