Fibrous Dysplasia

Fibrous dysplasia is a benign fibro-osseous developmental disorder in which normal medullary bone is replaced by fibrous tissue and immature woven bone. The cause is a postzygotic somatic mutation in the GNAS gene, and the bone that results remodels abnormally and is structurally weak.

The mutation. A somatic mutation at the Arg201 codon of GNAS, arising sporadically during early development; it is not inherited. Expressivity varies with the timing of the mutation.

Epidemiology. Fibrous dysplasia accounts for 5-7% of benign bone tumours. Monostotic disease has no sex predilection; polyostotic disease, and McCune-Albright syndrome in particular, shows a slight female predominance. Lesions usually stabilise after skeletal maturity.

Distribution. About 70% of cases are monostotic and 30% polyostotic, though the ratio is as high as 20:1 in some series. Craniofacial disease of the skull and facial bones accounts for 25% and is common in the polyostotic form. Age at presentation separates the two forms and is set out in the comparison table under Clinical Forms.

The cascade. Five steps take the mutation to the lesion:

1. Mutation at Arg201 prevents the GTPase activity of Gsα
2. Constitutive activation: Gsα remains in its active, GTP-bound state
3. Excess cAMP: adenylyl cyclase is continuously activated
4. Abnormal signalling: osteoblast function is dysregulated
5. Fibro-osseous metaplasia: normal marrow is replaced by fibrous tissue

Effect on remodelling. Increased RANKL promotes osteoclast activity and decreased OPG reduces the inhibition of bone resorption, while the abnormal osteoblasts lay down immature woven rather than lamellar bone. The loss of normal lamellar architecture is the structural weakness.

Gross appearance. White-tan fibrous tissue replaces the marrow and is gritty from the bone spicules within it. There is no distinct capsule, the lesion blending into normal bone, and the stroma is vascular and can be haemorrhagic.

Histology: the Chinese letters pattern. Irregular trabeculae of woven bone, C-shaped, S-shaped or alphabet-like, lie in a bland fibrous stroma of spindle cells, and the bone content ranges from minimal to extensive. The trabeculae have no osteoblastic rimming, and that is the key differentiator from ossifying fibroma, which has similar trabeculae with prominent rimming. Low-grade osteosarcoma is separated by cytological atypia and permeative growth, and osteofibrous dysplasia by its cortical location and its osteoblastic rimming.

Three forms: monostotic, polyostotic, and polyostotic with the extraskeletal features of McCune-Albright syndrome. Mazabraud syndrome adds intramuscular myxomas to either bony form.

Monostotic disease. A single bone is involved. The common sites, in order:

1. Ribs, the most common monostotic site
2. Proximal femur
3. Tibia
4. Craniofacial bones
5. Humerus

Between 50 and 70% are asymptomatic, found incidentally. The rest present with dull, aching bone pain that is worse with activity, with a pathological fracture through the weakened bone (sudden pain and deformity), or with swelling where an expansile craniofacial lesion sits. Deformity from progression is rare.

Polyostotic disease. Multiple bones are involved, with a unilateral predominance, especially in McCune-Albright syndrome. Craniofacial involvement is common, the long bones (femur, tibia) are frequently affected, and severe cases involve 20-30 or more bones. Patients present with progressive deformity (the shepherd's crook, limb bowing), multiple recurrent fractures at different sites, limb length discrepancy from the unilateral involvement, a limp or antalgic gait, and cranial nerve symptoms (vision, hearing loss) when the craniofacial skeleton is involved.

McCune-Albright syndrome. The classic triad, every element from the same GNAS mutation acting in a different tissue:

1. Polyostotic fibrous dysplasia, with unilateral predominance
2. Café-au-lait macules with irregular "coast of Maine" borders
3. Endocrinopathy, most commonly precocious puberty

The endocrine manifestations:

• Precocious puberty, the most common, especially in girls, with recurrent ovarian cysts
• Hyperthyroidism from autonomous nodular thyroid disease
• Growth hormone excess / acromegaly, which worsens craniofacial disease and optic compromise
• Cushing syndrome, neonatal, from adrenal hyperactivity
• FGF23-mediated hypophosphataemia: dysplastic bone over-produces FGF23, driving renal phosphate wasting that correlates with skeletal disease burden and worsens osteomalacia and fracture risk

The skin. Café-au-lait spots are present at birth or in early infancy and follow Blaschko lines in a unilateral distribution. Their irregular "coast of Maine" border is what separates them from the smooth "coast of California" macules of neurofibromatosis.

Mazabraud syndrome. Fibrous dysplasia, monostotic or polyostotic, with intramuscular myxomas: soft tissue masses in skeletal muscle adjacent to the affected bones, carrying the same GNAS mutation. It is rare, with fewer than 100 reported cases.

Inspection. Look for visible deformity (a varus femur, tibial bowing), measure true and apparent limb length for discrepancy, search the skin for the café-au-lait macules that would point to McCune-Albright syndrome, and watch the gait for an antalgic or Trendelenburg pattern.

Palpation. Bony expansion over the affected area, and tenderness if the lesion is symptomatic. Warmth is not typical unless there has been a fracture.

Named findings.

• Shepherd's crook deformity: proximal femoral varus with lateral bowing, produced by repetitive microfractures and abnormal stress remodelling in polyostotic disease, and progressing as a coxa vara
• Leonine facies: craniofacial expansion in severe polyostotic disease
• Limb atrophy: with chronic pain or disuse

Paget disease. An older patient, over 50, with a "blade of grass" advancing lytic front, a "cotton wool" appearance in the later stages, and a markedly elevated alkaline phosphatase.

Aneurysmal bone cyst. Eccentric, with a blown-out appearance on the radiograph and fluid-fluid levels on MRI, and no ground-glass matrix.

Low-grade osteosarcoma. Permeative growth, periosteal reaction (Codman, sunburst), cytological atypia on histology, and an older patient or a history of radiation.

Algorithm

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Observation. Asymptomatic monostotic lesions, small lesions without fracture risk, and stable disease after skeletal maturity are watched rather than treated: radiographs every 6-12 months initially, then annually once stable, looking for growth, pain and deformity.

Bisphosphonates. Indicated for symptomatic polyostotic disease, for bone pain not responding to NSAIDs, and to reduce fracture risk at high-risk sites. They inhibit osteoclast activity and reduce bone turnover.

• Pamidronate 30-60 mg IV every 3-6 months
• Zoledronic acid 4-5 mg IV annually
• Duration: several years, reassessed periodically

What they achieve. Reported pain relief in 60-80% of patients and a fall in alkaline phosphatase sit against the one placebo-controlled trial, the alendronate RCT (Boyce 2014), which reduced resorption markers and raised bone density but did not significantly improve pain or function. International consensus therefore reserves them for refractory or fracture-related bone pain, not as disease modification. They may reduce fracture risk, though the data are limited, and they do not reverse deformity. Side effects are flu-like symptoms after infusion, hypocalcaemia (supplement calcium and vitamin D), and rarely osteonecrosis of the jaw, so dental hygiene matters.

Newer agents. Denosumab, a RANKL inhibitor, has produced lesion regression in case reports of aggressive or refractory disease, but it has no controlled evidence and carries a serious rebound hypercalcaemia risk on discontinuation, particularly in children, so it is used only in specialist hands. Tocilizumab (anti-IL-6) is under investigation for FD-related pain.

Surgical indications.

1. Pathological fracture: treat the fracture, then address the lesion
2. Impending fracture: cortical thinning over 50%, or a lesion over 2.5 cm
3. Progressive deformity (shepherd's crook)
4. Neurological compromise from craniofacial lesions
5. Refractory pain despite medical therapy

Timing of surgery. After skeletal maturity when possible, because recurrence is lower; as an emergency for fractures and neurological compromise; and prophylactically for high-risk proximal femoral lesions.

Pathological fracture. The most common complication, occurring in 20-50% of polyostotic patients and most often in the proximal femur and tibia. Fractures are usually minimally displaced and are treated conservatively in a cast or brace where possible, with prophylactic fixation considered once they have healed.

Progressive deformity. The shepherd's crook, limb length discrepancy of up to 5-10 cm in severe cases, and angular deformity such as tibial bowing.

Cranial nerve compression. Decompress surgically if it progresses.

• Optic nerve: vision loss in 10% of craniofacial cases
• Auditory nerve: hearing loss
• Facial nerve: facial weakness

Malignant transformation. Under 1% at population level, with estimates commonly quoted as 0.4-1%. Referral series over-represent the risk: the Mayo Clinic cohort found 28 sarcomas among 1122 cases (Ruggieri 1994), and 46% of those transformations had received prior radiotherapy; radiation is the major avoidable risk factor. The risk is slightly higher in polyostotic and in craniofacial disease, and the craniofacial bones and the proximal femur are the commonest sites of transformation. The sarcomas in that series:

• Osteosarcoma, the most common, 19/28
• Fibrosarcoma, 5/28
• Chondrosarcoma, 3/28
• Malignant fibrous histiocytoma, 1/28

The warning signs in a long-standing lesion:

• New pain
• Rapid growth after skeletal maturity
• A soft tissue mass on imaging
• Periosteal reaction or cortical destruction

Prognosis in monostotic disease. Excellent. Lesions stabilise at skeletal maturity, surgery is curative in most cases, and recurrence after maturity is low, under 10%.

Prognosis in polyostotic disease. Variable, depending on extent, and the disease may progress through adulthood. Bisphosphonates improve quality of life, and functional outcomes are good with management.

Prognosis in McCune-Albright syndrome. Set by the endocrine complications. The skeletal disease is managed as for polyostotic disease, the endocrinopathy management is critical, and multidisciplinary follow-up is lifelong.

Global Epidemiology

Fibrous dysplasia is rare, with an estimated prevalence in the region of 1 in 4,000 to 1 in 10,000, accounting for roughly 5-7% of benign bone tumours. McCune-Albright syndrome is far rarer (estimated between 1 in 100,000 and 1 in 1,000,000). The full FD/MAS spectrum arises from the same somatic gain-of-function GNAS mutation; monostotic disease predominates (~70-80% of cases) and is distributed worldwide without strong geographic or ethnic clustering. Because the disorder presents across orthopaedics, endocrinology, ENT/craniofacial surgery and dentistry, under-recognition and wide variation in investigation and treatment are well documented internationally — the central problem the 2019 international consensus set out to address.

Side-by-Side Guidance

Multidisciplinary management: Complex FD, and McCune-Albright syndrome in particular, requires coordinated orthopaedic surgery, endocrinology, ENT/craniofacial surgery, ophthalmology and genetics input. The consensus model is a designated multidisciplinary team or rare-bone-disease referral centre, an approach mirrored across European reference networks (e.g. ERN BOND) and major North American and Australasian paediatric centres.

Bisphosphonate access and use: Intravenous pamidronate and zoledronic acid (and oral alendronate) are widely available; international consensus restricts their use to fracture-related or persistent bone pain rather than disease modification, reflecting the Boyce 2014 RCT. Denosumab has been used off-label in refractory disease but lacks controlled evidence and carries a notable rebound-hypercalcaemia risk, especially in children. Intravenous bisphosphonates are administered in a hospital or specialist-supervised setting; the funding and access route for infused agents varies between health systems, but the clinical indication — specialist-supervised use for refractory or fracture-related bone pain — is consistent internationally.

Genetic testing: Somatic GNAS mutation testing on lesional tissue (or, with sensitive assays, peripheral blood in MAS) can confirm atypical cases. It is used for diagnostic confirmation and counselling — the disorder is sporadic and not heritable, so cascade family testing is not indicated.

Surveillance and registries: Plain radiographs remain first-line; CT aids craniofacial/surgical planning and bone scintigraphy or whole-body MRI maps polyostotic burden. There is no large dedicated FD/MAS arthroplasty-style registry; longitudinal cohorts (notably the NIH natural-history cohort) and the FD/MAS consortium provide the principal pooled outcome data, and patient organisations maintain international registries to support rare-disease research.