McCune-Albright Syndrome

Normal signalling. A hormone binds its G protein-coupled receptor (GPCR), and Gs-alpha exchanges GDP for GTP and becomes active. Active Gs-alpha stimulates adenylyl cyclase to produce cAMP, which activates protein kinase A (PKA) and produces the cellular effects. Gs-alpha then switches itself off: its intrinsic GTPase activity hydrolyses GTP to GDP and returns it to the inactive state.

The mutation. The causative substitution almost always involves arginine 201 in exon 8, replaced by histidine or cysteine (R201H or R201C); a minority involve glutamine at codon 227. The mutant protein loses its GTPase activity, cannot hydrolyse GTP and stays constitutively active. cAMP is produced continuously and independently of hormone binding, and downstream signalling in the affected tissues is unregulated.

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One mutation, many tissues. The same excess of cAMP produces a different disease in each tissue that carries the mutation.

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Normal bone formation. Mesenchymal stem cells differentiate into mature osteoblasts, which lay down osteoid matrix that mineralises into normal lamellar bone.

What goes wrong. In fibrous dysplasia the GNAS1 mutation sits in the bone marrow stromal cells and arrests osteoblast differentiation at an immature stage. The cells produce fibrous connective tissue instead of normal bone, with woven-bone trabeculae in a Chinese-letter pattern, and no lamellar maturation follows. The fibrous tissue expands, the bone weakens, and deformity follows.

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The mechanical result. Bone replaced by fibrous tissue is weak in bending and in torsion. It fractures with minimal trauma and deforms progressively under physiological loading, and in the proximal femur that produces the classic shepherd's crook deformity. Growth disturbance adds a limb-length discrepancy.

Where the lesions are. In order of frequency:

1. Femur, the most commonly affected bone, the site of the shepherd's crook deformity
2. Tibia, with anterior bowing, the sabre shin
3. Pelvis, which may cause acetabular protrusion
4. Skull and facial bones, craniofacial fibrous dysplasia
5. Ribs, as painless swelling, with rare fractures
6. Humerus, less common than the lower limb

The lesions show a unilateral predominance, often on the same side, and their asymmetric distribution reflects the mosaic pattern. The disease progresses during growth and may stabilise after skeletal maturity.

Shepherd's crook deformity. Severe coxa vara and anterolateral bowing of the proximal femur, shaped like a shepherd's walking stick. Fibrous dysplasia weakens the proximal femur, weight-bearing drives it progressively into varus, and repeated microfractures and healing add to the deformity as the child grows, which may leave a significant limb-length discrepancy. The child presents with a limp and a Trendelenburg gait, a shortened limb held in external rotation, hip and thigh pain, and limited hip abduction.

Pathological fractures. The most common complication of fibrous dysplasia, and sometimes the presenting feature. They often heal with conservative treatment, but each fracture adds to the deformity, and the risk rises during growth spurts.

Pain. Bone pain from the lesions is common and debilitating. It is worse with activity and may limit mobility significantly.

Cafe-au-lait spots. Light brown ("coffee with milk") macules, present at birth or in early infancy and large, and may cover large areas of the body. Their borders are irregular and jagged, the coast of Maine. They are unilateral and respect the midline, lying on the same side as the bone lesions, a distribution that reflects their embryonic derivation. They differ from the spots of neurofibromatosis type 1 on each of these counts:

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Precocious puberty. The most common endocrine manifestation, in 50-80% of patients. It is GnRH-independent (peripheral, gonadotropin-independent), driven by autonomous gonadal hormone production. It is more common and earlier in girls, at 2-4 years, and boys may have testicular macroorchidism. In girls vaginal bleeding may be the first sign, with breast development before age 8 and an advanced bone age; growth accelerates at first, but final height is reduced.

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Other endocrine features. The endocrine work-up looks for each of these:

• Hyperthyroidism (30-50%): TSH-independent thyroid hormone production
• Growth hormone excess (10-20%): acromegaly or gigantism
• Cushing syndrome (rare): ACTH-independent cortisol production, usually presenting in infancy
• Renal phosphate wasting: FGF23 overproduction from the fibrous dysplasia lesions, causing hypophosphataemia and rickets-like features

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Craniofacial fibrous dysplasia. It involves the skull base, facial bones, orbit and mandible, and its complications are:

• Facial asymmetry and cosmetic concern
• Optic nerve compression, with vision loss (urgent)
• Hearing loss from temporal bone involvement
• Nasal obstruction
• Dental malocclusion

Stable lesions are observed, nerve compression is decompressed, and contouring for cosmesis is done at a time that remains controversial; the surgical detail is under Surgical Management.

Beyond the skeleton. Neonatal cholestasis occurs, and hepatic involvement is rare but recognised. Cardiac rhythm abnormalities are rare and related to phosphate wasting and electrolyte disturbance. Both reappear in the severe neonatal presentation described below.

Radiographs. The ground-glass appearance, a hazy, smoky bone density, is the characteristic finding. Around it:

• Well-defined margins with a thin sclerotic rim (the rind sign)
• Endosteal scalloping, the lesion expanding from within
• Bone expansion with an intact but thinned cortex
• No periosteal reaction unless fractured

CT. Used to assess craniofacial involvement, plan surgery and define the extent of lesions. It shows the ground-glass matrix clearly, along with cortical thinning and expansion and any encroachment on the nerve canals of the skull base.

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MRI. Used for the soft tissues, for suspected nerve compression and to rule out malignant transformation. Lesions are low to intermediate signal on T1 and variable, often high, on T2; they enhance with gadolinium, and cystic areas may be present.

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Bone scan (Tc-99m). The lesions take up tracer, so scintigraphy identifies all skeletal involvement and maps polyostotic disease. Consider it for the baseline assessment.

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Bone biochemistry. Alkaline phosphatase (ALP) is often elevated as a marker of bone turnover. Calcium and PTH are usually normal, phosphate may be low from FGF23-mediated wasting, and 25-OH vitamin D should be checked and optimised.

Endocrine work-up. This is essential for every patient with MAS.

Genetic testing. GNAS1 mutation analysis confirms the diagnosis when the clinical features are unclear. Blood may be negative, so affected tissue is the better sample; the pitfalls are set out under Diagnostic Criteria below.

Bone biopsy. Indicated for atypical radiographic features, concern for malignant transformation, or when genetic confirmation is needed, and it excludes osteosarcoma when there are concerning features. The histology shows a fibrous stroma of spindle cells with immature woven-bone trabeculae in a curvilinear "Chinese letter" pattern. The trabeculae have no osteoblastic rimming, the key diagnostic feature. Cartilage may be present in variable amounts, and some lesions show cystic degeneration.

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The team. Care is multidisciplinary. The orthopaedic surgeon manages the skeleton and a paediatric endocrinologist the hormonal disorders. A craniofacial surgeon manages facial involvement, an ophthalmologist monitors the optic nerves and an audiologist assesses hearing. A geneticist contributes to diagnosis and counselling, and a pain specialist to chronic pain.

Bisphosphonates treat pain. Bone pain, often significant, is the primary indication. They may reduce lesion activity, though that is controversial, and they do not prevent fractures or deformity progression or change the natural history of fibrous dysplasia. The pain response to intravenous bisphosphonate comes from observational series.

Oral bisphosphonates should not be used for this indication. Randomised placebo-controlled trials of alendronate and risedronate failed to reduce bone pain. The advice rests on that negative trial result, not merely on a preference for the intravenous route.

The intravenous regimens:

• Pamidronate IV (paediatric): 1 mg/kg/day for 3 days, every 3-6 months
• Zoledronic acid IV: 0.025-0.05 mg/kg, every 6 months

Giving them safely. Check calcium, phosphate and vitamin D before each cycle, and monitor renal function, bone turnover markers (ALP, CTX) and the clinical pain response. Ensure adequate vitamin D and calcium. Atypical fractures with long-term use are a concern whose relevance in fibrous dysplasia is controversial, and osteonecrosis of the jaw is rare in the paediatric population.

Phosphate wasting. FGF23-mediated hypophosphataemia is treated as in XLH, with oral phosphate supplementation and calcitriol to enhance absorption, monitoring for nephrocalcinosis. Burosumab (anti-FGF23) may be considered, with emerging data.

Vitamin D. Maintain 25-OH vitamin D above 75 nmol/L. It is essential for bone health and may help reduce fracture risk.

Precocious puberty. Because it is GnRH-independent, standard puberty blockers (GnRH agonists) do not work. The aims are to prevent premature epiphyseal closure, maximise final adult height and support the child psychologically through early development.

• Girls: aromatase inhibitors (anastrozole 1mg daily, letrozole), which block the conversion of androgens to oestrogens and reduce breast development and vaginal bleeding. They may be combined with a GnRH agonist if central puberty has also been triggered.
• Boys: antiandrogens (spironolactone, bicalutamide) and aromatase inhibitors; ketoconazole is rarely used.

Hyperthyroidism. Antithyroid medication (methimazole); it may require thyroidectomy if severe or refractory. Radioactive iodine is not recommended because of radiation concerns.

Growth hormone excess. Somatostatin analogues (octreotide, lanreotide), pegvisomant (a GH receptor antagonist), and pituitary surgery if an adenoma is identified.

Cushing syndrome. Managed as described for the neonatal presentation below.

What to watch and how often. Surveillance is lifelong and follows the disease into each system it involves.

Surveillance for malignant transformation is set out under Complications.

Acute pathological fractures. Standard fracture care principles apply. Healing usually occurs, because the fibrous tissue produces callus, but it may take longer, may need longer immobilisation, and the callus may be fibrous rather than normal bone. The recurrent fracture risk remains high and progressive deformity is expected without stabilisation, so assess every fracture for the deformity underneath it.

When to operate. Fixation is indicated for:

• Unstable fractures
• Significant displacement
• Pre-existing deformity requiring correction
• Impending fracture (prophylactic fixation)

Timing. Never operate on active, expanding lesions if possible. Bisphosphonates may help reduce lesion activity preoperatively.

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Intramedullary fixation is preferred over plates. A nail is load-sharing rather than load-bearing: it distributes stress along the whole bone, allows the fracture to heal without concentrating stress, and causes less stress shielding than a plate. It should span the entire lesion if possible, which protects the bone from refracture, and locking nails are worth considering in the femur and tibia. It accommodates the abnormal bone biology and, with an appropriate nail choice, the growing bone. A plate can cause stress risers and refracture at its ends, and curettage alone has a high recurrence rate.

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Indications. The absolute indications are:

• Significant functional impairment
• Progressive deformity
• Recurrent fractures
• Impending fracture (thin cortex, stress risers)

Pain not controlled with bisphosphonates, a limb-length discrepancy greater than 2 cm and cosmetic concerns are relative indications.

Correcting the shepherd's crook. A valgus osteotomy, single or multiple level, corrects the mechanical axis and is combined with intramedullary fixation. A severe, multiapical deformity needs multiple osteotomies threaded onto an intramedullary nail, the "shish kebab" technique, and gradual correction with an external fixator is possible.

Technique. Cut through normal bone if possible, because an osteotomy through a fibrous dysplasia lesion may heal slowly. Use a locked intramedullary nail spanning the entire lesion; you may need to ream through fibrous tissue.

The neck-shaft angle guides the choice.

Tibial deformity. A symptomatic sabre shin (anterior bowing) is treated by corrective osteotomy, which may need to be multiple, with intramedullary nail fixation.

The growing child. Use flexible intramedullary devices in young children and plan for nail exchange with growth. Limb-length monitoring is essential, and growth modulation is an option for a mild discrepancy.

Indications. Optic nerve compression that threatens vision, severe nasal obstruction and significant hearing loss from temporal bone involvement are urgent. Facial asymmetry and cosmesis, dental and occlusal problems, and stable lesions at skeletal maturity are elective.

Optic nerve decompression. Indicated for progressive vision loss, through an endoscopic or open approach, in collaboration with neurosurgery and ENT. Do not decompress an asymptomatic encased nerve. In the largest series 61% of nerves were completely encased and 88% of those had no optic neuropathy, while one of only six prophylactic decompressions ended in blindness. Encasement on CT is not an indication.

Facial contouring. Lesions may continue to expand during growth, so contouring is generally deferred until skeletal maturity. It shaves or burrs the prominent areas, and recurrence is a risk if the lesion is still active.

Principles. Resect conservatively, because fibrous dysplasia lesions may regrow, and preserve function over cosmesis. Staged procedures are often needed, and long-term follow-up is essential.