Maffucci Syndrome

Maffucci syndrome is a rare, non-hereditary disorder with multiple enchondromas (the bone lesions that define Ollier disease) and spindle cell haemangiomas (and sometimes venous malformations and lymphatic anomalies) of the skin and soft tissue. About 200 cases are reported, with no sex difference.

Mosaic variants of IDH1 (R132) or IDH2 are found in the lesions. Enchondromas and haemangiomas usually appear in childhood (before age 10 in 25% and by puberty in most), and are often asymmetric. Hands and feet are mainly affected, then the long bones, ribs, and pelvis.

Complications are skeletal deformity, limb shortening, pathological fracture, pain, and a very high risk of malignancy: chondrosarcoma in 20 to 40% (some series up to 50%), angiosarcoma and other vascular tumours, and other cancers including brain gliomas, pancreatic adenocarcinoma, ovarian tumours, and hepatobiliary cancers. Overall, more than 70% of patients develop at least one malignancy by their 40s.

Pathophysiology.

As in Ollier disease, IDH1 and IDH2 mutations produce 2-hydroxyglutarate that blocks cell differentiation, and the mosaic distribution accounts for the asymmetry. Blood vessel lesions are made of spindle cells and thin walled vascular channels, in which phleboliths (calcified thrombi) form because blood flow is slow. The risk of malignancy is due to the accumulation of additional genetic alterations in the abnormal clones.

Soft, bluish, compressible subcutaneous swellings (haemangiomas) on the hands, feet and limbs, and bony swellings and deformity of the fingers, with limb shortening and bowing. Vascular lesions may be tender, bleed, ulcerate, or cause pain with thrombosis. Pathological fractures are frequent. Lesions on the face and mouth can cause problems with feeding or breathing.

Examine the skin, limbs, joint range, limb length, gait, and neurological state. Ask about headaches, abdominal pain, weight loss, and gynaecological symptoms, since other cancers are common.

• Radiographs: multiple enchondromas and soft tissue phleboliths (round calcifications).
• MRI of haemangiomas shows lobulated lesions with high signal on T2, flow voids and phleboliths; whole body MRI maps the lesions and finds malignant change.
• Doppler ultrasound shows the vascular component; angiography for planned surgery.
• Biopsy of a suspicious lesion (growing, painful, ulcerating) by a sarcoma team. Genetic testing of lesional tissue for IDH1 and IDH2.
• Screening: brain MRI, abdominal imaging (pancreas, liver), and, in women, pelvic ultrasound as symptoms or surveillance plans require. Blood tests include full blood count, coagulation screen and D-dimer.

Differential diagnosis.

• Ollier disease and multiple hereditary exostoses.
• Venous and lymphatic malformations, and Klippel-Trenaunay syndrome.
• Blue rubber bleb naevus syndrome and Kaposi sarcoma.
• Chondrosarcoma and angiosarcoma arising in the lesions.

Management combines treatment of skeletal and vascular lesions with surveillance for cancer. There is no cure.

Surveillance. Review every 6 months, with whole body MRI every 1 to 2 years, and imaging of any painful or growing lesion. Screening for brain, pancreatic, liver and ovarian tumours as adults, with the oncology team's plan, and skin checks for angiosarcoma.

Skeletal treatment. Curettage and grafting, growth modulation, osteotomy and lengthening, and treatment of atypical cartilaginous tumour or chondrosarcoma by wide excision.

Vascular lesions.

• Compression garments, elevation and aspirin 75 mg orally once daily for painful thrombosis (avoid with active bleeding, peptic ulcer, thrombocytopenia, and children with viral illness); low molecular weight heparin for symptomatic thrombosis.
• Sclerotherapy (polidocanol 1 to 3%, injected under imaging, not exceeding 2 mg/kg in a session), laser, or surgical excision for painful, bleeding, ulcerated or disfiguring lesions.
• Sirolimus 0.8 mg/m2 orally twice daily, adjusted to a trough level of 5 to 15 ng/mL, is used off label by vascular anomaly specialists for large or symptomatic vascular lesions; check blood count, lipids, glucose and kidney function, avoid live vaccines and strong CYP3A4 inhibitors, and monitor for mouth ulcers and infection.

Operative antibiotic prophylaxis. Cefazolin 2 g intravenously (3 g when weight is 120 kg or over; 30 mg/kg to a maximum of 2 g in children) within 60 minutes before incision as a single dose (repeat after 4 hours or blood loss over 1500 mL); with severe penicillin allergy, vancomycin 15 mg/kg intravenously starting 90 to 120 minutes before incision as a single dose, with levels and creatinine checked in prolonged cases.

Analgesia.

• Paracetamol 1 g orally every 6 hours as needed for up to 5 to 7 days (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment).
• Ibuprofen 400 mg orally every 8 hours with food for up to 5 days (maximum 1200 mg daily); avoid with eGFR under 30 mL/min/1.73 m2, peptic ulcer, heart failure, thrombocytopenia or anticoagulant use.
• Oral morphine 5 to 10 mg every 4 hours as needed for severe pain for up to 3 days (start 2.5 to 5 mg with age over 75 or eGFR under 30 mL/min/1.73 m2; avoid exceeding 60 mg in 24 hours without senior review); monitor sedation and respiration and prescribe a laxative.

Monitoring. Skeletal and vascular lesions at 6-month visits. Blood count and coagulation in patients with extensive vascular lesions, because localised intravascular coagulopathy is common. Sirolimus levels and safety tests when used. Cancer surveillance every 6 to 12 months.

Referral and escalation. Refer every patient to a bone tumour service, vascular anomalies service and clinical genetics. Urgent referral for a growing or painful lesion, bleeding, neurological symptoms, abdominal symptoms, or suspected malignancy.

Special groups.

• Children: correct deformity and treat vascular lesions that affect function; family and psychological support.
• Adults: the cancer risk is very high; keep surveillance for life and act on new symptoms.
• Pregnancy: avoid sirolimus, NSAIDs in the third trimester, and use low molecular weight heparin for thrombosis; obstetric and haematology planning.
• Kidney impairment: avoid NSAIDs and reduce morphine doses.