Maffucci syndrome

Maffucci syndrome is a disorder that primarily affects the bones and skin.

Maffucci syndrome is characterized by:

• Multiple enchondromas, which are noncancerous (benign) growths of cartilage that develop within bones 
• Vascular lesions, sometimes called hemagiomas, which are tangles of abnormal blood vessels

The severity of the signs and symptoms seen in people with Maffucci syndrome can vary.

The features of Maffucci syndrome usually become apparent in early childhood. Enchondromas develop near the ends of bones, where normal growth occurs. Enchondromas most commonly occur in the bones of the hands and feet. They may also occur in:

• The skull
• The ribs
• The bones of the arms and legs
• The bones of the spine (vertebrae)

Enchondromas may cause bones to become weak and prone to fracture. They may also cause severe bone deformities, which can limit mobility. Enchondromas frequently stop forming in early adulthood.

In people with Maffucci syndrome, vascular lesions typically develop after the enchondromas. They often appear as red or purplish growths on the skin, most commonly on the hands, but they can also affect deep tissues, including organs inside the body. These lesions help distinguish Maffucci syndrome from a similar condition called Ollier disease, which also involves enchondromas. Vascular lesions may worsen over time.

Additional signs and symptoms that may be associated with Maffucci syndrome include:

• Bone pain  
• Short stature
• A spine that curves to the side (scoliosis) 
• Difficulty walking
• Underdeveloped muscles
• One arm or leg that is shorter than the other  
• Lymphangiomas, which are tangles of the thin tubes that carry lymph fluid (lymphatic vessels) 

Although the enchondromas that are associated with Maffucci syndrome start out as benign, they may develop into a type of bone cancer called chondrosarcoma. People with Maffucci syndrome also have an increased risk of other cancers, including cancer of the ovaries, pancreas, liver, brain, and spinal cord.

Maffucci syndrome is rare. Since it was first described in 1881, fewer than 300 cases have been reported. However, some researchers believe this number may be an underestimate, since some people with Maffucci syndrome likely do not receive a diagnosis and not all cases are reported in the scientific literature.

Genetic changes that contribute to disease are called pathogenic variants. Pathogenic variants in the IDH1 or IDH2 gene have been shown to cause Maffucci syndrome. These genes provide instructions for making enzymes called isocitrate dehydrogenases, which help convert a compound called isocitrate into another compound called 2-oxoglutarate. This process also produces a molecule called NADPH, which is necessary for many cellular activities.

The variants in the IDH1 or IDH2 gene that are associated with Maffucci syndrome are somatic, which means that they are acquired during a person’s lifetime and are present only in certain cells. These somatic variants generally occur during early embryonic development. In people with Maffucci syndrome, the somatic variants are typically found within the cells that make up the affected tissues, including the enchondromas and vascular lesions. However, the relationship between these variants and the specific features of Maffucci syndrome is not well understood. 

Somatic variants in other genes may account for some cases of Maffucci syndrome.

Genetic Testing Information

• Genetic Testing Registry: Maffucci syndrome

Genetic and Rare Diseases Information Center

• Maffucci syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• MULTIPLE ENCHONDROMATOSIS, MAFFUCCI TYPE

Scientific Articles on PubMed

• PubMed

• Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, McCarthy S, Fantin VR, Straley KS, Lobo S, Aston W, Green CL, Gale RE, Tirabosco R, Futreal A, Campbell P, Presneau N, Flanagan AM. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet. 2011 Nov 6;43(12):1262-5. doi: 10.1038/ng.994. Citation on PubMed
• Amyere M, Dompmartin A, Wouters V, Enjolras O, Kaitila I, Docquier PL, Godfraind C, Mulliken JB, Boon LM, Vikkula M. Common somatic alterations identified in maffucci syndrome by molecular karyotyping. Mol Syndromol. 2014 Dec;5(6):259-67. doi: 10.1159/000365898. Epub 2014 Aug 26. Citation on PubMed or Free article on PubMed Central
• El Abiad JM, Robbins SM, Cohen B, Levin AS, Valle DL, Morris CD, de Macena Sobreira NL. Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature. Am J Med Genet A. 2020 May;182(5):1093-1103. doi: 10.1002/ajmg.a.61530. Epub 2020 Mar 7. Citation on PubMed
• Herget GW, Strohm P, Rottenburger C, Kontny U, Krauss T, Bohm J, Sudkamp N, Uhl M. Insights into Enchondroma, Enchondromatosis and the risk of secondary Chondrosarcoma. Review of the literature with an emphasis on the clinical behaviour, radiology, malignant transformation and the follow up. Neoplasma. 2014;61(4):365-78. doi: 10.4149/neo_2014_046. Citation on PubMed
• Nejo T, Tanaka S, Ikemura M, Nomura M, Takayanagi S, Shin M, Ushiku T, Shibahara J, Saito N, Mukasa A. Maffucci syndrome complicated by three different central nervous system tumors sharing an IDH1 R132C mutation: case report. J Neurosurg. 2018 Dec 21;131(6):1829-1834. doi: 10.3171/2018.6.JNS18729. Print 2019 Dec 1. Citation on PubMed
• Pansuriya TC, Kroon HM, Bovee JV. Enchondromatosis: insights on the different subtypes. Int J Clin Exp Pathol. 2010 Jun 26;3(6):557-69. Citation on PubMed or Free article on PubMed Central
• Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovee JV. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2011 Nov 6;43(12):1256-61. doi: 10.1038/ng.1004. Citation on PubMed or Free article on PubMed Central
• Ranger A, Szymczak A. Do intracranial neoplasms differ in Ollier disease and maffucci syndrome? An in-depth analysis of the literature. Neurosurgery. 2009 Dec;65(6):1106-13; discussion 1113-5. doi: 10.1227/01.NEU.0000356984.92242.D5. Citation on PubMed
• Superti-Furga A, Spranger J, Nishimura G. Enchondromatosis revisited: new classification with molecular basis. Am J Med Genet C Semin Med Genet. 2012 Aug 15;160C(3):154-64. doi: 10.1002/ajmg.c.31331. Epub 2012 Jul 12. Citation on PubMed
• Verdegaal SH, Bovee JV, Pansuriya TC, Grimer RJ, Ozger H, Jutte PC, San Julian M, Biau DJ, van der Geest IC, Leithner A, Streitburger A, Klenke FM, Gouin FG, Campanacci DA, Marec-Berard P, Hogendoorn PC, Brand R, Taminiau AH. Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients. Oncologist. 2011;16(12):1771-9. doi: 10.1634/theoncologist.2011-0200. Epub 2011 Dec 6. Citation on PubMed or Free article on PubMed Central
• Wang YP, Di WJ, Qin SL, Yang S, Wang Z, Xu YF, Han PF. A rare presentation of Maffucci syndrome: A case report and literature review. Exp Ther Med. 2023 Jul 25;26(3):435. doi: 10.3892/etm.2023.12134. eCollection 2023 Sep. Citation on PubMed