Enchondromatosis (Ollier Disease and Maffucci Syndrome)

The two syndromes. Enchondromatosis is the group of conditions in which enchondromas arise in numbers rather than singly. Ollier disease is multiple enchondromas in a unilateral or markedly asymmetric distribution with no soft-tissue haemangiomas; Maffucci syndrome is the same skeletal disease plus soft-tissue spindle cell haemangiomas. Both are sporadic, caused by somatic mutations in IDH1 or IDH2 rather than inherited ones, so the recurrence risk in offspring is very low.

Who. Ollier disease occurs in approximately 1 in 100,000 live births and Maffucci syndrome is rarer still, of the order of 1 in 1,000,000. Both declare themselves in childhood, typically in the first decade and often younger in Maffucci syndrome, and males and females are affected equally.

The risk that governs everything else. In the largest series - Verdegaal's 161 patients - the observed incidence of secondary chondrosarcoma was 40%, and the figure is driven by where the disease sits. Confined to the hands and feet the incidence was 15%; once long bones or the pelvis were involved it was 43-46%, and pelvic and axial involvement carries a higher risk than appendicular disease. Transformation is usually a problem of adult life.

The Maffucci number. Maffucci syndrome is conventionally taught as carrying the higher risk and it may well do, and it also carries an increased risk of non-skeletal malignancy including gliomas and mesenchymal ovarian tumours. The number attached to it in textbooks is another matter.

The names. Louis Ollier, a French surgeon, described multiple enchondromatosis in 1899; Angelo Maffucci, an Italian pathologist, had recognised the association of enchondromas with haemangiomas in 1881. Outcomes were historically dismal; the discovery of the IDH mutations in 2011 and structured surveillance have allowed earlier detection of transformation and better survival.

The mutation. Pansuriya and colleagues found somatic mutations of IDH1 - the commoner - or IDH2 in 87% of enchondromas and secondary chondrosarcomas in Ollier disease and Maffucci syndrome. The mutations are somatic rather than germline, which is why the disease is sporadic, and they arise early in development in a mosaic distribution, which is why the lesions favour one side of the body.

• IDH1, chromosome 2q34: R132C is the most frequent, with R132H, R132L and R132G also reported
• IDH2, chromosome 15q26: R172S is the commonest subtype, and IDH2 mutations are less frequent than IDH1

What mosaicism means in the clinic. Genetic testing of blood is usually negative because the mutation lives in the affected tissue, so testing is performed on lesional tissue rather than on a blood sample. How much of the skeleton is involved depends on how early in development the mutation arose. Genetic counselling is where the sporadic, non-hereditary nature of the disease gets explained to a family.

The oncometabolite. Normal IDH1 and IDH2 convert isocitrate to alpha-ketoglutarate. The disease-causing mutations at IDH1 R132 and IDH2 R172 are neomorphic gain-of-function changes: the enzyme does not simply lose its function, it acquires a new one, reducing alpha-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates to very high levels.

Why that stops cartilage maturing. D-2-HG resembles alpha-ketoglutarate closely enough to competitively inhibit the alpha-ketoglutarate-dependent dioxygenases - most importantly the TET DNA demethylases and the Jumonji-domain histone demethylases, and the prolyl-hydroxylases that regulate HIF. The resulting DNA and histone hypermethylation silences differentiation genes and arrests mesenchymal and chondrocyte maturation, so cartilage rests persist in the medullary cavity as enchondromas instead of undergoing normal endochondral ossification.

Why one mutation is not enough. The same IDH mutation is present in benign and malignant lesions alike, so it cannot by itself account for transformation; additional hits in CDKN2A, TP53 and RB1 accumulate over time. The axis is also a treatment target and a biomarker: ivosidenib, a mutant-IDH1 inhibitor, lowers plasma 2-HG toward normal and stabilises some advanced IDH-mutant chondrosarcomas, and circulating 2-HG can serve as a disease marker.

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Beyond bone. The same IDH mutations occur in gliomas, which is the basis of the increased brain-tumour risk described in Maffucci syndrome, and Maffucci patients also develop mesenchymal ovarian and other primary tumours. New neurological symptoms in a patient with enchondromatosis are investigated rather than attributed to the skeletal disease.

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Histology, and why it disappoints. The benign lesion is hypocellular hyaline cartilage; the transformed lesion is cellular, atypical and permeates the bone around it.

The syndromes. Classification rests on what accompanies the enchondromas outside the skeleton - haemangiomas, osteochondromas or nothing at all.

Distribution. Ollier disease is unilateral or predominantly affects one side, commonly involves the hands and feet, and frequently involves the long bones of the lower limb, where it may cause significant limb length discrepancy. Maffucci syndrome distributes its enchondromas much as Ollier disease does and adds spindle cell haemangiomas, which may lie in the soft tissues or in the viscera. Disease that is bilateral and symmetrical should prompt a search for haemangiomas, which would make it Maffucci syndrome, or for osteochondromas, which would make it metachondromatosis.

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Severity. Severity is described by the number of lesions, the limb length discrepancy and the functional impact. More extensive disease correlates with a higher malignancy risk, and an earlier age at presentation often indicates more severe disease.

In childhood the presenting complaint is usually shape. A parent notices that one leg is shorter or one hand is knobbly, or the child is referred after a radiograph taken for minor trauma shows lesions nobody was looking for.

• Limb deformity noticed by the parents, usually a leg length difference
• Palpable masses in the hands or feet
• Gait abnormality from the limb length discrepancy
• Angular deformity, varus or valgus, of a long bone
• An incidental radiographic finding after minor trauma

In adolescence and adult life the same disease presents through its failures: the bone breaks, the deformity progresses, or a lesion starts to hurt.

• Pathological fracture through weakened bone
• Progressive deformity worsening with growth
• Pain in a lesion - the red flag for malignant transformation
• Palpable soft-tissue mass - chondrosarcoma with soft-tissue extension
• Functional impairment from severe deformity

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Look. Measure both leg lengths from the anterior superior iliac spine to the medial malleolus, assess varus and valgus alignment, and note the shortened digits and expanded phalanges of the hand. Look for soft-tissue masses - haemangiomas in Maffucci syndrome, extraosseous extension of a tumour in either - and watch the patient walk for a limp or a Trendelenburg gait.

Feel. Palpate every accessible lesion in turn. Tenderness in any of them is the red flag; a compressible soft-tissue mass is a haemangioma; warmth over a lesion suggests active growth. Palpate deliberately for extraosseous extension around the bony masses rather than only over them.

Move. Check range of motion at all major joints, assess rotational as well as angular deformity, and record something functional - grip strength, walking distance. A neurovascular examination of all four limbs, checking pulses and sensation, completes it.

Record. Map the lesions on a skeletal diagram, photograph the visible deformities and haemangiomas, and write down the limb lengths and joint angles so the next clinic has something to compare with. Any painful lesion is documented as such, because that is the entry to urgent imaging.

Enchondroma or osteochondroma. Enchondromas are intramedullary, inside the bone, with rings-and-arcs calcification. Osteochondromas are surface lesions with a cartilage cap pointing away from the joint. Metachondromatosis is the syndrome with both.

Ollier or metachondromatosis. Metachondromatosis is autosomal dominant, so there is usually a family history, it produces both enchondromas and osteochondromas, and its malignancy risk is much lower than Ollier's.

Algorithm

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The point of surveillance. The whole strategy is early detection: a chondrosarcoma found small and without metastases carries about 90% five-year survival after wide excision, while one found late, large and metastatic carries under 30%. That difference is the entire argument for seeing these patients every year for life.

The annual visit. Ask about new pain in any lesion and characterise it, about new weakness or loss of motion or a change in gait, about visible new or enlarging masses, about weight loss, fatigue and night sweats, and about any fracture since the last visit. Then inspect all the limbs for new deformity, asymmetry or masses, palpate every accessible lesion for tenderness, measure the limb lengths, assess the angular and rotational deformities, and in Maffucci syndrome examine every haemangioma for change.

Imaging at the annual visit is selective. Radiograph the areas that are symptomatic or that concern you on examination, keep a low threshold for MRI of any painful lesion or palpable change, and always compare with the previous study rather than reading the new one alone. CT of the chest belongs to staging, once chondrosarcoma is suspected.

Teaching the patient is part of the protocol. They are the ones who will notice the change first, so they need the red flags in plain language, a demonstration of how to palpate their own accessible lesions monthly, an instruction to report new symptoms without waiting for the annual appointment, and an honest account of the malignancy risk.

When to operate on the skeleton. Four things take a patient with enchondromatosis to theatre, and only one of them is the tumour.

1. Limb length discrepancy causing gait abnormality or functional impairment
2. Angular deformity causing joint malalignment or cosmetic concern
3. Pathological fracture requiring stabilisation
4. Malignant transformation requiring wide excision

Limb length discrepancy. Measure the true leg length from the anterior superior iliac spine to the medial malleolus, confirm it with a scanogram or CT scanogram, and then work out the predicted discrepancy at skeletal maturity, which is the number treatment is planned against.

• Under 2cm - a shoe lift, usually well tolerated
• 2-5cm - epiphysiodesis of the contralateral side while the child is still growing
• Over 5cm, or once skeletal maturity removes the epiphysiodesis option - limb lengthening

Timing an epiphysiodesis is the whole operation. It needs a child with at least 1-2 years of growth remaining and a normal contralateral limb, which Ollier disease usually provides, and the timing comes from growth charts and skeletal age with the Paley multiplier: about 1-1.5 years of growth left for 1cm of correction, 3-4 years for 3cm. In practice that is roughly 11-13 years in girls and 13-15 years in boys, and radiographs every six months afterwards show whether the limbs are equalising.

The operation itself is small. Percutaneous screws or a drill across the distal femoral and proximal tibial physes of the normal side, or an 8-plate, or the traditional open drill-and-curettage epiphysiodesis: a simple outpatient procedure either way. What it does is slow the long limb, so it cannot correct a discrepancy that already exists.

Angular deformity. Assess it on long-leg alignment films, measure the varus or valgus angle, and look at the joint line orientation before planning anything. Mild deformity in an asymptomatic patient is observed; the choice in the rest is between guiding the growth that remains and cutting the bone.

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Chondrosarcoma: the principle. A chondrosarcoma arising in enchondromatosis is treated by wide excision with negative margins. Curettage is inadequate, with recurrence after it approaching 50-70%. Quoted margins for low-grade disease vary between 5-10mm of bone with a cuff of soft tissue and a full 2cm; the higher grades demand the wider margin. Achieving it may mean resection of the proximal femur or of the pelvis, or amputation for a large tumour.

Getting there in order. Stage before you cut and biopsy before you resect.

1. MRI of the whole affected bone for soft-tissue extent and intramedullary involvement
2. CT of the chest for pulmonary metastases, present in under 5% at diagnosis for low-grade tumours
3. CT-guided core biopsy along an excisable trajectory, with expert musculoskeletal pathology review
4. Tumour board, with the orthopaedic oncologist, radiologist and pathologist in the room
5. Plan the reconstruction and counsel the patient - limb salvage against amputation, function, recurrence risk - and optimise nutrition, smoking and psychological support before surgery

In theatre. En bloc resection with a cuff of normal tissue, frozen sections to confirm the margins while the patient is still asleep, reconstruction that restores limb length and joint function, and the entire specimen to the pathologist so that every section can be graded. Chondrosarcoma responds to neither chemotherapy nor radiotherapy, so the margin is the treatment.

Reconciling that with the curettage literature. El Masry's 113 patients with low-grade appendicular chondrosarcoma treated by extended curettage with a cryoadjuvant and cement had only 2.7% local recurrence at a mean of 110 months, and ESMO and NCCN both accept intralesional surgery for atypical cartilaginous tumours of the appendicular skeleton. Those series were neither syndromic nor axial, and El Masry's cohort does not address transformation within Ollier or Maffucci disease at all. Wide excision remains the position for a secondary chondrosarcoma in these syndromes, and suspected chondrosarcoma is referred to a sarcoma centre before biopsy.

Maffucci syndrome: the second tumour. These patients carry a dual risk - chondrosarcoma from the enchondromas, as in Ollier disease, and angiosarcoma from the spindle cell haemangiomas, which is theirs alone. The spindle cell haemangioma is itself now classified as benign, and angiosarcoma arising in one is described historically, which is precisely why a change in a previously stable lesion is taken seriously.

• Rapid enlargement of a haemangioma
• Change in colour, texture or firmness of a vascular lesion
• Bleeding or ulceration
• Pain in a previously painless haemangioma

MRI shows a heterogeneous mass and the biopsy shows a high-grade sarcoma with vascular channels. Treatment is wide excision with margins, which at some sites means amputation because margins cannot be achieved otherwise, and the prognosis is poor: angiosarcoma is aggressive and metastasises early. Surveillance therefore includes annual examination of all the haemangiomas, with a low threshold for biopsying any that change.

When not to operate. An asymptomatic lesion is surveilled rather than curetted. Hold off also on a patient with a suspected malignancy who has not been staged, on a poor soft-tissue envelope, and on a growing skeleton, where the timing needs thought; where several procedures are planned, stage them appropriately.

Curettage and grafting is the operation for the symptomatic benign lesion, and it is done through a window large enough to see the whole cavity.

The hand. Approach a phalanx or metacarpal through a dorsal longitudinal or mid-lateral incision and raise a rectangular cortical window, preserved for closure. Curette the cavity completely with small curettes; small defects often need no graft and heal with fibrous tissue, and a K-wire is used only for an unstable fracture. Motion begins at 2-4 weeks.

What is different about the hand. Multiple lesions are staged 6-8 weeks apart rather than done together. A pathological fracture is allowed to heal for 4-6 weeks before curettage. The digital nerve is protected during exposure, soft tissue handled meticulously because the tendons adhere, and an adjuvant is rarely needed.

Deformity correction. Plan on full-length alignment films to document the mechanical axis: identify the centre of rotation of angulation (CORA), which is the apex of the deformity and where the osteotomy belongs, and measure the correction against the normal contralateral side. Correct to the planned alignment with an alignment jig or navigation and fix rigidly - plate and screws, a locking plate, are the most reliable - grafting the site if it is needed. Place the screws to avoid the lesions.

Lengthening hardware. Either a circular external fixator (Ilizarov or Taylor Spatial Frame) or an internal lengthening nail (PRECICE, FITBONE) will do it; the choice turns on the deformity, the bone available and what the patient will tolerate on the limb for months.

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Resection margins for a secondary chondrosarcoma follow the grade, and so does the reconstruction.

Reconstruction: mechanical or biological. An endoprosthesis is the choice for a diaphyseal or juxta-articular resection - modular (MUTARS, GMRS) or custom, extendable in the skeletally immature, cemented for immediate stability or press-fit, with the capsule and tendons reattached to the implant. The biological alternatives are an intercalary or osteoarticular allograft, a vascularised fibula combined with an allograft (the Capanna technique), bone transport by distraction osteogenesis for a defect, or extracorporeal irradiation and reimplantation of the patient's own resected bone. An intercalary allograft suits the mid-diaphysis and a modular endoprosthesis the metaphysis and epiphysis; an allograft-prosthetic composite combines the two; and amputation remains the answer for neurovascular involvement or a massive tumour.

The haemangiomas in Maffucci syndrome are treated for what they do, not for what they are. Cosmetic concern about a visible lesion, functional impairment where one limits joint motion, recurrent bleeding, painful thrombophlebitis and rapid enlargement are the reasons to intervene.

• Observation for small asymptomatic lesions
• Sclerotherapy with sodium tetradecyl sulfate or polidocanol
• Nd:YAG laser for cutaneous lesions
• Surgical excision for large or symptomatic lesions
• Embolisation before surgery for vascular lesions

What goes wrong, and how often. Malignant transformation is the complication that kills, but deformity and fracture are the ones that fill the clinic.

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After curettage the problems are local and mostly minor: recurrence in 5-15% from incomplete removal, re-fracture in 5-10% where a large defect was not adequately grafted, infection in 2-3%, and stiffness in 10-20% of hand cases where mobilisation was delayed.

After major reconstruction they are larger. Allograft nonunion occurs at the host-graft junction in 10-20% and allograft fracture in 5-10% years later; endoprostheses loosen in 5-10% at ten years; infection runs at 5-15% for major reconstructions; and a limb length discrepancy may persist despite the reconstruction.

The cost of a lifelong condition. These patients have on average 3-5 operations over a lifetime, chronic pain in 20-40%, functional limitation in the severe cases, visible asymmetry and scars, and fatigue from the disease burden. Alongside that sits cancer anxiety that never entirely goes away, depression from chronic illness, body image difficulty in adolescence, social isolation and strained relationships, interrupted schooling and work, the burden of frequent appointments and the financial cost of lifelong care.

And why the care is multidisciplinary. Psychology, genetic counselling and social work belong in this clinic alongside surgery, oncology and physiotherapy, and the patient support groups do work that none of them can.

After curettage and grafting the progression follows graft incorporation, which is what the serial radiographs are there to show.

Rehabilitating a hand. The first week is a bulky dressing, elevation and finger motion out of the splint; the dressing comes off in the second week and active exercises begin; weeks three and four add gentle grip strengthening and scar massage, with a volar resting splint at night only if it is needed and oedema controlled by Coban wrap, elevation and retrograde massage. Progressive strengthening with putty runs from weeks 4-6, light work from 6-8 weeks and full return to sport or manual work by 8-12 weeks.

What follow-up after a benign lesion looks like. A baseline radiograph immediately after surgery, then films at 6 weeks for healing and graft incorporation, 3 months for recurrence and 6 months for remodelling, and annually thereafter for life - the last of these being malignancy surveillance rather than graft surveillance. MRI is for pain or a suspicious change. Clinically, the wound should be healed by two weeks, the pain improving steadily, and a hand should have full motion by 6-8 weeks; night pain, a new mass or rapid growth at any point is a red flag, and the other known lesions continue to be monitored.

After a resection for malignancy the follow-up is oncological and intensive at first. Cross-sectional restaging runs alongside the clinic schedule below: MRI of the surgical site every 6 months for 2 years, then annually, for local recurrence, and CT of the chest every 6 months for 5 years for metastases. Surveillance of the remaining enchondromas continues throughout.

During distraction the lengthening is run at 1mm per day, in four increments of 0.25mm, with weekly radiographs to watch the regenerate, daily pin site care, and daily physiotherapy for motion and muscle stretching. Slow the rate for premature consolidation and increase it for a poor regenerate.

During consolidation the frame or nail stays until the bone will take the load: roughly 36 days per centimetre lengthened, with cortical bridging as the radiographic criterion - three of the four cortices, and all four before an external frame comes off - then a cast or brace for 4-6 weeks after frame removal. Bone density may take 12 months or more to normalise.

After an endoprosthesis, isometrics and continuous passive motion if permitted in the first two weeks, active motion and gait training with aids from two to six weeks, progressive weight-bearing and resistance work from six to twelve weeks, community ambulation and stairs by 3-6 months, and thereafter activity modification, avoiding high-impact activities to protect the prosthesis.

Who else the patient sees. The orthopaedic oncologist for the reconstruction, the medical oncologist for systemic surveillance, the hand therapist where the hand was operated on, and the geneticist for family counselling and mutation testing.

What to watch for in the long term. Prosthetic loosening, wear and infection run at about 1-2% per year; allografts fail by nonunion, fracture or infection; new primary tumours of the brain, ovary and hepatobiliary tract belong to Maffucci syndrome; depression, anxiety and body image need asking about; and fertility questions are answered through genetic counselling.

Surgery works; the disease persists. The operations for benign disease do what they are asked to do.

Function in the upper limb is generally excellent after curettage of an isolated hand lesion, with DASH scores near normal for single lesions and fine motor function preserved unless several digits are involved. Multiple lesions may leave residual weakness, but work capacity is usually maintained.

Function in the lower limb turns on limb length and on whether a lesion sits next to a joint. Most patients achieve community ambulation, the discrepancy is managed by shoe raise or surgery, hip and knee function depends on juxta-articular involvement, sport is often modified, and 10-20% of those with severe disease need a walking aid.

Life expectancy is normal in the absence of malignancy. With malignancy it depends on grade and treatment, and when death is disease-related it is usually the malignancy that causes it. Maffucci syndrome adds the non-skeletal tumours; the haemangiomas themselves are rarely life-threatening. Work disability affects 15-25% of those with severe involvement, schooling is interrupted by surgery, sport is usually modified, independence is usually maintained, and wheelchair use is rare, under 5% even of severe cases.

Grade 1 is the commonest grade in Ollier disease, and it responds to wide excision; grade 2 recurs more often and may metastasise late; grade 3 metastasises early. Lower figures are quoted for the same tumours - five-year survival of 90% for grade 1, 60-70% for grade 2 and 30-40% for grade 3, given elsewhere as 90% for grade 1 and 50-60% for grades 2-3 together, with ten-year survival of 80%, 40-50% and under 20% across grades 1 to 3 - so quote these survivals as a range rather than a single number. The prognostic factors are largely the features of the disease itself.

• Favourable: unilateral distribution, fewer lesions, no large bone involvement, later age at presentation, IDH1 rather than IDH2 mutation, Ollier rather than Maffucci disease, and early detection of transformation
• Unfavourable: bilateral or extensive involvement, IDH2 mutation, Maffucci syndrome, large axial lesions, multiple haemangiomas, late detection with a larger tumour, and dedifferentiated transformation

Counselling, honestly. There is good news to give, and it should be given first: the condition is not hereditary and in most cases will not be passed to their children, life expectancy is normal without malignancy, many lesions remain stable and silent, and the operations usually work. Set against that, this is a lifelong condition needing surveillance, several operations may be needed over a lifetime, the risk of transformation is substantial - roughly 40% overall in Ollier disease, 15% for hand and foot disease and 43-46% with long-bone or pelvic involvement - and Maffucci syndrome adds its non-skeletal cancers. The actions asked of the patient are simple: come every year, report new pain, swelling or growth at once, take genetic counselling before starting a family, and use the support groups.

Global Epidemiology

Enchondromatosis is rare and almost universally sporadic. Ollier disease has an estimated prevalence in the order of 1 in 100,000, and Maffucci syndrome is considerably rarer. Both are caused by post-zygotic somatic mosaic IDH1/IDH2 mutations and are therefore non-hereditary, with the same mutational spectrum seen worldwide (no consistent ethnic or geographic predilection). In the largest international multicentre series (161 patients across 13 European centres) the cross-sectional incidence of secondary chondrosarcoma was 40%, rising with long-bone, flat-bone and especially pelvic involvement (Verdegaal et al, The Oncologist 2011) DOI. The defining IDH1/IDH2 mutation prevalence of 87% in enchondromas is consistent across populations (Pansuriya et al, Nature Genetics 2011) DOI.

Guideline & Society Guidance (Side-by-Side)

There is no disease-specific international guideline for enchondromatosis; management is extrapolated from cartilage-tumour and sarcoma frameworks. The table summarises how the major bodies frame the relevant cartilage-tumour pathway.

Registry & High-Volume Evidence