Fibrous Dysplasia & McCune–Albright Syndrome Explained: GNAS Mosaicism, Ground-Glass Bone Lesions, Endocrine Hyperfunction and Treatment

What Is Fibrous Dysplasia?

Central Concept

Central pathway:

Bone

Skin

Endocrine tissue

Together, this spectrum is:

FD/MAS is caused by somatic gain-of-function GNAS variants and therefore has a mosaic distribution. (PubMed Central (PMC))

Opening — Use This Content

A child develops a painless expansile bone lesion.

Radiography shows a characteristic:

Another patient has multiple skeletal lesions, recurrent fractures and deformity.

Another presents with:

• café-au-lait pigmentation;
• precocious puberty;
• hyperthyroidism;
• or growth-hormone excess.

At first these findings may appear unrelated.

But they can result from the same biological event:

The mutation occurs after fertilization.

Therefore only some cells inherit it.

This creates:

If affected cells are mainly skeletal, the patient may present primarily with:

If multiple tissues are involved, manifestations may include:

forming the spectrum traditionally called:

The phenotype depends largely on:

and:

What Is Fibrous Dysplasia?

Fibrous dysplasia is a mosaic skeletal disorder in which affected bone is replaced by abnormal:

Normal lamellar bone architecture is disrupted.

Affected bone may become:

• structurally weak;
• expanded;
• deformed;
• painful;
• susceptible to fracture.

Important:

It is a developmental disorder of skeletal cells caused by mosaic GNAS activation.

Normal Bone Versus Fibrous Dysplasia

Normal bone depends on coordinated activity of:

• skeletal progenitor cells;
• osteoblasts;
• osteocytes;
• osteoclasts;
• mineralization pathways.

In fibrous dysplasia, affected skeletal progenitor cells fail to produce normal mature bone architecture.

Instead, normal bone and marrow are replaced to varying degrees by:

This compromises normal skeletal structure.

GNAS and cAMP Signaling

GNAS

The major molecular driver is:

GNAS encodes the stimulatory G-protein alpha subunit:

Gsα participates in receptor-mediated signaling through:

Activating GNAS variants cause inappropriate persistent signaling.

Therefore:

This explains both skeletal and endocrine manifestations. (PubMed Central (PMC))

Why Is The Mutation Mosaic?

The pathogenic variant occurs:

Therefore the embryo already contains multiple cells when the mutation arises.

Only descendants of the mutated cell carry the variant.

Thus:

This is:

Timing Matters

A useful conceptual principle is:

Earlier postzygotic mutation

Potentially:

Later postzygotic mutation

Potentially:

But do not present this as a precise rule predicting an individual patient's phenotype.

The key memory is:

Is Fd/Mas Inherited?

This deserves a prominent callout:

The pathogenic GNAS variant is postzygotic and somatic.

GeneReviews reports no verified vertical transmission and considers recurrence risk to siblings essentially similar to the general population. (NCBI)

Therefore:

This makes a useful contrast with the preceding skeletal genetics articles.

The FD/MAS Spectrum

Disease Spectrum

Use:

Potential manifestations include:

Skeleton

Fibrous dysplasia

Skin

Café-au-lait pigmentation

Gonads

Autonomous sex-steroid production

Thyroid

Thyroid lesions/hyperthyroidism

Pituitary

Growth-hormone excess ± hyperprolactinemia

Kidney/bone

FGF23-mediated renal phosphate wasting

Adrenal gland

Rare neonatal hypercortisolism

Not every patient has every feature.

Monostotic Fibrous Dysplasia

Monostotic FD means:

It may be:

• discovered incidentally;
• identified after pain;
• identified after fracture;
• detected because of swelling or deformity.

It does not automatically imply systemic McCune–Albright syndrome.

Polyostotic Fibrous Dysplasia

Polyostotic FD means:

Patients may have greater risk of:

• deformity;
• fractures;
• scoliosis;
• mobility problems;
• clinically important skeletal burden.

Disease burden varies greatly.

Mccune–Albright Syndrome

McCune–Albright syndrome represents the multisystem end of the FD/MAS spectrum.

Classic teaching emphasizes the triad:

But:

Modern understanding recognizes a broader mosaic GNAS disorder involving various endocrine and non-endocrine tissues. (NCBI)

Café-Au-Lait Pigmentation

Skin lesions may be present at birth or appear early.

They are typically:

• hyperpigmented;
• irregularly bordered;
• often segmental;
• related to mosaic distribution.

A classic descriptive term for the irregular border is:

Café-au-lait lesions occur in other disorders.

Why Endocrine Hyperfunction Occurs

The same activating GNAS signaling that affects skeletal cells can produce autonomous activity in endocrine tissue.

Simplified:

This may produce:

• estrogen excess;
• testosterone excess;
• thyroid hormone excess;
• growth-hormone excess;
• cortisol excess in rare neonatal disease.

Therefore:

Endocrine Manifestations

Precocious Puberty In Girls

This is one of the classic manifestations.

Autonomous ovarian cyst activity can produce episodic:

leading to:

• breast development;
• vaginal bleeding;
• accelerated growth;
• advancement of bone age.

The process can be intermittent.

Therefore a single normal estradiol measurement does not necessarily exclude prior autonomous ovarian activity.

Why Precocious Puberty Matters

Repeated estrogen exposure can accelerate:

If progression is substantial:

Current GeneReviews emphasizes that treatment decisions focus particularly on preventing clinically important bone-age advancement rather than simply treating every isolated bleeding episode. (NCBI)

Gonadal Disease In Boys

Boys may develop:

• testicular lesions;
• macro-orchidism;
• Sertoli/Leydig cell abnormalities;
• autonomous testosterone production in some cases.

Not every structural testicular lesion produces precocious puberty.

Therefore:

Routine biopsy is not appropriate simply because a typical lesion exists; atypical, enlarging or concerning lesions require specialist evaluation. (NCBI)

Thyroid Disease

Thyroid involvement may include:

• heterogeneous gland changes;
• nodules;
• hyperthyroidism.

Autonomous thyroid function results from activating GNAS signaling.

Untreated hyperthyroidism may worsen:

• bone turnover;
• skeletal morbidity;
• cardiovascular burden.

Therefore endocrine disease should not be regarded as unrelated to the skeletal phenotype.

Growth-Hormone Excess

MAS can involve:

often with hyperprolactinemia.

Clinical effects may include:

• accelerated growth;
• acromegalic features;
• worsening craniofacial FD;
• increased skull-base morbidity.

This is especially important because:

The international consensus emphasizes control of GH excess, and GeneReviews describes medical therapy as central; pituitary surgery is challenging because disease is often diffuse and skull-base FD complicates access. (PubMed Central (PMC))

Avoid Pituitary Radiotherapy When Possible

This requires careful wording.

Radiation exposure involving FD tissue has historically raised concern about malignant transformation.

Therefore radiotherapy for MAS-associated pituitary disease should generally be avoided where effective alternatives exist and reserved for exceptional specialist circumstances.

The international consensus and GeneReviews treat radiation as a last-resort approach. (PubMed Central (PMC))

Neonatal Hypercortisolism

Rare infants with extensive MAS may develop:

This can be severe and potentially life-threatening.

It is not a common manifestation.

FGF23 and Renal Phosphate Wasting

FGF23 And Fibrous Dysplasia

This is an essential connection to the existing phosphate cluster.

FD lesions can produce excessive:

FGF23 acts in the kidney to:

Therefore:

Important Nuance: FGF23 Level Versus Phosphate Wasting

Not every patient with FD has hypophosphatemia.

Clinically important phosphate wasting is more likely with substantial disease burden, but the phenotype varies.

The student should assess:

and, when indicated:

rather than assuming phosphate status from the diagnosis alone.

Why Phosphate Wasting Matters

Hypophosphatemia can independently worsen:

• bone pain;
• weakness;
• fractures;
• mineralization;
• skeletal deformity.

Therefore:

The patient may have a treatable superimposed:

GeneReviews specifically emphasizes correcting inadequately treated hypophosphatemia before considering bisphosphonate treatment for FD-related pain. (NCBI)

• Renal Phosphate Wasting Explained
• FGF23 Disorders Explained
• Hypophosphatemia Explained
• Osteomalacia Explained

Pain, Fractures and Deformity

Bone Pain

Bone pain is common but variable.

Potential contributors include:

• active FD lesions;
• fractures;
• stress injury;
• deformity;
• mechanical loading;
• arthritis;
• muscle dysfunction;
• hypophosphatemia;
• other unrelated pain disorders.

Therefore:

Fractures

FD bone may be mechanically weak.

Fractures may occur particularly in weight-bearing bones.

Potential consequences include:

• pain;
• deformity;
• loss of mobility;
• progressive angulation.

Repeated fractures around the proximal femur are particularly important.

Shepherd'S-Crook Deformity

A classic severe proximal femoral deformity is:

It reflects progressive:

associated with mechanically weak dysplastic bone.

This is an important radiological and orthopedic teaching point.

Scoliosis

Spinal FD can contribute to:

Progression may occur, particularly with substantial skeletal disease.

Severe scoliosis can impair:

• posture;
• function;
• respiratory mechanics.

Craniofacial Fibrous Dysplasia

Craniofacial Fibrous Dysplasia

Craniofacial FD can involve:

• skull;
• skull base;
• facial bones;
• orbit;
• paranasal sinuses.

It may cause:

• facial asymmetry;
• expansion;
• pain;
• dental abnormalities;
• hearing problems;
• visual concerns.

However:

This is especially important for optic-nerve encasement.

Optic-Nerve Encasement

Craniofacial FD may surround the:

Imaging can therefore appear alarming.

But:

Therefore:

This distinction is essential. (NCBI)

Do Not Prophylactically Decompress An Asymptomatic Optic Nerve

Prophylactic optic-nerve decompression in an asymptomatic patient is contraindicated because intervention itself can worsen visual outcome.

Patients with actual optic neuropathy require expert craniofacial/neuro-ophthalmological assessment. (PubMed Central (PMC))

This is one of the article's highest-yield clinical messages.

Hearing

Craniofacial FD may affect auditory structures.

Potential problems include:

• conductive hearing loss;
• sensorineural hearing impairment;
• external auditory canal narrowing.

Symptoms should trigger appropriate audiological/ENT evaluation.

Radiology

Radiology — Central Section

Radiographic appearance varies according to:

• age;
• skeletal location;
• lesion composition.

The classic descriptor is:

Other features can include:

• expansile lesions;
• cortical thinning;
• bone enlargement;
• deformity;
• heterogeneous density.

Why “Ground Glass”?

The abnormal mixture of:

• immature woven bone;
• fibrous stroma;
• variable mineralization;

produces a relatively homogeneous hazy radiographic density traditionally described as:

It is a radiological descriptor, not the underlying pathology itself.

Plain Radiography

Plain radiographs are useful for:

• initial lesion characterization;
• fractures;
• long-bone deformity;
• follow-up of specific orthopedic problems.

Characteristic appearances can strongly support FD in the correct clinical context.

CT

CT is particularly useful for:

because it defines:

• lesion anatomy;
• skull-base involvement;
• orbital relationships;
• sinus involvement;
• cranial foramina.

Imaging should answer a clinical question.

MRI

MRI may be useful when evaluating:

• soft-tissue relationships;
• neurological complications;
• atypical lesions;
• possible cystic change;
• suspected malignant transformation.

FD signal characteristics can be variable.

Therefore:

Bone Scintigraphy

Bone scintigraphy can help determine:

particularly when evaluating polyostotic involvement.

The international consensus includes skeletal burden assessment as part of staging. (PubMed Central (PMC))

Diagnosis, Biopsy and Genetic Testing

Biopsy

Biopsy is not mandatory for every classic lesion.

It becomes more useful when:

• imaging is atypical;
• diagnosis is uncertain;
• an isolated lesion lacks convincing clinical context;
• malignancy or another pathology is suspected.

The principle is:

but:

Histology

Histology classically demonstrates irregular trabeculae of woven bone within fibrous stroma.

A traditional descriptive phrase is:

But do not overemphasize this phrase as if it alone establishes diagnosis.

The complete clinicoradiological context matters.

Genetic Testing

Molecular testing may identify an activating:

But mosaicism creates an important limitation.

Peripheral blood may contain:

even when the lesion itself carries the mutation.

Therefore:

Affected tissue generally has greater diagnostic yield than blood.

GeneReviews emphasizes that molecular sensitivity depends heavily on the tissue tested and assay methodology. (NCBI)

Diagnosis

Diagnosis integrates:

Initial Skeletal Assessment

The clinical assessment should determine:

• monostotic versus polyostotic disease;
• pain;
• previous fractures;
• deformity;
• gait/function;
• scoliosis;
• craniofacial involvement;
• dental symptoms.

Biochemistry should particularly consider:

• calcium;
• phosphate;
• renal function;
• ALP;
• vitamin-D context;
• PTH where indicated;
• renal phosphate wasting where phosphate is low.

Endocrine Assessment

The endocrine phenotype should be assessed based on:

• age;
• symptoms;
• growth pattern;
• pubertal development;
• thyroid findings;
• craniofacial disease;
• other clinical clues.

Malignant Transformation and Red Flags

Malignant Transformation

FD lesions are overwhelmingly:

Malignant transformation is:

Possible malignancies include sarcomatous transformation.

Instead teach:

Red Flags

Concerning features include:

• new rapidly progressive pain;
• rapidly enlarging mass;
• new swelling;
• new neurological deficit;
• unexpected destructive imaging changes;
• soft-tissue mass.

These require specialist assessment and appropriate imaging/biopsy.

Radiation Exposure

Radiotherapy involving FD lesions has historically been associated with concern for malignant transformation.

Therefore:

This is particularly relevant in MAS-associated pituitary disease. (PubMed Central (PMC))

Clinical Staging

Management Principles

There is currently no established routinely used medication that eradicates GNAS-mutant skeletal lesions or reliably reverses the overall FD disease course.

Management therefore focuses on:

• preserving function;
• treating fractures;
• correcting deformity;
• controlling pain;
• correcting phosphate wasting;
• controlling endocrine hyperfunction;
• protecting vision/hearing;
• dental care;
• monitoring clinically important complications.

The international consensus emphasizes multidisciplinary management. (PubMed Central (PMC))

Treat Endocrine Disease

This is a major skeletal-management principle:

Therefore identify and appropriately manage:

• precocious puberty;
• hyperthyroidism;
• GH excess;
• clinically important phosphate wasting;
• other relevant endocrinopathies.

Treat Phosphate Wasting

Clinically significant renal phosphate wasting should be addressed because untreated hypophosphatemia can worsen:

• pain;
• weakness;
• mineralization;
• fracture risk.

The exact phosphate/active-vitamin-D regimen belongs under specialist metabolic-bone management and should not be invented here.

Internal link prominently to:

See renal phosphate wasting.

and:

See FGF23-mediated phosphate wasting.

Treatment Principles

Bisphosphonates

Bisphosphonates are antiresorptive drugs.

In FD:

They have not been shown to:

or:

GeneReviews specifically states that bisphosphonates have not been shown to affect progression and limits their role primarily to FD-related bone pain. (NCBI)

Before Bisphosphonate Treatment

Before attributing pain to FD and moving toward antiresorptive therapy, evaluate potentially correctable contributors such as:

Inadequately treated phosphate wasting can substantially worsen bone pain. (NCBI)

Also assess:

• fracture/stress fracture;
• mechanical deformity;
• vitamin-D status where clinically appropriate;
• other causes of pain.

Oral Versus IV Bisphosphonate Evidence

The educational message is:

• IV bisphosphonates have been used for significant FD-related pain;
• oral bisphosphonate trials have not demonstrated convincing benefit for FD pain;
• BMD changes should not be mistaken for evidence that the underlying lesion has been cured.

Denosumab

Denosumab is:

It inhibits RANKL and can markedly suppress lesion activity and bone turnover.

Research has shown potentially substantial effects on lesion activity and pain, but discontinuation can produce:

and:

GeneReviews describes promising adult data but emphasizes important safety concerns and ongoing study. A small 2026 pediatric open-label study also reported improvements, but only five patients were studied, so it does not establish routine pediatric therapy. (NCBI)

Therefore:

Surgery

Surgery may be needed for:

• fractures;
• progressive deformity;
• mechanical dysfunction;
• selected craniofacial problems;
• severe scoliosis.

Surgery should focus on:

not simply removing every radiographically abnormal area.

Curettage And Bone Grafting

Simple curettage of extensive FD lesions often has limited long-term effectiveness because abnormal tissue can persist or recur.

In craniofacial disease, the international consensus specifically advises against simple curettage as a routine strategy because it is ineffective and may increase complications. (PubMed Central (PMC))

Proximal Femoral Disease

Proximal femoral FD deserves special attention because repeated loading can drive:

• fracture;
• progressive varus;
• bowing;
• shepherd's-crook deformity.

Orthopedic management aims to preserve:

Craniofacial Surgery

Surgery may be appropriate for:

• functional impairment;
• significant deformity;
• progressive symptomatic disease;
• selected compressive complications.

But:

The goal is preservation/restoration of function and appropriate correction of deformity.

Pain Management

Pain management should begin by asking:

Possible causes:

• FD lesion activity;
• fracture;
• stress fracture;
• deformity;
• arthritis;
• muscular/mechanical pain;
• hypophosphatemia;
• neuropathic pain;
• unrelated pathology.

Management can include:

• treating the cause;
• rehabilitation;
• appropriate analgesia;
• selected bisphosphonate therapy for persistent FD-related pain;
• multidisciplinary pain care where necessary.

Rehabilitation

Physical therapy and rehabilitation can support:

• muscle strength;
• gait;
• balance;
• mobility;
• function;
• recovery after fractures/surgery;
• adaptation to deformity.

The goal is:

Pregnancy

Pregnancy can occur in women with FD/MAS.

Clinical management should consider:

• endocrine status;
• skeletal burden;
• pain;
• mobility;
• previous fractures;
• obstetric factors.

Management should be individualized.

Surveillance

Surveillance should be:

not identical for every patient.

Important domains include:

• skeletal pain/function;
• deformity;
• fracture;
• scoliosis;
• phosphate status;
• growth/puberty in children;
• thyroid disease;
• GH excess where relevant;
• vision/hearing in craniofacial disease.

For craniofacial FD, GeneReviews recommends neuro-ophthalmologic assessment and notes that CT frequency should be individualized, with approximately five-year intervals suggested in stable contexts and earlier imaging when clinically indicated. (NCBI)

Master Pathophysiology Algorithm

Three branches:

BONE

Pain / fracture / deformity

ENDOCRINE

Precocious puberty / hyperthyroidism / GH excess / others

SKIN

Café-au-lait lesions

Bottom:

Master Diagnostic Algorithm

Pain?

Fracture?

Deformity?

Café-au-lait?

Early puberty?

Thyroid/GH clues?

Ground-glass?

Expansion?

Deformity?

Monostotic?

Polyostotic?

Craniofacial?

Especially:

Phosphate

Phosphate low?

based on phenotype.

Classic phenotype?

Clinical + radiological diagnosis may be sufficient.

Atypical / uncertain?

Craniofacial Decision Pathway

Yes

Even if optic canal is encased:

No — optic neuropathy suspected

Determine cause and appropriate intervention.

Bottom:

(NCBI)

Differential Comparisons

Fd Versus Osteogenesis Imperfecta

Fd Versus Hypophosphatasia

Fd Versus Osteopetrosis

Fd Versus Paget Disease

Internal link to the existing Paget article.

Worked Clinical Cases

Case 1 — Ground-glass lesion

A teenager has an incidental expansile femoral lesion with ground-glass matrix.

Key thought: fibrous dysplasia.

Determine skeletal extent and clinical context before assuming MAS.

Case 2 — One bone only

Patient has a classic FD lesion confined to one rib and no extraskeletal manifestations.

Classification

Not automatically McCune–Albright syndrome.

Case 3 — Multiple bones

Child has lesions involving femur, pelvis and skull.

Classification

Assess endocrine and phosphate abnormalities.

Case 4 — Early vaginal bleeding

Young girl has café-au-lait pigmentation and episodic vaginal bleeding with ovarian cyst activity.

Mechanism

Consider MAS.

Case 5 — Low phosphate

Patient with extensive polyostotic FD develops bone pain and hypophosphatemia.

Wrong approach

“Pain is simply from the lesions.”

Better approach

Case 6 — Optic canal encasement

CT shows craniofacial FD completely surrounding an optic canal, but visual examination is normal.

Wrong action

Automatic prophylactic decompression.

Correct principle

Observe with appropriate specialist follow-up. (NCBI)

Case 7 — Progressive visual loss

Patient with craniofacial FD develops objective deterioration in vision.

Action

This is different from asymptomatic radiological encasement.

Case 8 — Shepherd's crook

Patient with polyostotic FD develops progressive proximal femoral varus and bowing.

Diagnosis

Orthopedic mechanical assessment is required.

Case 9 — Bone pain and bisphosphonate request

Adult with FD requests bisphosphonates to “remove the lesion.”

Answer

Bisphosphonates may have a role for selected persistent FD-related bone pain but:

(NCBI)

Case 10 — Denosumab request

Patient asks whether denosumab is now established treatment.

Answer

Research is promising, but important rebound mineral-metabolism risks remain and evidence is insufficient for routine standard use. (NCBI)

Case 11 — Negative blood GNAS test

Patient has convincing polyostotic FD but peripheral-blood testing is negative.

Wrong conclusion

“No GNAS mutation, therefore no FD.”

Correct principle

Affected tissue may have higher diagnostic yield.

Case 12 — Skull FD + GH excess

Patient has progressive craniofacial FD and elevated GH/IGF-1.

Lesson

Control of GH excess is an important component of skeletal management.

Common Mistakes

Mistake 1

Fibrous dysplasia is simply fibrosis of bone. This is incorrect.

Mistake 2

FD is a germline inherited GNAS disorder. This is incorrect.

Mistake 3

Every child of a patient with FD/MAS has a high inheritance risk. This is incorrect.

Mistake 4

Every FD patient has McCune–Albright syndrome. This is incorrect.

Mistake 5

The complete classic MAS triad is required for diagnosis. This is incorrect.

Mistake 6

Monostotic FD means mild MAS. This is incorrect.

Mistake 7

Every FD lesion has an identical ground-glass appearance. This is incorrect.

Mistake 8

Ground-glass appearance alone proves FD in every setting. This is incorrect.

Mistake 9

Every classic FD lesion requires biopsy. This is incorrect.

Mistake 10

A negative blood GNAS test excludes FD/MAS. This is incorrect.

Mistake 11

All FD-related pain comes directly from the lesion. This is incorrect.

Mistake 12

Hypophosphatemia is unrelated to FD. This is incorrect.

Mistake 13

Every patient with FD has phosphate wasting. This is incorrect.

Mistake 14

Optic-canal encasement means the patient needs decompression. This is incorrect.

Mistake 15

Prophylactic optic-nerve decompression protects vision. This is incorrect.

Mistake 16

Bisphosphonates remove FD lesions. This is incorrect.

Mistake 17

Bisphosphonates are proven to stop FD progression. This is incorrect.

Mistake 18

Denosumab is now routine first-line FD therapy. This is incorrect.

Mistake 19

Endocrine abnormalities are unrelated to skeletal disease. This is incorrect.

Mistake 20

FD/MAS is only a bone disorder. This is incorrect.

FD/MAS in One Minute

Three major tissues:

Bone

Ground glass

Pain

Fracture

Deformity

Skin

Endocrine

Precocious puberty

Hyperthyroidism

GH excess

Also remember:

Craniofacial rule:

Treatment:

Not:

Final:

Frequently Asked Questions

Key Take-Home Messages

Fibrous dysplasia/McCune–Albright syndrome begins with:

Therefore:

Affected skeletal cells produce:

leading to:

The same mutation in endocrine tissues can cause:

Therefore always think beyond the skeleton.

The same skeletal lesions can also increase:

leading to:

which may independently worsen skeletal disease.

For craniofacial FD:

and:

For treatment:

Bisphosphonates:

but:

Denosumab:

And the final memory statement: