Fibrous Dysplasia

Somatic mosaic MONDO:0000845 Pathograph 21 Bone remodeling disease Acquired disease

Fibrous dysplasia is a rare, non-inherited somatic mosaic skeletal disorder caused by post-zygotic activating GNAS variants. Normal bone and marrow are replaced by fibro-osseous tissue containing immature woven bone and fibrous stroma, producing structurally weak lesions that may be monostotic or polyostotic. Clinical burden depends on the mosaic distribution of involved tissues and includes bone pain, deformity, pathologic fracture, craniofacial or appendicular skeletal involvement, FGF23-mediated hypophosphatemia, and functional impairment. When fibrous dysplasia is accompanied by cafe-au-lait macules or hyperfunctioning endocrinopathies, the presentation falls within the McCune-Albright syndrome spectrum.

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1
Mappings
1
Definitions
1
Inheritance
4
Pathophys.
1
Histopath.
36
Phenotypes
21
Pathograph
1
Genes
6
Treatments
5
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0000845 fibrous dysplasia
skos:exactMatch Orphanet ORPHA:249
Orphanet ORPHA:249 lists MONDO:0000845 as an exact cross-reference for fibrous dysplasia of bone.
📘

Definitions

1
Orphanet fibrous dysplasia definition
A rare benign primary bone dysplasia in which normal bone and marrow are progressively replaced by fibrous connective tissue in one or multiple bones, causing pain, deformity, pathologic fracture, or cranial nerve deficits depending on lesion location.
OTHER
Show evidence (2 references)
ORPHA:249 SUPPORT Other
"A rare, benign, primary bone dysplasia characterized by progressive replacement of normal bone and marrow with fibrous connective tissue"
Orphanet defines fibrous dysplasia by replacement of bone and marrow with fibrous connective tissue.
PMID:31037426 SUPPORT Human Clinical
"Fibrous dysplasia is an uncommon mosaic disorder in which bone is replaced by"
The clinical review supports fibrous dysplasia as a mosaic bone-replacement disorder.
👪

Inheritance

1
Not applicable
Fibrous dysplasia is not inherited vertically; it results from post-zygotic somatic mosaic GNAS activation.
Show evidence (2 references)
ORPHA:249 SUPPORT Other
"Not applicable"
Orphanet marks inheritance as not applicable.
PMID:27492469 SUPPORT Human Clinical
"FD/MAS arises sporadically, and there are no confirmed cases of vertical transmission."
The clinical review supports non-inherited, sporadic occurrence.
⚙

Pathophysiology

4
Somatic GNAS activation in mosaic skeletal progenitors
Post-zygotic activating GNAS variants cause constitutive Gs-alpha/cAMP signaling in a mosaic population of skeletal progenitors. Mosaicism is essential to viability and determines whether disease is monostotic, polyostotic, or syndromic with extraskeletal manifestations.
skeletal stem/progenitor cell link
adenylate cyclase-activating G protein-coupled receptor signaling pathway link ↑ INCREASED
Downstream
Impaired osteogenic differentiation and marrow replacement Constitutive Gs-alpha/cAMP signaling disrupts maturation of osteogenic progenitors.
Show evidence (2 references)
PMID:27492469 SUPPORT Human Clinical
"post-zygotic GNAS mutations acquired early in embryogenesis lead to a somatic mosaic disease state"
The review supports the proximal mosaic GNAS activation mechanism.
PMID:31037426 SUPPORT Human Clinical
"somatic mosaicism, which allows for close association of mutation-bearing cells with normal cells, is essential"
The review explains why mosaicism is central to FD/MAS pathogenesis.
Impaired osteogenic differentiation and marrow replacement
GNAS-activated osteogenic progenitors fail to mature normally. Normal marrow and trabecular bone are replaced by fibro-osseous tissue containing fibrous stroma and immature woven bone, weakening the affected skeleton.
osteoblast lineage cell link
osteoblast differentiation link ↓ DECREASED ossification link ⚠ ABNORMAL
Downstream
Fibrous dysplasia of the bones Fibro-osseous replacement is the tissue basis of FD bone lesions.
Abnormal bone structure Abnormal woven bone and fibrous stroma produce structurally abnormal bone.
Osteolysis Dysplastic lesions undergo active remodeling and bone resorption.
Show evidence (2 references)
PMID:27492469 SUPPORT Human Clinical
"Bone and bone marrow are thus replaced by proliferating BMSCs, resulting in fibro-osseous tissue typically devoid of hematopoietic marrow"
The review describes replacement of normal bone and marrow by fibro-osseous tissue.
PMID:31037426 SUPPORT Human Clinical
"The immature osteoprogenitors proliferate and produce excess amounts of abnormal bone matrix, consisting predominantly of woven bone."
The review explains the immature woven-bone matrix produced in lesions.
Structurally weak fibro-osseous bone lesions
FD lesions weaken affected bone and produce pain, deformity, fractures, cortical thinning, bowing, coxa vara, gait disturbance, and axial or craniofacial skeletal morbidity according to lesion location.
bone remodeling link ⚠ ABNORMAL
Downstream
Bone pain Structural lesion burden and complications contribute to bone pain.
Pathologic fracture Weak dysplastic bone predisposes to fractures.
Bowing of the long bones Lesions in weight-bearing long bones can deform under mechanical stress.
Antalgic gait Skeletal pain and deformity cause antalgic gait.
Show evidence (1 reference)
PMID:31037426 SUPPORT Human Clinical
"The resulting skeleton is weakened and prone to fractures and deformity, resulting in pain and functional impairment."
The review links fibro-osseous lesions to the major skeletal complications.
FGF23-mediated phosphate wasting
Active dysplastic osteogenic cells can overproduce FGF23. FGF23 decreases renal phosphate reabsorption and active vitamin D, causing hypophosphatemia with rickets or osteomalacia in patients with high disease burden.
osteogenic cell link
phosphate ion homeostasis link ⚠ ABNORMAL
Downstream
Hypophosphatemia FGF23-mediated renal phosphate wasting lowers circulating phosphate.
Rickets Childhood phosphate wasting can produce rickets.
Osteomalacia Phosphate wasting can produce osteomalacia in later presentations.
Show evidence (2 references)
PMID:31037426 SUPPORT Human Clinical
"Nearly 50% of patients with FD/MAS exhibit some degree of renal phosphate wasting"
The review supports phosphate wasting as a common metabolic branch.
PMID:27492469 SUPPORT Human Clinical
"Fibroblast growth factor-23 (FGF23) is overproduced by FD cells"
The review identifies FD cells as the source of excess FGF23.
✶

Histopathology

1
Fibro-osseous lesion with woven bone and fibrous stroma
Classic lesions contain fibrous stroma around irregular curvilinear trabeculae of woven bone, often described as a Chinese writing pattern, with stellate osteoblasts, Sharpey fibers, and excess osteoid.
Show evidence (2 references)
PMID:27492469 SUPPORT Human Clinical
"low to moderately cellular fibrous stroma surround irregular, curvilinear trabeculae of woven bone"
The review describes the characteristic histologic architecture.
PMID:31037426 SUPPORT Human Clinical
"thin, irregularly arranged, discontinuous trabeculae, consisting mostly of woven bone, surrounded by abundant fibrous stroma"
The bench-to-bedside review describes classic appendicular and axial skeletal histology.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Fibrous Dysplasia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

36
Ear 1
Hearing impairment VERY_RARE Hearing impairment (HP:0000365)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000365 | Hearing impairment | Very rare (<4-1%)"
Orphanet lists hearing impairment as very rare.
Endocrine 2
Hyperthyroidism VERY_RARE Hyperthyroidism (HP:0000836)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000836 | Hyperthyroidism | Very rare (<4-1%)"
Orphanet lists hyperthyroidism as very rare.
Thyroid carcinoma VERY_RARE Thyroid carcinoma (HP:0002890)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002890 | Thyroid carcinoma | Very rare (<4-1%)"
Orphanet lists thyroid carcinoma as very rare.
Eye 1
Visual loss VERY_RARE Visual loss (HP:0000572)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000572 | Visual loss | Very rare (<4-1%)"
Orphanet lists visual loss as very rare.
Head and Neck 1
Abnormality of the mandible FREQUENT Abnormal mandible morphology (HP:0000277)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000277 | Abnormality of the mandible | Frequent (79-30%)"
Orphanet lists mandibular abnormality as frequent.
Limbs 2
Bowing of the long bones FREQUENT Bowing of the long bones (HP:0006487)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0006487 | Bowing of the long bones | Frequent (79-30%)"
Orphanet lists bowing of the long bones as frequent.
Coxa vara OCCASIONAL Coxa vara (HP:0002812)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002812 | Coxa vara | Occasional (29-5%)"
Orphanet lists coxa vara as occasional.
Metabolism 1
Hypophosphatemia FREQUENT Hypophosphatemia (HP:0002148)
Show evidence (2 references)
ORPHA:249 SUPPORT Other
"HP:0002148 | Hypophosphatemia | Frequent (79-30%)"
Orphanet lists hypophosphatemia as frequent.
PMID:31037426 SUPPORT Human Clinical
"overt hypophosphatemia is uncommon and typically affects patients with greater overall disease burden"
The review links hypophosphatemia to skeletal disease burden and FGF23-mediated phosphate wasting.
Musculoskeletal 5
Osteolysis VERY_FREQUENT Osteolysis (HP:0002797)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002797 | Osteolysis | Very frequent (99-80%)"
Orphanet lists osteolysis as very frequent.
Rickets FREQUENT Rickets (HP:0002748)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002748 | Rickets | Frequent (79-30%)"
Orphanet lists rickets as frequent.
Pathologic fracture FREQUENT Pathologic fracture (HP:0002756)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002756 | Pathologic fracture | Frequent (79-30%)"
Orphanet lists pathologic fracture as frequent.
Scoliosis OCCASIONAL Scoliosis (HP:0002650)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002650 | Scoliosis | Occasional (29-5%)"
Orphanet lists scoliosis as occasional.
Osteomalacia OCCASIONAL Osteomalacia (HP:0002749)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002749 | Osteomalacia | Occasional (29-5%)"
Orphanet lists osteomalacia as occasional.
Nervous System 1
Gait disturbance OCCASIONAL Gait disturbance (HP:0001288)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0001288 | Gait disturbance | Occasional (29-5%)"
Orphanet lists gait disturbance as occasional.
Constitutional 1
Bone pain FREQUENT Bone pain (HP:0002653)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002653 | Bone pain | Frequent (79-30%)"
Orphanet lists bone pain as frequent.
Growth 2
Short stature OCCASIONAL Short stature (HP:0004322)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0004322 | Short stature | Occasional (29-5%)"
Orphanet lists short stature as occasional.
Lower limb asymmetry OCCASIONAL Lower limb asymmetry (HP:0100559)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0100559 | Lower limb asymmetry | Occasional (29-5%)"
Orphanet lists lower limb asymmetry as occasional.
Other 19
Fibrous dysplasia of the bones OBLIGATE Fibrous dysplasia of the bones (HP:0010734)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0010734 | Fibrous dysplasia of the bones | Obligate (100%)"
Orphanet lists fibrous dysplasia of the bones as obligate.
Abnormal skull morphology VERY_FREQUENT Abnormal skull morphology (HP:0000929)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000929 | Abnormal skull morphology | Very frequent (99-80%)"
Orphanet lists abnormal skull morphology as very frequent.
Abnormal bone structure VERY_FREQUENT Abnormal bone structure (HP:0003330)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0003330 | Abnormal bone structure | Very frequent (99-80%)"
Orphanet lists abnormal bone structure as very frequent.
Abnormal axial skeleton morphology VERY_FREQUENT Abnormal axial skeleton morphology (HP:0009121)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0009121 | Abnormal axial skeleton morphology | Very frequent (99-80%)"
Orphanet lists abnormal axial skeleton morphology as very frequent.
Abnormality of limbs VERY_FREQUENT Abnormality of limbs (HP:0040064)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0040064 | Abnormality of limbs | Very frequent (99-80%)"
Orphanet lists limb abnormality as very frequent.
Abnormality of the maxilla FREQUENT Abnormal maxilla morphology (HP:0000326)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000326 | Abnormality of the maxilla | Frequent (79-30%)"
Orphanet lists maxillary abnormality as frequent.
Thin bony cortex FREQUENT Thin bony cortex (HP:0002753)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002753 | Thin bony cortex | Frequent (79-30%)"
Orphanet lists thin bony cortex as frequent.
Abnormality of femur morphology FREQUENT Abnormal femur morphology (HP:0002823)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0002823 | Abnormality of femur morphology | Frequent (79-30%)"
Orphanet lists femur morphology abnormality as frequent.
Elevated circulating alkaline phosphatase concentration FREQUENT Elevated circulating alkaline phosphatase concentration (HP:0003155)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0003155 | Elevated circulating alkaline phosphatase concentration | Frequent (79-30%)"
Orphanet lists elevated alkaline phosphatase as frequent.
Cortical irregularity FREQUENT Cortical irregularity (HP:0005731)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0005731 | Cortical irregularity | Frequent (79-30%)"
Orphanet lists cortical irregularity as frequent.
Patchy reduction of bone mineral density FREQUENT Patchy reduction of bone mineral density (HP:0010657)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0010657 | Patchy reduction of bone mineral density | Frequent (79-30%)"
Orphanet lists patchy reduction of bone mineral density as frequent.
Abnormal zygomatic bone morphology FREQUENT Abnormal zygomatic bone morphology (HP:0010668)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0010668 | Abnormal zygomatic bone morphology | Frequent (79-30%)"
Orphanet lists zygomatic bone morphology abnormality as frequent.
Abnormality of facial skeleton FREQUENT Abnormal facial skeleton morphology (HP:0011821)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0011821 | Abnormality of facial skeleton | Frequent (79-30%)"
Orphanet lists facial skeleton abnormality as frequent.
Antalgic gait FREQUENT Antalgic gait (HP:0031955)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0031955 | Antalgic gait | Frequent (79-30%)"
Orphanet lists antalgic gait as frequent.
Ovarian cyst VERY_RARE Ovarian cyst (HP:0000138)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000138 | Ovarian cyst | Very rare (<4-1%)"
Orphanet lists ovarian cyst as very rare.
Elevated circulating growth hormone concentration VERY_RARE Elevated circulating growth hormone concentration (HP:0000845)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0000845 | Elevated circulating growth hormone concentration | Very rare (<4-1%)"
Orphanet lists elevated growth hormone as very rare.
Large cafe-au-lait macules with irregular margins VERY_RARE Large cafe-au-lait macules with irregular margins (HP:0005605)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0005605 | Large cafe-au-lait macules with irregular margins | Very rare (<4-1%)"
Orphanet lists large cafe-au-lait macules with irregular margins as very rare.
Precocious puberty in females VERY_RARE Precocious puberty in females (HP:0010465)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0010465 | Precocious puberty in females | Very rare (<4-1%)"
Orphanet lists precocious puberty in females as very rare.
Neoplasm of the breast VERY_RARE Neoplasm of the breast (HP:0100013)
Show evidence (1 reference)
ORPHA:249 SUPPORT Other
"HP:0100013 | Neoplasm of the breast | Very rare (<4-1%)"
Orphanet lists breast neoplasm as very rare.
🧬

Genetic Associations

1
Post-zygotic activating GNAS variants (Causative somatic mosaic activating variant)
Show evidence (2 references)
PMID:31037426 SUPPORT Human Clinical
"post-zygotic activating mutations in GNAS, resulting in dysregulated GαS-protein"
The review identifies post-zygotic activating GNAS mutations as the causal molecular lesion.
PMID:27492469 SUPPORT Human Clinical
"FD/MAS is caused by somatic activating mutations in GNAS"
The translational review independently supports somatic activating GNAS mutations.
💊

Treatments

6
Multidisciplinary supportive management
Action: supportive care MAXO:0000950
Management is supportive and individualized, with treatment of endocrinopathies, pain evaluation, orthoses, physical therapy, radiologic surveillance, and subspecialty care based on lesion distribution.
Mechanism Target:
MODULATES Structurally weak fibro-osseous bone lesions — Supportive management reduces morbidity from lesions but does not alter the causal mosaic GNAS defect.
Show evidence (1 reference)
PMID:31037426 SUPPORT Human Clinical
"Management in FD is supportive, with the goal of optimizing function and minimizing morbidity."
The review identifies supportive care as the core management strategy.
Physical therapy and low-impact strengthening
Action: physical therapy MAXO:0000011
Physical therapy and low-impact exercise help maintain muscle strength and mobility while avoiding prolonged immobilization.
Target Phenotypes: Antalgic gait ↗
Show evidence (1 reference)
PMID:31037426 SUPPORT Human Clinical
"Physical therapy is an important component of FD management."
The review supports physical therapy as part of management.
Oral phosphate and active vitamin D for hypophosphatemia
Action: Pharmacotherapy NCIT:C15986
Agent: phosphate ↗ calcitriol ↗
FGF23-mediated renal phosphate wasting in fibrous dysplasia/McCune-Albright syndrome is managed with oral phosphate supplementation plus active vitamin D, such as calcitriol or another activated vitamin D analogue.
Mechanism Target:
BYPASSES FGF23-mediated phosphate wasting — Oral phosphate and active vitamin D treat the downstream phosphate deficit without correcting mosaic GNAS activation or FGF23 excess.
Show evidence (1 reference)
PMID:27492469 SUPPORT Human Clinical
"Similar to other disorders of FGF23 excess, hypophosphatemia is managed with oral phosphorus and calcitriol."
The review directly supports oral phosphorus and calcitriol for FGF23-excess hypophosphatemia.
Target Phenotypes: Hypophosphatemia ↗
Show evidence (2 references)
PMID:27492469 SUPPORT Human Clinical
"Similar to other disorders of FGF23 excess, hypophosphatemia is managed with oral phosphorus and calcitriol."
The review directly supports this treatment combination for hypophosphatemia in FD/MAS.
PMID:31037426 SUPPORT Human Clinical
"Hypophosphatemia is managed similarly to other diseases of FGF23 excess with oral phosphorous and activated vitamin D analogues"
The bench-to-bedside review independently supports oral phosphorus and active vitamin D analogues.
Surgery for fracture, deformity, or functional compromise
Action: surgical procedure MAXO:0000004
Surgery can preserve function, reduce pain, stabilize fractures, correct deformity, or address craniofacial functional compromise; prophylactic optic nerve decompression is avoided without visual compromise.
Target Phenotypes: Pathologic fracture ↗ Bowing of the long bones ↗
Show evidence (1 reference)
PMID:31037426 SUPPORT Human Clinical
"Treatment often consists of surgery to preserve function and reduce pain"
The review supports surgery for selected functional and painful skeletal complications.
Intravenous bisphosphonate therapy for moderate to severe bone pain
Action: bisphosphonate agent therapy MAXO:0000954
Agent: bisphosphonate ↗
Intravenous bisphosphonates may be considered for persistent moderate to severe FD-related bone pain after evaluation for fracture, metabolic, or orthopedic drivers. Controlled alendronate data do not support disease modification or reliable pain improvement.
Target Phenotypes: Bone pain ↗
Show evidence (2 references)
PMID:27492469 SUPPORT Human Clinical
"Intravenous bisphosphonates may be helpful for persistent, moderate to severe pain"
The translational review supports cautious use of intravenous bisphosphonates for persistent moderate to severe pain.
PMID:25033066 SUPPORT Human Clinical
"no significant effect on serum osteocalcin, pain, or functional parameters."
The placebo-controlled alendronate trial limits claims by showing no significant pain or function benefit.
Denosumab only in research protocols
Action: Pharmacotherapy NCIT:C15986
Agent: denosumab ↗
Denosumab targets RANKL-driven osteoclastogenesis and has shown promise in case reports, but safety concerns including rebound hypercalcemia mean use should be limited to research protocols.
Mechanism Target:
MODULATES Impaired osteogenic differentiation and marrow replacement — Denosumab targets downstream RANKL-mediated osteoclast activity, not the upstream GNAS mosaicism.
Show evidence (1 reference)
PMID:27492469 SUPPORT Human Clinical
"denosumab may hold promise as a potential treatment for FD, however given these safety concerns its use should be limited to research protocols."
The review supports denosumab only as an investigational option with safety caveats.
{ }

Source YAML

click to show 
name: Fibrous Dysplasia
category: Somatic mosaic
creation_date: "2026-05-09T17:35:00Z"
updated_date: "2026-05-09T17:35:00Z"
synonyms:
- Fibrous dysplasia of bone
- FD
- Fibrous dysplasia/McCune-Albright syndrome
- FD/MAS
description: >
  Fibrous dysplasia is a rare, non-inherited somatic mosaic skeletal disorder
  caused by post-zygotic activating GNAS variants. Normal bone and marrow are
  replaced by fibro-osseous tissue containing immature woven bone and fibrous
  stroma, producing structurally weak lesions that may be monostotic or
  polyostotic. Clinical burden depends on the mosaic distribution of involved
  tissues and includes bone pain, deformity, pathologic fracture, craniofacial
  or appendicular skeletal involvement, FGF23-mediated hypophosphatemia, and
  functional impairment. When fibrous dysplasia is accompanied by cafe-au-lait
  macules or hyperfunctioning endocrinopathies, the presentation falls within
  the McCune-Albright syndrome spectrum.
disease_term:
  preferred_term: fibrous dysplasia
  term:
    id: MONDO:0000845
    label: fibrous dysplasia
parents:
- Bone remodeling disease
- Acquired disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000845
      label: fibrous dysplasia
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:249
    mapping_justification: >
      Orphanet ORPHA:249 lists MONDO:0000845 as an exact cross-reference for
      fibrous dysplasia of bone.
external_assertions:
- name: Orphanet fibrous dysplasia of bone record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:249
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=249
  description: >
    Orphanet's ORPHA:249 structured record provides the disease definition,
    non-applicable inheritance, age-of-onset categories, epidemiology, exact
    MONDO mapping, and HPO phenotype rows used in this entry.
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0000845 | Exact"
    explanation: Orphanet maps ORPHA:249 exactly to the MONDO identifier used by this entry.
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:Q78.1 | Exact"
    explanation: Orphanet lists the ICD-10 exact mapping for fibrous dysplasia of bone.
definitions:
- name: Orphanet fibrous dysplasia definition
  definition_type: OTHER
  description: >
    A rare benign primary bone dysplasia in which normal bone and marrow are
    progressively replaced by fibrous connective tissue in one or multiple
    bones, causing pain, deformity, pathologic fracture, or cranial nerve
    deficits depending on lesion location.
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, benign, primary bone dysplasia characterized by progressive replacement of normal bone and marrow with fibrous connective tissue"
    explanation: Orphanet defines fibrous dysplasia by replacement of bone and marrow with fibrous connective tissue.
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibrous dysplasia is an uncommon mosaic disorder in which bone is replaced by"
    explanation: The clinical review supports fibrous dysplasia as a mosaic bone-replacement disorder.
inheritance:
- name: Not applicable
  description: >
    Fibrous dysplasia is not inherited vertically; it results from post-zygotic
    somatic mosaic GNAS activation.
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Not applicable"
    explanation: Orphanet marks inheritance as not applicable.
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FD/MAS arises sporadically, and there are no confirmed cases of vertical transmission."
    explanation: The clinical review supports non-inherited, sporadic occurrence.
prevalence:
- population: Worldwide
  percentage: Unknown
  notes: Orphanet records worldwide point prevalence as unknown.
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records unknown worldwide point prevalence.
progression:
- phase: Onset
  age_range: Childhood to adulthood
  notes: Orphanet lists childhood, adolescent, and adult onset categories.
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet lists childhood onset.
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adolescent"
    explanation: Orphanet lists adolescent onset.
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet lists adult onset.
- phase: Lesion accrual and chronic skeletal morbidity
  age_range: Childhood through adulthood
  notes: >
    Lesion burden and morbidity vary by mosaic distribution; many clinical
    lesions arise in childhood, while pain and complications can persist into
    adulthood.
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical bone lesions usually present prior to 5 years old, and the majority of lesions are present by age 15"
    explanation: The review summarizes typical timing of clinically apparent bone lesions.
genetic:
- name: Post-zygotic activating GNAS variants
  association: Causative somatic mosaic activating variant
  relationship_type: CAUSATIVE
  variant_origin: SOMATIC
  gene_term:
    preferred_term: GNAS
    term:
      id: hgnc:4392
      label: GNAS
  features: >
    Activating post-zygotic GNAS variants produce constitutive Gs-alpha/cAMP
    signaling in a mosaic distribution. Germline activating GNAS variants are
    presumed embryonic lethal, explaining the lack of vertical transmission.
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "post-zygotic activating mutations in GNAS, resulting in dysregulated GαS-protein"
    explanation: The review identifies post-zygotic activating GNAS mutations as the causal molecular lesion.
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FD/MAS is caused by somatic activating mutations in GNAS"
    explanation: The translational review independently supports somatic activating GNAS mutations.
pathophysiology:
- name: Somatic GNAS activation in mosaic skeletal progenitors
  description: >
    Post-zygotic activating GNAS variants cause constitutive Gs-alpha/cAMP
    signaling in a mosaic population of skeletal progenitors. Mosaicism is
    essential to viability and determines whether disease is monostotic,
    polyostotic, or syndromic with extraskeletal manifestations.
  gene:
    preferred_term: GNAS
    term:
      id: hgnc:4392
      label: GNAS
  cell_types:
  - preferred_term: skeletal stem/progenitor cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  biological_processes:
  - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    term:
      id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "post-zygotic GNAS mutations acquired early in embryogenesis lead to a somatic mosaic disease state"
    explanation: The review supports the proximal mosaic GNAS activation mechanism.
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "somatic mosaicism, which allows for close association of mutation-bearing cells with normal cells, is essential"
    explanation: The review explains why mosaicism is central to FD/MAS pathogenesis.
  downstream:
  - target: Impaired osteogenic differentiation and marrow replacement
    causal_link_type: DIRECT
    description: Constitutive Gs-alpha/cAMP signaling disrupts maturation of osteogenic progenitors.
    evidence:
    - reference: PMID:31037426
      reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "uncontrolled GαS-mediated signaling impairs the differentiation of osteogenic progenitors into mature osteoblasts and osteocytes."
      explanation: The review links Gs-alpha activation to impaired osteogenic differentiation.
- name: Impaired osteogenic differentiation and marrow replacement
  description: >
    GNAS-activated osteogenic progenitors fail to mature normally. Normal marrow
    and trabecular bone are replaced by fibro-osseous tissue containing fibrous
    stroma and immature woven bone, weakening the affected skeleton.
  cell_types:
  - preferred_term: osteoblast lineage cell
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bone and bone marrow are thus replaced by proliferating BMSCs, resulting in fibro-osseous tissue typically devoid of hematopoietic marrow"
    explanation: The review describes replacement of normal bone and marrow by fibro-osseous tissue.
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The immature osteoprogenitors proliferate and produce excess amounts of abnormal bone matrix, consisting predominantly of woven bone."
    explanation: The review explains the immature woven-bone matrix produced in lesions.
  downstream:
  - target: Fibrous dysplasia of the bones
    causal_link_type: DIRECT
    description: Fibro-osseous replacement is the tissue basis of FD bone lesions.
  - target: Abnormal bone structure
    causal_link_type: DIRECT
    description: Abnormal woven bone and fibrous stroma produce structurally abnormal bone.
  - target: Osteolysis
    causal_link_type: DIRECT
    description: Dysplastic lesions undergo active remodeling and bone resorption.
- name: Structurally weak fibro-osseous bone lesions
  description: >
    FD lesions weaken affected bone and produce pain, deformity, fractures,
    cortical thinning, bowing, coxa vara, gait disturbance, and axial or
    craniofacial skeletal morbidity according to lesion location.
  biological_processes:
  - preferred_term: bone remodeling
    term:
      id: GO:0046849
      label: bone remodeling
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The resulting skeleton is weakened and prone to fractures and deformity, resulting in pain and functional impairment."
    explanation: The review links fibro-osseous lesions to the major skeletal complications.
  downstream:
  - target: Bone pain
    causal_link_type: DIRECT
    description: Structural lesion burden and complications contribute to bone pain.
  - target: Pathologic fracture
    causal_link_type: DIRECT
    description: Weak dysplastic bone predisposes to fractures.
  - target: Bowing of the long bones
    causal_link_type: DIRECT
    description: Lesions in weight-bearing long bones can deform under mechanical stress.
  - target: Antalgic gait
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Pain, deformity, fracture, coxa vara, and leg-length discrepancy alter gait mechanics.
    description: Skeletal pain and deformity cause antalgic gait.
- name: FGF23-mediated phosphate wasting
  description: >
    Active dysplastic osteogenic cells can overproduce FGF23. FGF23 decreases
    renal phosphate reabsorption and active vitamin D, causing hypophosphatemia
    with rickets or osteomalacia in patients with high disease burden.
  cell_types:
  - preferred_term: osteogenic cell
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: phosphate ion homeostasis
    term:
      id: GO:0055062
      label: phosphate ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly 50% of patients with FD/MAS exhibit some degree of renal phosphate wasting"
    explanation: The review supports phosphate wasting as a common metabolic branch.
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibroblast growth factor-23 (FGF23) is overproduced by FD cells"
    explanation: The review identifies FD cells as the source of excess FGF23.
  downstream:
  - target: Hypophosphatemia
    causal_link_type: DIRECT
    description: FGF23-mediated renal phosphate wasting lowers circulating phosphate.
  - target: Rickets
    causal_link_type: DIRECT
    description: Childhood phosphate wasting can produce rickets.
  - target: Osteomalacia
    causal_link_type: DIRECT
    description: Phosphate wasting can produce osteomalacia in later presentations.
histopathology:
- name: Fibro-osseous lesion with woven bone and fibrous stroma
  description: >
    Classic lesions contain fibrous stroma around irregular curvilinear
    trabeculae of woven bone, often described as a Chinese writing pattern, with
    stellate osteoblasts, Sharpey fibers, and excess osteoid.
  diagnostic: true
  evidence:
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low to moderately cellular fibrous stroma surround irregular, curvilinear trabeculae of woven bone"
    explanation: The review describes the characteristic histologic architecture.
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thin, irregularly arranged, discontinuous trabeculae, consisting mostly of woven bone, surrounded by abundant fibrous stroma"
    explanation: The bench-to-bedside review describes classic appendicular and axial skeletal histology.
phenotypes:
- name: Fibrous dysplasia of the bones
  frequency: OBLIGATE
  diagnostic: true
  phenotype_term:
    preferred_term: Fibrous dysplasia of the bones
    term:
      id: HP:0010734
      label: Fibrous dysplasia of the bones
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010734 | Fibrous dysplasia of the bones | Obligate (100%)"
    explanation: Orphanet lists fibrous dysplasia of the bones as obligate.
- name: Abnormal skull morphology
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal skull morphology
    term:
      id: HP:0000929
      label: Abnormal skull morphology
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000929 | Abnormal skull morphology | Very frequent (99-80%)"
    explanation: Orphanet lists abnormal skull morphology as very frequent.
- name: Osteolysis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Osteolysis
    term:
      id: HP:0002797
      label: Osteolysis
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002797 | Osteolysis | Very frequent (99-80%)"
    explanation: Orphanet lists osteolysis as very frequent.
- name: Abnormal bone structure
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal bone structure
    term:
      id: HP:0003330
      label: Abnormal bone structure
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003330 | Abnormal bone structure | Very frequent (99-80%)"
    explanation: Orphanet lists abnormal bone structure as very frequent.
- name: Abnormal axial skeleton morphology
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal axial skeleton morphology
    term:
      id: HP:0009121
      label: Abnormal axial skeleton morphology
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009121 | Abnormal axial skeleton morphology | Very frequent (99-80%)"
    explanation: Orphanet lists abnormal axial skeleton morphology as very frequent.
- name: Abnormality of limbs
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormality of limbs
    term:
      id: HP:0040064
      label: Abnormality of limbs
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040064 | Abnormality of limbs | Very frequent (99-80%)"
    explanation: Orphanet lists limb abnormality as very frequent.
- name: Abnormality of the mandible
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the mandible
    term:
      id: HP:0000277
      label: Abnormal mandible morphology
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000277 | Abnormality of the mandible | Frequent (79-30%)"
    explanation: Orphanet lists mandibular abnormality as frequent.
- name: Abnormality of the maxilla
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the maxilla
    term:
      id: HP:0000326
      label: Abnormal maxilla morphology
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000326 | Abnormality of the maxilla | Frequent (79-30%)"
    explanation: Orphanet lists maxillary abnormality as frequent.
- name: Hypophosphatemia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002148 | Hypophosphatemia | Frequent (79-30%)"
    explanation: Orphanet lists hypophosphatemia as frequent.
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overt hypophosphatemia is uncommon and typically affects patients with greater overall disease burden"
    explanation: The review links hypophosphatemia to skeletal disease burden and FGF23-mediated phosphate wasting.
- name: Bone pain
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002653 | Bone pain | Frequent (79-30%)"
    explanation: Orphanet lists bone pain as frequent.
- name: Rickets
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002748 | Rickets | Frequent (79-30%)"
    explanation: Orphanet lists rickets as frequent.
- name: Thin bony cortex
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thin bony cortex
    term:
      id: HP:0002753
      label: Thin bony cortex
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002753 | Thin bony cortex | Frequent (79-30%)"
    explanation: Orphanet lists thin bony cortex as frequent.
- name: Pathologic fracture
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pathologic fracture
    term:
      id: HP:0002756
      label: Pathologic fracture
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002756 | Pathologic fracture | Frequent (79-30%)"
    explanation: Orphanet lists pathologic fracture as frequent.
- name: Abnormality of femur morphology
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of femur morphology
    term:
      id: HP:0002823
      label: Abnormal femur morphology
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002823 | Abnormality of femur morphology | Frequent (79-30%)"
    explanation: Orphanet lists femur morphology abnormality as frequent.
- name: Elevated circulating alkaline phosphatase concentration
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003155 | Elevated circulating alkaline phosphatase concentration | Frequent (79-30%)"
    explanation: Orphanet lists elevated alkaline phosphatase as frequent.
- name: Cortical irregularity
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cortical irregularity
    term:
      id: HP:0005731
      label: Cortical irregularity
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005731 | Cortical irregularity | Frequent (79-30%)"
    explanation: Orphanet lists cortical irregularity as frequent.
- name: Bowing of the long bones
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006487 | Bowing of the long bones | Frequent (79-30%)"
    explanation: Orphanet lists bowing of the long bones as frequent.
- name: Patchy reduction of bone mineral density
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Patchy reduction of bone mineral density
    term:
      id: HP:0010657
      label: Patchy reduction of bone mineral density
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010657 | Patchy reduction of bone mineral density | Frequent (79-30%)"
    explanation: Orphanet lists patchy reduction of bone mineral density as frequent.
- name: Abnormal zygomatic bone morphology
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal zygomatic bone morphology
    term:
      id: HP:0010668
      label: Abnormal zygomatic bone morphology
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010668 | Abnormal zygomatic bone morphology | Frequent (79-30%)"
    explanation: Orphanet lists zygomatic bone morphology abnormality as frequent.
- name: Abnormality of facial skeleton
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of facial skeleton
    term:
      id: HP:0011821
      label: Abnormal facial skeleton morphology
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011821 | Abnormality of facial skeleton | Frequent (79-30%)"
    explanation: Orphanet lists facial skeleton abnormality as frequent.
- name: Antalgic gait
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Antalgic gait
    term:
      id: HP:0031955
      label: Antalgic gait
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031955 | Antalgic gait | Frequent (79-30%)"
    explanation: Orphanet lists antalgic gait as frequent.
- name: Gait disturbance
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001288 | Gait disturbance | Occasional (29-5%)"
    explanation: Orphanet lists gait disturbance as occasional.
- name: Scoliosis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002650 | Scoliosis | Occasional (29-5%)"
    explanation: Orphanet lists scoliosis as occasional.
- name: Osteomalacia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Osteomalacia
    term:
      id: HP:0002749
      label: Osteomalacia
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002749 | Osteomalacia | Occasional (29-5%)"
    explanation: Orphanet lists osteomalacia as occasional.
- name: Coxa vara
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Coxa vara
    term:
      id: HP:0002812
      label: Coxa vara
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002812 | Coxa vara | Occasional (29-5%)"
    explanation: Orphanet lists coxa vara as occasional.
- name: Short stature
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Occasional (29-5%)"
    explanation: Orphanet lists short stature as occasional.
- name: Lower limb asymmetry
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Lower limb asymmetry
    term:
      id: HP:0100559
      label: Lower limb asymmetry
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100559 | Lower limb asymmetry | Occasional (29-5%)"
    explanation: Orphanet lists lower limb asymmetry as occasional.
- name: Ovarian cyst
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Ovarian cyst
    term:
      id: HP:0000138
      label: Ovarian cyst
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000138 | Ovarian cyst | Very rare (<4-1%)"
    explanation: Orphanet lists ovarian cyst as very rare.
- name: Hearing impairment
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000365 | Hearing impairment | Very rare (<4-1%)"
    explanation: Orphanet lists hearing impairment as very rare.
- name: Visual loss
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Visual loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000572 | Visual loss | Very rare (<4-1%)"
    explanation: Orphanet lists visual loss as very rare.
- name: Hyperthyroidism
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Hyperthyroidism
    term:
      id: HP:0000836
      label: Hyperthyroidism
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000836 | Hyperthyroidism | Very rare (<4-1%)"
    explanation: Orphanet lists hyperthyroidism as very rare.
- name: Elevated circulating growth hormone concentration
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Elevated circulating growth hormone concentration
    term:
      id: HP:0000845
      label: Elevated circulating growth hormone concentration
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000845 | Elevated circulating growth hormone concentration | Very rare (<4-1%)"
    explanation: Orphanet lists elevated growth hormone as very rare.
- name: Large cafe-au-lait macules with irregular margins
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Large cafe-au-lait macules with irregular margins
    term:
      id: HP:0005605
      label: Large cafe-au-lait macules with irregular margins
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005605 | Large cafe-au-lait macules with irregular margins | Very rare (<4-1%)"
    explanation: Orphanet lists large cafe-au-lait macules with irregular margins as very rare.
- name: Precocious puberty in females
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Precocious puberty in females
    term:
      id: HP:0010465
      label: Precocious puberty in females
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010465 | Precocious puberty in females | Very rare (<4-1%)"
    explanation: Orphanet lists precocious puberty in females as very rare.
- name: Thyroid carcinoma
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Thyroid carcinoma
    term:
      id: HP:0002890
      label: Thyroid carcinoma
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002890 | Thyroid carcinoma | Very rare (<4-1%)"
    explanation: Orphanet lists thyroid carcinoma as very rare.
- name: Neoplasm of the breast
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Neoplasm of the breast
    term:
      id: HP:0100013
      label: Neoplasm of the breast
  evidence:
  - reference: ORPHA:249
    reference_title: Fibrous dysplasia of bone (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100013 | Neoplasm of the breast | Very rare (<4-1%)"
    explanation: Orphanet lists breast neoplasm as very rare.
diagnosis:
- name: Radiographic and CT imaging
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >
    Typical lesions show homogeneous radiolucency with a ground-glass
    appearance, cortical thinning, endosteal scalloping, and sometimes a
    sclerotic rind sign. Craniofacial lesions are best assessed with CT or MRI.
  results: Imaging can establish the diagnosis when findings and clinical context are characteristic.
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prototypical FD lesion is homogeneous and radiolucent on radiographs and computed tomography scan, with a “ground glass” appearance"
    explanation: The review supports characteristic radiographic/CT diagnosis.
- name: Lesion biopsy and tissue GNAS testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >
    Isolated monostotic disease may require biopsy, ideally with genetic testing
    on affected tissue, because the causative variant is somatic mosaic and may
    be absent from blood.
  results: Detection of an activating GNAS variant in lesional tissue supports diagnosis.
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "isolated monostotic FD without accompanying extraskeletal features typically requires a biopsy, preferably with genetic testing on affected tissue, to establish the diagnosis."
    explanation: The review supports biopsy and tissue genetic testing in isolated monostotic cases.
treatments:
- name: Multidisciplinary supportive management
  description: >
    Management is supportive and individualized, with treatment of
    endocrinopathies, pain evaluation, orthoses, physical therapy, radiologic
    surveillance, and subspecialty care based on lesion distribution.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Structurally weak fibro-osseous bone lesions
    treatment_effect: MODULATES
    description: Supportive management reduces morbidity from lesions but does not alter the causal mosaic GNAS defect.
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management in FD is supportive, with the goal of optimizing function and minimizing morbidity."
    explanation: The review identifies supportive care as the core management strategy.
- name: Physical therapy and low-impact strengthening
  description: >
    Physical therapy and low-impact exercise help maintain muscle strength and
    mobility while avoiding prolonged immobilization.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Antalgic gait
    term:
      id: HP:0031955
      label: Antalgic gait
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical therapy is an important component of FD management."
    explanation: The review supports physical therapy as part of management.
- name: Oral phosphate and active vitamin D for hypophosphatemia
  description: >
    FGF23-mediated renal phosphate wasting in fibrous dysplasia/McCune-Albright
    syndrome is managed with oral phosphate supplementation plus active vitamin
    D, such as calcitriol or another activated vitamin D analogue.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: phosphate
      term:
        id: CHEBI:26020
        label: phosphate
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
  target_phenotypes:
  - preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  target_mechanisms:
  - target: FGF23-mediated phosphate wasting
    treatment_effect: BYPASSES
    description: >
      Oral phosphate and active vitamin D treat the downstream phosphate deficit
      without correcting mosaic GNAS activation or FGF23 excess.
    evidence:
    - reference: PMID:27492469
      reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Similar to other disorders of FGF23 excess, hypophosphatemia is managed with oral phosphorus and calcitriol."
      explanation: The review directly supports oral phosphorus and calcitriol for FGF23-excess hypophosphatemia.
  evidence:
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to other disorders of FGF23 excess, hypophosphatemia is managed with oral phosphorus and calcitriol."
    explanation: The review directly supports this treatment combination for hypophosphatemia in FD/MAS.
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypophosphatemia is managed similarly to other diseases of FGF23 excess with oral phosphorous and activated vitamin D analogues"
    explanation: The bench-to-bedside review independently supports oral phosphorus and active vitamin D analogues.
- name: Surgery for fracture, deformity, or functional compromise
  description: >
    Surgery can preserve function, reduce pain, stabilize fractures, correct
    deformity, or address craniofacial functional compromise; prophylactic optic
    nerve decompression is avoided without visual compromise.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_phenotypes:
  - preferred_term: Pathologic fracture
    term:
      id: HP:0002756
      label: Pathologic fracture
  - preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:31037426
    reference_title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment often consists of surgery to preserve function and reduce pain"
    explanation: The review supports surgery for selected functional and painful skeletal complications.
- name: Intravenous bisphosphonate therapy for moderate to severe bone pain
  description: >
    Intravenous bisphosphonates may be considered for persistent moderate to
    severe FD-related bone pain after evaluation for fracture, metabolic, or
    orthopedic drivers. Controlled alendronate data do not support disease
    modification or reliable pain improvement.
  treatment_term:
    preferred_term: bisphosphonate agent therapy
    term:
      id: MAXO:0000954
      label: bisphosphonate agent therapy
    therapeutic_agent:
    - preferred_term: bisphosphonate
      term:
        id: CHEBI:77383
        label: 1,1-bis(phosphonic acid)
  target_phenotypes:
  - preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intravenous bisphosphonates may be helpful for persistent, moderate to severe pain"
    explanation: The translational review supports cautious use of intravenous bisphosphonates for persistent moderate to severe pain.
  - reference: PMID:25033066
    reference_title: "A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no significant effect on serum osteocalcin, pain, or functional parameters."
    explanation: The placebo-controlled alendronate trial limits claims by showing no significant pain or function benefit.
- name: Denosumab only in research protocols
  description: >
    Denosumab targets RANKL-driven osteoclastogenesis and has shown promise in
    case reports, but safety concerns including rebound hypercalcemia mean use
    should be limited to research protocols.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: denosumab
      term:
        id: NCIT:C61313
        label: Denosumab
  target_mechanisms:
  - target: Impaired osteogenic differentiation and marrow replacement
    treatment_effect: MODULATES
    description: Denosumab targets downstream RANKL-mediated osteoclast activity, not the upstream GNAS mosaicism.
  evidence:
  - reference: PMID:27492469
    reference_title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "denosumab may hold promise as a potential treatment for FD, however given these safety concerns its use should be limited to research protocols."
    explanation: The review supports denosumab only as an investigational option with safety caveats.
references:
- reference: ORPHA:249
  title: Fibrous dysplasia of bone
  found_in:
  - Fibrous_Dysplasia-deep-research-fallback.md
- reference: PMID:18489744
  title: McCune-Albright syndrome.
  found_in:
  - Fibrous_Dysplasia-deep-research-fallback.md
- reference: PMID:25033066
  title: "A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone."
  found_in:
  - Fibrous_Dysplasia-deep-research-fallback.md
- reference: PMID:27492469
  title: "Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives."
  found_in:
  - Fibrous_Dysplasia-deep-research-fallback.md
- reference: PMID:31037426
  title: "Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review."
  found_in:
  - Fibrous_Dysplasia-deep-research-fallback.md
clinical_trials: []
datasets: []
notes: >-
  ORPHA:249 contains additional occasional and very rare phenotype rows not
  expanded in this initial entry. The included phenotype set covers all ORPHA
  obligate, very frequent, and frequent rows plus selected clinically important
  skeletal, sensory, endocrine, pigmentary, and malignancy-associated features.
📚

References & Deep Research

References

5
ORPHA:249
Fibrous dysplasia of bone
No top-level findings curated for this source.
PMID:18489744
McCune-Albright syndrome.
No top-level findings curated for this source.
PMID:25033066
A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone.
No top-level findings curated for this source.
PMID:27492469
Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives.
No top-level findings curated for this source.
PMID:31037426
Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review.
No top-level findings curated for this source.

Deep Research

1
Fibrous Dysplasia Research Fallback ▸

Fibrous Dysplasia Research Fallback

Deep-research provider attempts were bounded and did not produce usable output:

  • just research-disorder falcon Fibrous_Dysplasia was terminated by the 120-second wrapper after provider silence.
  • just research-disorder openai Fibrous_Dysplasia was terminated by the 60-second wrapper after provider silence.

Local curation proceeded from generated Orphanet and PubMed caches:

  • ORPHA:249: structured record for fibrous dysplasia of bone, including definition, non-applicable inheritance, onset categories, unknown worldwide prevalence, exact MONDO mapping, and phenotype frequency rows.
  • PMID:31037426: bench-to-bedside review covering GNAS mosaicism, bone/marrow replacement, FGF23 phosphate wasting, imaging diagnosis, supportive management, surgery, bisphosphonates, and denosumab research limitations.
  • PMID:27492469: clinical/translational review covering somatic GNAS activation, histology, clinical manifestations, management, bisphosphonate limitations, and denosumab safety concerns.
  • PMID:25033066: randomized placebo-controlled alendronate trial in polyostotic fibrous dysplasia.
  • PMID:18489744: McCune-Albright syndrome review, already present in the repository cache and used as background reference provenance.

Scope note: no provider-generated synthesis was used. YAML claims are limited to cached Orphanet/PubMed snippets available locally.