Maffucci Syndrome

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Practice Essentials

Maffucci syndrome is characterized by enchondromas with venous malformations with or without spindle cell hemangiomas. It was first reported by Maffucci in 1881 after a 40-year-old woman died from complications following amputation of an arm. The patient had frequent and severe hemorrhage from a vascular tumor for which she was admitted to the hospital. In view of the profuse bleeding, an amputation was performed and the patient died from infection. Maffucci reported a thorough autopsy that described all the main points of the syndrome named after him. In 1941, Carleton et al proposed the eponym Maffucci syndrome.

Maffucci syndrome is a rare mosaic genetic disorder that affects both males and females. It is associated with heterozygous somatic mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes.[1, 2]  In 2021, an L309I mutation in the ELKS/RAB6-interacting/CAST family member 2 (ERC2) gene was also identified as being associated with Maffucci syndrome.[3]

Maffucci syndrome is characterized by benign enlargements of cartilage (enchondromas), bone deformities, and venous malformations. No racial or sexual predilection is apparent in Maffucci syndrome. No familial pattern of inheritance has been shown. Maffucci syndrome manifests early in life, usually around age 4-5 years, with 25% of cases being congenital. Patients apparently are of average intelligence, and no associated mental or psychiatric abnormalities seem to be present. About 160 cases of Maffucci syndrome have been published in the English literature.[4, 5, 6, 1] Note the image below.



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Characteristic venous malformations on the patient's right upper extremity. These vascular malformations are benign and asymptomatic.

Causes

Maffucci syndrome has no familial pattern of inheritance and appears sporadically. It has been shown to be associated with heterozygous somatic mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes.[1, 2]

Complications

Neoplastic changes occur in enchondromas. Chondrosarcoma is the most common neoplasm in this syndrome, affecting about 30% of patients (see Pathophysiology).

Enchondromas can cause a fracture, leading to further complications, such as shortened or unequal length limbs.

Varied but rare complications and associations of Maffucci syndrome have been reported in the literature, including giant tubular adenoma of the breast,[7] pedal synovial sarcoma,[8]  nasopharynx clival enchondroma,[9]  and intrahepatic cholangiocarcinoma.[10]

Prognosis

Patients with Maffucci syndrome usually lead reasonably normal lives with a normal life expectancy if no malignant transformation occurs. Although the skeletal malformations can sometimes be crippling, patients have managed to perform activities of daily living rather well.

Treatment

No medical care is needed in Maffucci syndrome patients who are asymptomatic. Patients do need careful follow-up care to evaluate any changes in the skin and bone lesions. 

Physical activity is not limited for Maffucci syndrome. Some patients may have difficulty ambulating because of the bone abnormalities.

Patient education

Patients can obtain further information from the following source: The National Organization for Rare Disorders, Inc (NORD), PO Box 1968, 55 Kenosia Avenue, Danbury, CT 06813-1968, (203) 744-0100 or (800) 999-6673. Contact NORD by e-mail at orphan@rarediseases.org.

Pathophysiology

Heterozygous mutations in IDH1 and IDH2 are associated with both Maffucci syndrome and Ollier disease. These mutations permit the accumulation of D-2-hydroxyglutarate, which is associated with tumor formation. An additional mutation associated with Maffucci syndrome, in ERC2, was identified by Cheng et al. This mutation is likely responsible for hemangioma formation in Maffucci syndrome by causing increased endothelial intracellular calcium concentrations. Notably, ERC2 mutations have not been identified in Ollier disease patients, likely accounting for the lack of hemangiomas in that syndrome.[3]

Maffucci syndrome affects the skin and the skeletal systems. Superficial and deep vascular lesions (venous malformations) often protrude as soft nodules or tumors, usually on the distal extremities, but they can appear anywhere. They can be bilateral or unilateral, but they usually are asymmetric. Venous-lymphatic malformations and hemangioendotheliomas can occur but are much less common.[11, 12, 13, 14] Enchondromas are benign cartilaginous tumors with the potential for malignant transformation. They can appear anywhere, but they usually are found on the phalanges and the long bones. These bone abnormalities usually are asymmetric and can cause secondary fractures. Approximately 30-37% of enchondromas develop into a chondrosarcoma.

The venous malformations in Maffucci syndrome manifest as blue subcutaneous nodules that can be emptied by pressure. Thrombi often form within vessels and develop into phleboliths. Under microscopic examination, these phleboliths appear as calcified vessels.

Enchondromas develop from the mesodermal dysplasia associated with Maffucci syndrome. As the bones grow, some cartilage material is left behind and grows irregularly, developing into the characteristic bone deformities. Bone irregularities in Maffucci syndrome include shortened length of the long bones, unequal leg length, pathologic fractures, and malunion of fractures.[15]

In Maffucci syndrome, neoplastic changes occur in enchondromas. Chondrosarcoma is the most common neoplasm in this syndrome, affecting about 30% of patients. The average age for neoplastic change in Maffucci syndrome patients is 40 years. Vascular neoplasms have occurred in 4 reported cases: 2 hemangiosarcomas and 2 lymphangiosarcomas. Other malignancies associated with Maffucci syndrome include pancreatic and hepatic adenocarcinoma, ovarian tumors, brain gliomas, astrocytomas, and other types of sarcomas.[6]

Epidemiology

Maffucci syndrome is rare. Fewer than 100 cases of Maffucci syndrome have been reported in the United States with about 160 total case reports in the English literature. No increased frequency of Maffucci syndrome occurs because of race. Maffucci syndrome appears to be sporadically inherited. No sexual bias is present. Lesions of Maffucci syndrome are first noted usually by age 4-5 years.

History

Parents of a child with Maffucci syndrome first notice soft, blue-colored growths on the distal aspects of the extremities. Patients with Maffucci syndrome are usually short in stature and may have unequal arm or leg lengths due to the bone abnormalities. In Maffucci syndrome, venous malformations have also been reported in extracutaneous sites such as the leptomeninges, eyes, respiratory tract, and GI tract. The cutaneous vascular malformations may also be present on mucosal surfaces. The lesions typically are compressible, soft, red-blue papules and nodules.[2]  As noted in the case of a 12-year-old female patient, endochromas may appear in a single, unilateral extremity.[16]

Physical Examination

Enchondromas usually are found in the hands (89%), but they can be found on, although not limited to, the foot, tibia, fibula, femur, humerus, ribs, and skull. The tumors appear as nodular outgrowths and can cause a fracture, leading to further complications, such as shortened or unequal length limbs. Patients who are severely affected can have difficulty walking and manually manipulating objects. Note the images below. 



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Enchondroma on the left elbow.



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Venous malformations on a patient's right hand.

Approach Considerations

The lead physician must conduct regular physical examinations and monitor for any changes that may suggest the development of chondrosarcomas, the most common neoplasm in this syndrome.

Radiologic evaluation of suspicious areas should be conducted. Evidence of malignant transformation includes cortical destruction, endosteal cortical erosion, and zones of lucency within a previously mineralized area. Note the image below.



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Radiograph of a patient's hands showing enchondromas and phleboliths. Areas of translucency represent enchondromas, and opaque spots represent phlebol....

A biopsy should then be performed on suspicious radiologic areas. Needle biopsy should provide a diagnosis. Bone biopsy may be needed if the enchondroma is undergoing any changes.

CT and/or MRI can help in the evaluation of the lesion and its surrounding soft tissue.

Chondrosarcomas, the most common malignant neoplasm associated with Maffucci syndrome, are diagnosed by poorly differentiated pleomorphic chondrocytes.[17, 18]

Also see Enchondroma and Enchondromatosis.

Imaging Studies

Sharif et al note that chondral tumors in the setting of enchondromatosis often show certain features in high-grade malignant transformation on magnetic resonance imaging. These features include soft tissue and bone edema as well as periosteal reaction.[19]  Serial MRI studies may be a reasonable part of chondrosarcoma surveillance in Maffucci syndrome patients.  

Approach Considerations

The managing physician should arrange the proper consultations for the treatment of the patient.

Management of venous malformations may be more conservative or more aggressive depending on the individual's symptoms and the severity of the lesions. The location of the lesions, number of lesions, recurrences, progression of the lesions, and potential complications all are important factors to consider in treating venous malformations.

Symptomatic patients may benefit from anticoagulation, compression dressings, or sclerotherapy.[20] Some case reports have described antiangiogenic therapies, such as rapamycin injections, in the oncology literature, with varied success.[21, 22]

Neodymium-doped yttrium aluminum garnet (Nd:Yag) laser treatment has also been reported to effectively treat venous malformations[23] and may be efficacious for small, superficial lesions.[24]

Consider surgical excision in patients with symptomatic venous malformations in whom more conservative approaches have failed.

Consultations

The following consultations may be helpful:

Author

Stephanie Juliet Campbell, DO, Chief Resident Physician, Tri-County Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Nicholas V Nguyen, MD, Director of Pediatric Dermatology, Akron Children's Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France

Disclosure: Nothing to disclose.

Raymond T Kuwahara, MD, MBA, Dermatologist

Disclosure: Nothing to disclose.

Acknowledgements

Ron Rasberry, MD Associate Professor, Department of Dermatology, University of Tennessee Health Science Center College of Medicine; Chief of Dermatology, Veterans Affairs Medical Center at Memphis

Ron Rasberry, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, Arkansas Medical Society, Association of Military Surgeons of the US, Royal Society of Medicine, and Southern Medical Association

Disclosure: Nothing to disclose.

References

  1. Prokopchuk O, Andres S, Becker K, Holzapfel K, Hartmann D, Friess H. Maffucci syndrome and neoplasms: a case report and review of the literature. BMC Res Notes. 2016 Feb 27. 9:126. [View Abstract]
  2. Paller AS, Mancini AJ. Vascular Disorders of Infancy and Childhood. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 5th ed. Milton, Ontario: Elsevier Canada; 2015. 302-3.
  3. Cheng P, Chen K, Zhang S, Mu KT, Liang S, Zhang Y. IDH1 R132C and ERC2 L309I Mutations Contribute to the Development of Maffucci's Syndrome. Front Endocrinol (Lausanne). 2021. 12:763349. [View Abstract]
  4. Faik A, Allali F, El Hassani S, Hajjaj-Hassouni N. Maffucci's syndrome: a case report. Clin Rheumatol. 2006 Feb. 25(1):88-91. [View Abstract]
  5. Tilsley DA, Burden PW. A case of Maffucci's syndrome. Br J Dermatol. 1981 Sep. 105(3):331-6. [View Abstract]
  6. Ngai C, Ding DY, Rapp TB. Maffucci Syndrome. An Interesting Case and a Review of the Literature. Bull Hosp Jt Dis (2013). 2015 Dec. 73 (4):282-5. [View Abstract]
  7. Mazingi D, Mbanje C, Jakanani G, et al. Maffucci's syndrome in association with giant tubular adenoma of the breast: Case report and literature review. Int J Surg Case Rep. 2019. 63:147-152. [View Abstract]
  8. Gammoudi R, Aounallah A, Belajouza C, Nouira R. Synovial sarcoma complicating Maffucci syndrome. Indian J Dermatol Venereol Leprol. 2019 May-Jun. 85 (3):291-294. [View Abstract]
  9. Velagapudi S, Alshammari SM, Velagapudi S. Maffucci Syndrome with Clival Enchondroma in Nasopharynx: A Case Report. Indian J Otolaryngol Head Neck Surg. 2019 Oct. 71 (Suppl 1):652-656. [View Abstract]
  10. Kobayashi R, Shimizu A, Kubota K, et al. Maffucci Syndrome with Intrahepatic Cholangiocarcinoma: A Case Report. Case Rep Oncol. 2021 Sep-Dec. 14 (3):1347-1352. [View Abstract]
  11. Shepherd V, Godbolt A, Casey T. Maffucci's syndrome with extensive gastrointestinal involvement. Australas J Dermatol. 2005 Feb. 46(1):33-7. [View Abstract]
  12. Fernandez-Aguilar S, Fayt I, Noel JC. Spindle cell vulvar hemangiomatosis associated with enchondromatosis: a rare variant of Maffucci's syndrome. Int J Gynecol Pathol. 2004 Jan. 23(1):68-70. [View Abstract]
  13. Auyeung J, Mohanty K, Tayton K. Maffucci lymphangioma syndrome: an unusual variant of Ollier's disease, a case report and a review of the literature. J Pediatr Orthop B. 2003 Mar. 12(2):147-50. [View Abstract]
  14. Sun GH, Myer CM 3rd. Otolaryngologic manifestations of Maffucci's syndrome. Int J Pediatr Otorhinolaryngol. 2009 Jul. 73(7):1015-8. [View Abstract]
  15. Lubahn JD, Bachoura A. Enchondroma of the Hand: Evaluation and Management. J Am Acad Orthop Surg. 2016 Sep. 24 (9):625-33. [View Abstract]
  16. Verma GG, Jain VK, Iyengar KP. Monomelic Maffucci syndrome. BMJ Case Rep. 2021 Mar 3. 14 (3):[View Abstract]
  17. Albregts AE, Rapini RP. Malignancy in Maffucci's syndrome. Dermatol Clin. 1995 Jan. 13(1):73-8. [View Abstract]
  18. Kaplan RP, Wang JT, Amron DM, Kaplan L. Maffucci's syndrome: two case reports with a literature review. J Am Acad Dermatol. 1993 Nov. 29(5 Pt 2):894-9. [View Abstract]
  19. Sharif B, Rajakulasingam R, Sharifi S, O'Donnell P, Saifuddin A. MRI features of low-grade and high-grade chondrosarcoma in enchondromatosis. Skeletal Radiol. 2021 Aug. 50 (8):1637-1646. [View Abstract]
  20. Steiner F, FitzJohn T, Tan ST. Surgical treatment for venous malformation. J Plast Reconstr Aesthet Surg. 2013 Dec. 66 (12):1741-9. [View Abstract]
  21. Riou S, Morelon E, Guibaud L, Chotel F, Dijoud F, Marec-Berard P. Efficacy of rapamycin for refractory hemangioendotheliomas in Maffucci's syndrome. J Clin Oncol. 2012 Aug 10. 30 (23):e213-5. [View Abstract]
  22. Li Z, Zhao B, Zhang Y, Tu C, Zheng Y, He X, et al. Failure of rapamycin in the treatment of multiple haemangiomas associated with Maffucci syndrome. Clin Exp Dermatol. 2015 Dec. 40 (8):951-4. [View Abstract]
  23. Radmanesh M, Radmanesh R. Successful treatment of isolated venous malformation with 1444-nm fiberoptic Nd-YAG laser. J Cosmet Laser Ther. 2016. 18 (2):91-4. [View Abstract]
  24. Scherer K, Waner M. Nd:YAG lasers (1,064 nm) in the treatment of venous malformations of the face and neck: challenges and benefits. Lasers Med Sci. 2007 Jun. 22 (2):119-26. [View Abstract]
  25. Spitz JL. Maffucci syndrome. Genodermatosis, A Clinical Guide to Genetic Skin Disorders. Baltimore, Md: Lippincott Williams & Wilkins; 2005. 118-9.

Characteristic venous malformations on the patient's right upper extremity. These vascular malformations are benign and asymptomatic.

Enchondroma on the left elbow.

Venous malformations on a patient's right hand.

Radiograph of a patient's hands showing enchondromas and phleboliths. Areas of translucency represent enchondromas, and opaque spots represent phleboliths.

Characteristic venous malformations on the patient's right upper extremity. These vascular malformations are benign and asymptomatic.

Enchondroma on the left elbow.

Radiograph of a patient's hands showing enchondromas and phleboliths. Areas of translucency represent enchondromas, and opaque spots represent phleboliths.

Venous malformations on a patient's right hand.