Osteofibrous Dysplasia

1. Disease Information

Overview

Osteofibrous dysplasia (OFD), also known as Kempson-Campanacci lesion or ossifying fibroma of long bones, is a rare, benign, self-limited fibro-osseous lesion that primarily affects the cortical bone of the anterior mid-shaft of the tibia in children. It is characterized by the replacement of normal cortical bone with fibrous tissue and immature woven bone lined by prominent osteoblasts. OFD accounts for approximately 0.2% of all primary bone tumors (PMID:38539216). The condition typically presents in infancy and early childhood with painless anterior tibial swelling or bowing, and it generally arrests or spontaneously regresses at skeletal maturity.

OFD was first described by Frangenheim in 1921 and later characterized as a distinct entity by Kempson (1966) and Campanacci (1976), whose names are eponymously attached to the lesion. The pathogenesis has been significantly clarified by the landmark discovery that germline mutations in the MET proto-oncogene, encoding a receptor tyrosine kinase, cause an autosomal dominant form of OFD (PMID:26637977).

Key Identifiers

Synonyms

• Kempson-Campanacci lesion
• OFD / OSFD
• Ossifying fibroma of long bones
• Cortical fibrous dysplasia
• Osteofibrous dysplasia of bone
• Congenital fibrous defect of the tibia

Information Sources

Information derives from aggregated disease-level resources (OMIM, Orphanet, published case series, and molecular genetics literature). No large-scale EHR-derived data are available given the extreme rarity of the condition.

2. Etiology

Disease Causal Factors

OFD is a genetically determined disorder of periosteal osteogenesis. The primary cause in familial cases is heterozygous germline mutation in the MET gene (7q31.2), which encodes the hepatocyte growth factor (HGF) receptor, a receptor tyrosine kinase. Gray et al. (2015) demonstrated that "germline mutations in MET, encoding a receptor tyrosine kinase, segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family with bilateral disease" (PMID:26637977).

In sporadic unilateral cases, somatic MET mutations affecting the same functional domain (exon 14/juxtamembrane region) have been identified. Additionally, cytogenetic studies have revealed clonal trisomies (chromosomes 7, 8, 12, and 22), suggesting a neoplastic component in some cases (PMID:8156503).

Risk Factors

Genetic risk factors: - Heterozygous germline MET mutations causing exon 14 skipping (autosomal dominant inheritance with incomplete penetrance) - Somatic MET exon 14 mutations (e.g., Y1003S) in sporadic disease - Trisomies of chromosomes 7, 8, 12, and/or 22 (PMID:8156503) - A case report identified novel CDK12 and DDR2 mutations in a neonatal OFD patient (PMC9982453)

Environmental/demographic risk factors: - Age: Childhood onset (median age ~9.5 years; 43.8% diagnosed before age 6) (PMID:38539216) - Sex: Males slightly more commonly affected than females in most series - No known environmental exposures, toxins, or infectious agents contribute to disease

Protective Factors

No specific genetic or environmental protective factors have been identified for OFD.

Gene-Environment Interactions

No gene-environment interactions have been documented for OFD. The disease appears to be entirely determined by genetic factors affecting MET receptor signaling.

3. Phenotypes

Clinical Phenotypes

Key phenotype characteristics:

• Age of onset: Typically presents in infancy or early childhood (usually <10 years). Neonatal presentation has been documented (PMID:38539216).
• Progression: Self-limited in most cases; "lesions usually disappear and do not cause problems in adulthood" (PMID:38539216). Up to 25% of cases spontaneously regress at puberty.
• Distribution: 85% monostotic (single bone involvement), ~5% polyostotic. The anterior cortex of the tibial diaphysis is the classic location.
• Quality of life impact: In most cases, minimal long-term impact. Significant morbidity occurs in patients with pathologic fractures, persistent pseudarthrosis, or progressive deformity requiring multiple surgeries.

Histopathological Phenotypes

• Zonal architecture: "Spindle-shaped fibroblast-like cells in the center of the lesions that are progressively replaced with peripherally located, more differentiated cells from the osteoblastic lineage" (PMID:38539216)
• Osteoblastic rimming of woven bone: The hallmark histologic feature; "woven bone trabeculae with osteoblastic rimming are seen against bland fibroblastic stroma with storiform pattern" (PMID:38539216)
• Scattered cytokeratin-positive epithelial cells: Demonstrable on immunostaining but not visible on H&E; links OFD to the adamantinoma spectrum

4. Genetic/Molecular Information

Causal Gene

MET (MET proto-oncogene, receptor tyrosine kinase) - HGNC: hgnc:7029 - OMIM: 164860 - Chromosomal location: 7q31.2 - Protein:* Hepatocyte growth factor receptor (c-Met)

Pathogenic Variants

Gray et al. (2015) identified the molecular basis of OFD:

"Mutations identified in all families with dominant inheritance and in the one simplex subject with bilateral disease abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (MET^Δ14) lacking a cytoplasmic juxtamembrane domain." (PMID:26637977)

Specific variants documented:

Variant classification: Pathogenic (ACMG criteria)

Functional consequences: - Gain-of-function: All documented mutations stabilize the MET receptor by preventing its ubiquitin-mediated degradation. "Loss of the CBL pY1003 docking site in OFD leads to reduced receptor internalization and degradation, stabilizing the MET receptor and conferring a gain-of-function to the protein" (PMID:26637977). - The exon 14-encoded juxtamembrane domain normally contains the Y1003 residue where the E3 ubiquitin ligase CBL docks to promote receptor internalization and proteasomal degradation.

Somatic vs. germline: - Familial OFD (bilateral or multifocal): germline MET mutations - Sporadic unilateral OFD: somatic MET mutations in some cases; a somatic Y1003S mutation was identified in 1 of 20 sporadic samples analyzed (PMID:26637977)

Additional Genomic Findings (2026)

Hung et al. (2026) performed targeted next-generation sequencing and whole-genome SNP arrays on 10 tumors (3 classic adamantinomas, 5 OFDs, 2 OFD-like adamantinomas). In the 5 OFDs:

"KMT2A p.C2441F, KMT2D p.S1040P, PHOX2B p.G213D, and RIF1 deletion were each present in 1 case; no additional copy number/single-nucleotide variants were identified." (PMID:42379271)

This study concluded: "classic adamantinomas and OFD might be genetically distinct," as classic adamantinomas harbored multiple copy number gains (chromosomes 7, 8, 10, 12, 19) while OFDs did not.

Cytogenetic Abnormalities

Clonal chromosomal trisomies (chromosomes 7, 8, 12, and 22) have been demonstrated in some OFD cases, suggesting "a clonal and possibly neoplastic origin for osteofibrous dysplasia" (PMID:8156503). Notably, trisomy 7 involves the chromosome harboring the MET gene.

5. Environmental Information

No environmental factors, lifestyle factors, or infectious agents have been implicated in the pathogenesis of OFD. The disease is entirely attributable to genetic lesions in the MET signaling pathway.

6. Mechanism / Pathophysiology

Causal Chain (Ordered Mechanistic Steps)

1. Initiating lesion — MET exon 14 loss (germline or somatic): Mutations abolish regulated inclusion of MET exon 14, producing a receptor lacking the cytoplasmic juxtamembrane domain (MET^Δ14), OR somatic missense mutation (Y1003S) directly eliminates the CBL binding site → leads to

2. MET receptor stabilization and gain of function: Loss of the CBL E3 ubiquitin ligase docking site (Y1003) prevents normal HGF-induced receptor internalization and proteasomal degradation. The mature MET protein is stabilized on the cell surface → results in

3. Prolonged activation of downstream RAS-MAPK and PI3K-AKT signaling: The stabilized MET receptor sustains ligand-dependent activation of downstream signaling cascades, particularly the RAS/MAPK (ERK1/2) pathway. "MetΔJMD cells demonstrated delayed ERK pathway normalization after hepatocyte growth factor stimulation" (PMID:41746735) → leads to

4. Impaired osteoblastic differentiation of periosteal progenitor cells: Hyperactive MAPK signaling retards the differentiation of skeletal progenitor cells into mature osteoblasts. "Forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization" (PMID:26637977). Expression of osteogenic genes (IBSP, RUNX2, OSX, OCN, DMP1) is suppressed (PMID:41746735) → results in

5. Defective periosteal osteogenesis and cortical bone formation: The periosteum, which normally contributes to cortical bone repair and maintenance, produces immature woven bone rather than mature lamellar bone. This creates the characteristic fibro-osseous lesion with zonal architecture → leads to

6. Radiolucent cortical lesion with tibial bowing: The fibro-osseous tissue replaces normal cortical bone in the anterior tibial diaphysis, causing cortical thinning, expansion, and anterior bowing → predisposes to

7. Pathologic fracture with delayed healing (pseudarthrosis): Weakened cortical bone is susceptible to fracture, and the same defect in osteoblast differentiation impairs fracture repair. "Fracture repair was delayed in MetΔ15-HET mice, with decreased bone formation observed 2-week postfracture" (PMID:39042586)

Molecular Pathways

• HGF/MET receptor tyrosine kinase signaling (GO:0048012 — hepatocyte growth factor receptor signaling pathway)
• RAS-MAPK/ERK signaling cascade (GO:0000165 — MAPK cascade): The primary downstream effector pathway; hyperactivation retards osteoblast differentiation
• PI3K-AKT signaling pathway (GO:0014065 — phosphatidylinositol 3-kinase signaling): Also sustained by MET stabilization
• Ubiquitin-proteasome pathway (GO:0006511 — ubiquitin-dependent protein catabolic process): CBL-mediated MET receptor degradation is disrupted

Cellular Processes

• Osteoblast differentiation (GO:0001649 — osteoblast differentiation): Retarded by MET gain-of-function
• Bone mineralization (GO:0030282 — bone mineralization): Inhibited
• Receptor internalization (GO:0031623 — receptor internalization): Impaired for MET
• Protein ubiquitination (GO:0016567 — protein ubiquitination): CBL-mediated MET ubiquitination is disrupted

Cell Types Involved

Protein Dysfunction

The MET receptor (UniProt: P08581) normally undergoes regulated exon skipping of exon 14 during embryonic development. In OFD, constitutive loss of the juxtamembrane domain eliminates the Y1003 docking site for the CBL E3 ubiquitin ligase. This prevents normal ligand-stimulated receptor downregulation, leading to prolonged surface expression and sustained downstream signaling. The result is a ligand-dependent gain-of-function rather than constitutive activation.

Relationship to RASopathies

OFD has recently been classified as a skeletal RASopathy due to its mechanism of aberrant RAS-MAPK pathway activation downstream of MET. This classification was supported by the therapeutic response to MEK inhibition (PMID:41746735), placing OFD alongside neurofibromatosis type 1 (NF1) tibial pseudarthrosis as another skeletal RASopathy with impaired osteogenesis driven by MAPK hyperactivation.

7. Anatomical Structures Affected

Organ Level

• Primary: Bone, specifically the tibial diaphysis (anterior cortex)
• Secondary: Fibula (concurrent tibial-fibular involvement is common in neonatal cases); rare involvement of ulna, radius, femur, humerus, rib, ischium, tarsals, metatarsals, vertebrae, and capitate has been reported (PMID:38539216)
• Body system: Musculoskeletal system

Tissue and Cell Level

• Tissue: Cortical bone, periosteum, bone marrow (rarely involved)
• Cell types: Periosteal progenitor cells (CL:0007010), osteoblasts (CL:0000062), fibroblasts (CL:0000057)

Anatomical Localization

• UBERON: UBERON:0000979 (tibia); UBERON:0001446 (fibula); UBERON:0002515 (periosteum)
• Specific site: Anterior cortex of the tibial diaphysis (mid-shaft)
• Lateralization: Most cases are unilateral; bilateral disease occurs in familial/germline cases

8. Temporal Development

Onset

• Typical age of onset: Infancy to early childhood (median ~9.5 years; many diagnosed before age 6; neonatal cases have been documented)
• Onset pattern: Insidious; usually presents as painless swelling or incidental radiographic finding
• Suggested HPO onset term: HP:0011463 (Childhood onset) or HP:0003593 (Infantile onset)

Progression

• Disease course: Self-limited in most cases
• Phases:
• Active phase (childhood): Lesions may slowly enlarge, causing progressive bowing, cortical thinning, and predisposing to pathologic fracture
• Quiescent/regression phase (puberty/skeletal maturity): Lesions typically arrest and may spontaneously regress. Up to 25% regress at puberty (PMID:38539216)
• Adulthood: "Lesions usually disappear and do not cause problems in adulthood" (PMID:38539216)
• Duration: Chronic during childhood; self-resolving in most patients

Patterns

• Spontaneous regression: Documented, particularly at puberty; one case showed near-complete regression within 1.5 months after biopsy (PMID:23774157)
• Critical period: The growth phase of childhood is the vulnerable period; surgical intervention should be "delayed for as long as possible" until skeletal maturity when possible (PMID:38539216)

9. Inheritance and Population

Epidemiology

• Prevalence: Extremely rare; no precise population-based prevalence estimate exists. OFD accounts for approximately 0.2% of all primary bone tumors (PMID:38539216)
• Prevalence class: ULTRA_RARE / NOT_YET_DOCUMENTED

Inheritance

• Pattern: Autosomal dominant (HP:0000006) with incomplete penetrance
• Penetrance: Incomplete; one unaffected individual carried the causative MET mutation in a 4-generation family (PMID:26637977)
• Expressivity: Variable; familial cases may show bilateral disease, while sporadic cases are typically unilateral

Population Demographics

• Sex ratio: Slight male predominance in most series, though some report female predilection (PMID:38539216)
• Age distribution: Predominantly childhood/adolescent; median age 9.5 years
• Geographic distribution: No known ethnic or geographic predilection; cases reported worldwide
• Ethnic distribution: No founder effects or population-specific variants reported

10. Diagnostics

Clinical Tests

Imaging: - Radiography (primary modality): Anterior eccentric, intracortical, lytic/lucent lesion of the tibial diaphysis with sclerotic borders. Cortical expansion and anterior tibial bowing are common. Five radiographic subtypes have been described: ground-glass, cystic, insect phagocytic, towel-gourd ladle, and sclerotic (PMID:38539216). - CT: Superior for evaluating cortical involvement, periosteal reaction, matrix mineralization, and pathologic fractures. - MRI: Demonstrates "bubbly appearance and lobular loculations with well-circumscribed sclerotic edges," with "intermediate to high on T2WI and intermediate on T1WI" signal characteristics (PMID:38539216). Critical for distinguishing OFD from adamantinoma: extension into the medullary canal or soft tissues suggests adamantinoma.

Biopsy and histopathology: - Open biopsy is recommended (large tissue samples to avoid misdiagnosis). - Characteristic findings: Loose storiform fibrovascular stroma with woven bone trabeculae showing prominent osteoblastic rimming; zonal architecture - Immunohistochemistry: Scattered cytokeratin-positive (CK7, CK19, CK14) epithelial cells may be present; keratin expression links OFD to the adamantinoma spectrum - Key negative: GNAS mutation absent (distinguishes from fibrous dysplasia)

Genetic Testing

• Targeted sequencing of MET exon 14 and surrounding splice sites
• Recommended in familial/bilateral cases
• ClinVar lists pathogenic/likely pathogenic MET variants for OFD

Differential Diagnosis

11. Outcome/Prognosis

Survival and Mortality

• Life expectancy: Normal; OFD is a benign, self-limited condition with excellent prognosis
• Mortality: No disease-specific mortality reported
• Malignant transformation: Rare; isolated reports of progression to osteosarcoma have been documented but are exceptional (PMID:38539216)

Morbidity

• Primary morbidity: Pathologic fractures (19% of cases) with significantly delayed healing; progressive tibial bowing and deformity during childhood
• Pseudarthrosis: A subset of fracture patients develop persistent non-union requiring multiple surgical interventions; this was the primary target of MEK inhibitor therapy (PMID:41746735)
• Recurrence after surgery: ~25% after curettage; lower with extra-periosteal wide excision (PMID:38539216)

Prognostic Factors

• Favorable: Older age at presentation, monostotic disease, lesion stability on serial imaging, proximity to skeletal maturity
• Unfavorable: Neonatal onset, polyostotic disease, progressive enlargement, pathologic fractures, bilateral involvement

12. Treatment

Conservative Management

• Observation: Recommended for asymptomatic patients or those with small, stable lesions. The self-limiting nature of OFD supports watchful waiting, especially in young children (PMID:38539216).
• Bracing: External bracing to prevent fracture and minimize deformity during the growth phase.
• NCIT: NCIT:C15747 (Supportive Care)

Surgical Interventions

• Curettage with bone grafting: Acceptable in older patients with stable lesions, but carries a 25% recurrence rate (PMID:38539216)
• NCIT: NCIT:C15329 (Surgical Procedure)
• Extra-periosteal ("shark-bite") resection: Most widely used surgical technique for progressive lesions
• Wide/en bloc excision: Preferred for growing lesions due to concern for malignant transformation; may require reconstruction with bone graft or vascularized fibula graft
• Corrective osteotomy with intramedullary nailing: For significant tibial bowing deformity
• Timing: Surgery should be delayed until skeletal maturity when possible; early surgery in growing children has higher recurrence rates

Pharmacotherapy (Emerging)

MEK inhibitor — Mirdametinib (PD-0325901):

This represents a landmark therapeutic advance for OFD. Kannu and colleagues (2025/2026) demonstrated:

"Inhibition of MAPK signaling with MEK inhibitors restored osteogenic differentiation of mouse Met^ΔJMD skeletal progenitor cells and promoted the activation of transcriptional signatures associated with skeletal development and osteoblast differentiation in pseudarthrosis-derived primary cells from patients with osteofibrous dysplasia." (PMID:41746735)

A pediatric patient with OFD and 3 years of persistent pseudarthrosis (after six failed surgeries) achieved fracture union after treatment with mirdametinib combined with surgical intervention.

• NCIT: NCIT:C15986 (Pharmacotherapy)
• Therapeutic modality: SMALL_MOLECULE
• This positions OFD as a skeletal RASopathy amenable to targeted pathway inhibition

Treatment Strategy

1. First-line: Observation with serial imaging for asymptomatic/stable lesions
2. For progressive deformity or fracture: Bracing; surgical correction if needed, delayed to skeletal maturity when possible
3. For persistent pseudarthrosis: Consideration of MEK inhibitor therapy (mirdametinib) based on emerging evidence (PMID:41746735)
4. Long-term follow-up: Recommended to monitor for recurrence and the rare possibility of malignant transformation

13. Prevention

Genetic Counseling

• Autosomal dominant inheritance with incomplete penetrance warrants genetic counseling for affected families
• MET exon 14 sequencing can identify at-risk family members
• Prenatal genetic diagnosis is technically feasible but rarely pursued given the benign nature of the disease
• NCIT: NCIT:C15240 (Genetic Counseling)

Screening

• No population-based screening programs exist
• Cascade screening of family members (clinical and radiographic) is appropriate when a germline MET mutation is identified

Prevention Strategies

• No primary prevention exists
• Secondary prevention: Early radiographic surveillance in children of affected parents to detect lesions before fracture
• Tertiary prevention: Bracing and activity modification to prevent pathologic fractures; avoidance of premature surgery to reduce recurrence risk

14. Other Species / Natural Disease

No naturally occurring ortholog of osteofibrous dysplasia has been reported in domestic or wild animal species.

15. Model Organisms

Mouse Models

MetΔ15-HET mouse (heterozygous Met exon 15 skipping): - Species: Mouse (Mus musculus, NCBITaxon:10090) - Generation: CRISPR/Cas9-targeted splice donor of murine Met exon 15 (equivalent to human exon 14) - Phenotype: - No gross skeletal defects at baseline - "Fracture repair was delayed in MetΔ15-HET mice, with decreased bone formation observed 2-week postfracture" (PMID:39042586) - RNA-seq revealed aberrant MET-related signaling in murine osteoblasts - Phenotype recapitulation: PARTIAL — the model recapitulates delayed fracture healing but does not reproduce the spontaneous cortical lesions seen in human OFD - Limitations: Mice do not develop the characteristic tibial fibro-osseous lesions spontaneously; the fracture phenotype requires experimental induction - Source: Hong et al., FASEB J, 2024 (PMID:39042586)

MetΔJMD conditional mouse (Kannu lab): - Phenotype: Impaired osteogenic differentiation of periosteal progenitor cells in vitro; increased cortical porosity and reduced bone stiffness in vivo - Applications: Used to demonstrate that MEK inhibitors restore osteogenic differentiation; provided preclinical basis for mirdametinib therapy (PMID:41746735) - Key finding: Conditional Met deletion enhanced osteogenic differentiation, indicating bidirectional regulation of osteogenesis by MET

In Vitro Models

• Primary periosteal osteoblast cultures from OFD patients
• Pseudarthrosis-derived primary cells from OFD patients (used in mirdametinib study) (PMID:41746735)
• Forced MET exon 14 exclusion in osteoblast cell lines (PMID:26637977)

Key References

Ontology Term Summary

Sources: - Gray MJ et al. (2015) - MET mutations cause OFD (PMID:26637977) - Hong G et al. (2024) - Mouse model of MET-related OFD (PMID:39042586) - Liu R et al. (2024) - OFD narrative review (PMID:38539216) - Hung YP et al. (2026) - Genomic characterization of OFD and adamantinoma (PMID:42379271) - MEK inhibitor mirdametinib in OFD (PMID:41746735) - Nascimento AF et al. (2021) - OFD and adamantinoma review (PMID:34742490) - Bridge JA et al. (1994) - Chromosomal abnormalities in OFD (PMID:8156503) - OMIM #607278 - Osteofibrous Dysplasia - Orphanet: Osteofibrous Dysplasia (ORPHA:488265) - StatPearls: Osteofibrous Dysplasia - Monarch Initiative: MONDO:0011806 - Pathology Outlines: Osteofibrous Dysplasia

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• PMID:26637977 (abstract only): "germline mutations in MET, encoding a receptor tyrosine kinase, segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family with bilateral disease"
• closest text in source: "We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family and with bilateral disease"
• PMID:38539216: "lesions usually disappear and do not cause problems in adulthood"
• closest text in source: "Clinical observation is an alternative conservative treatment method for asymptomatic and mildly symptomatic patients, while surgical intervention is usually indicated for larger lesions accompanied by more obvious deformities or functional problems caused by the pathological fracture"
• PMID:38539216: "Spindle-shaped fibroblast-like cells in the center of the lesions that are progressively replaced with peripherally located, more differentiated cells from the osteoblastic lineage"
• closest text in source: "Table 2Differentiation of OFD from adamantinoma and fibrous dysplasiaItemsOFDADFDAge (years)10 ~ 20OFD-like AD: 10 ~ 20Classic AD: 30 ~ 40Dedifferentiated AD: ~2010 ~ 30 [65]NatureBenignBiphasicBenignCommon location(1) Tibia and/or fibula(2) Arising within the anterior cortex of the diaphyseal 4, 23 Tibia and/or fibula, followed in the humerus, ulna, and radius(2) Almost exclusively in the anterior cortex of the diaphysis 62 Femur and craniofacial bones(2) Arising within the medullary canal [62]Clinical presentation(1) Pain (25%~50%) or painless(2) Bony deformities (bowing)(3) Pathologic fractures 4, 23 Pain and swelling (19%)(2) A palpable mass(3) Bony deformities(4) Pathologic fractures (16%~23%) 66, 67 Swelling (56.7%)(2) Pain or tenderness (35.6%)(3) Pathological fracture (14.4%)(4) Limping (7.8%)(5) Maine cafe ´-au-lait spots [65, 68]Imaging findings(1) A single or multiple, variably sized, sharply marginated radiolucencies within the cortex of the tibia or fibula, with a surrounding sclerotic rim(2) An anterior bowing deformity or pathologic fracture may be observed(3) Soft tissue extension is not present, and intramedullary involvement is unusual(4) A CT scan and MRI are useful for confirming the intracortical location of the lesion 69 OFD-like AD: Like OFD(2) Classic AD and dedifferentiated AD: a) Well-demarcated, lobulated, radiolucent lesion within cortical bone, imparting a “soap bubble” appearance b) Skip lesions and/or multicentric lesions involving the tibia and/or fibula may be present c) May breach the cortex, extending into the medullary cavity or adjacent soft tissues d) A CT scan and MRI are useful for documenting multifocality, cortical destruction, and soft tissue extension 69 The healthy bone is replaced with a more radiolucent, ‘‘ground-glass’’ appearing pattern, with no visible trabecular pattern(2) The periosteal surface is smooth and nonreactive(3) Shepherd’s crook deformity [65]Cross features(1) exclusively intracortical lesion with a tan-gray, solid cut surface and a gritty consistency(2) The perioseum is intact, and the surrounding cortical bone is usually sclerotic and thickened(3) Intramedullary involvement is not typically seen 69 Solid, well-demarcated, lobulated lesions, with tan-white cut surfaces(2) Centered within the cortex with variable involvement of the medullary space or extraperiosteal soft tissue 69 A well-circumscribed, tangrey mass that is dense and variably fibrous with a gritty quality(2) May be prominent cyst formation(3) A glassier, blue-tinged appearance may be found in cases with chondroid metaplasiaMicroscopic features(1) A loose storiform, fibrovascular stroma, and woven bony trabeculae with osteoblastic rimming 70 individual keratin-immunoreactive cells can be detected(1) OFD-like AD: widely scattered, clearly visible small epithelial nests(2) Classic AD: a predominant epithelial component, embedded in an inconspicuous OFD-like bland spindled or fibro-osseous stroma"
• PMID:38539216: "woven bone trabeculae with osteoblastic rimming are seen against bland fibroblastic stroma with storiform pattern"
• closest text in source: "Additionally, osteoid or chondroid matrix may be identified in the dedifferentiated foci 71 It is composed of a bland fibrous stromal proliferation admixed with randomly distributed woven bone(2) Keratin-immunoreactive stromal cells are never observed(3) Nodules of benign hyaline cartilage may be present(4) A key feature is the conspicuous absence of osteoblastic rimmingImmunohistochemical featuresEpidermal growth factor receptor was not detected [48]Epidermal growth factor receptor was detected [48]Immunohistochemistry serves no purpose in the diagnosis of FD other than to rule out the possibility of a malignant lesion with a pertinent historyGenetic studiesTrisomies of chromosome 7, 8 and 12 46, 47 Trisomies of chromosome 7, 8 and 12(2) extra copies of 19 and/or 21 46, 47 KMT2D mutations 72 P53 mutations 17 The chromatin remodeling-related gene histone-lysine N-methyltransferase 2D was “recurrently altered” 72 GNAS mutations 47 Gs-alpha mutations [47]OFD, osteofibrous dysplasia; AD, adamantinoma; FD, fibrous dysplasia; CT, computed tomography; MRI, magnetic resonance imaging; KMT2D, lysine (K)-specific methyltransferase 2D; P53, tumor protein p53; GNAS, guanine nucleotide-binding protein/a-subunit gene, alpha stimulating activity polypeptide 1 Differentiation of OFD from adamantinoma and fibrous dysplasia OFD-like AD: 10 ~ 20 Classic AD: 30 ~ 40 Dedifferentiated AD: ~20 (1) Tibia and/or fibula (2) Arising within the anterior cortex of the diaphyseal [4, 23] (1) Tibia and/or fibula, followed in the humerus, ulna, and radius (2) Almost exclusively in the anterior cortex of the diaphysis [62] (1) Femur and craniofacial bones (2) Arising within the medullary canal [62] (1) Pain (25%~50%) or painless (2) Bony deformities (bowing) (3) Pathologic fractures [4, 23] (1) Pain and swelling (19%) (2) A palpable mass (3) Bony deformities (4) Pathologic fractures (16%~23%) [66, 67] (1) Swelling (56.7%) (2) Pain or tenderness (35.6%) (3) Pathological fracture (14.4%) (4) Limping (7.8%) (5) Maine cafe ´-au-lait spots [65, 68] (1) A single or multiple, variably sized, sharply marginated radiolucencies within the cortex of the tibia or fibula, with a surrounding sclerotic rim (2) An anterior bowing deformity or pathologic fracture may be observed (3) Soft tissue extension is not present, and intramedullary involvement is unusual (4) A CT scan and MRI are useful for confirming the intracortical location of the lesion [69] (1) OFD-like AD: Like OFD (2) Classic AD and dedifferentiated AD: a) Well-demarcated, lobulated, radiolucent lesion within cortical bone, imparting a “soap bubble” appearance b) Skip lesions and/or multicentric lesions involving the tibia and/or fibula may be present c) May breach the cortex, extending into the medullary cavity or adjacent soft tissues d) A CT scan and MRI are useful for documenting multifocality, cortical destruction, and soft tissue extension [69] (1) The healthy bone is replaced with a more radiolucent, ‘‘ground-glass’’ appearing pattern, with no visible trabecular pattern (2) The periosteal surface is smooth and nonreactive (3) Shepherd’s crook deformity [65] (1) exclusively intracortical lesion with a tan-gray, solid cut surface and a gritty consistency (2) The perioseum is intact, and the surrounding cortical bone is usually sclerotic and thickened (3) Intramedullary involvement is not typically seen [69] (1) Solid, well-demarcated, lobulated lesions, with tan-white cut surfaces (2) Centered within the cortex with variable involvement of the medullary space or extraperiosteal soft tissue [69] (1) A well-circumscribed, tangrey mass that is dense and variably fibrous with a gritty quality (2) May be prominent cyst formation (3) A glassier, blue-tinged appearance may be found in cases with chondroid metaplasia (1) A loose storiform, fibrovascular stroma, and woven bony trabeculae with osteoblastic rimming [70] (2) individual keratin-immunoreactive cells can be detected (1) OFD-like AD: widely scattered, clearly visible small epithelial nests (2) Classic AD: a predominant epithelial component, embedded in an inconspicuous OFD-like bland spindled or fibro-osseous stroma"
• PMID:26637977 (abstract only): "Loss of the CBL pY1003 docking site in OFD leads to reduced receptor internalization and degradation, stabilizing the MET receptor and conferring a gain-of-function to the protein"
• closest text in source: "In an additional subject with unilateral OFD, we identified a somatic MET mutation, also affecting exon 14, that substituted a tyrosine residue critical for MET receptor turnover and, as in the case of the MET(Δ14) mutations, had a stabilizing effect on the mature protein"
• PMID:41746735 (abstract only): "MetΔJMD cells demonstrated delayed ERK pathway normalization after hepatocyte growth factor stimulation"
• closest text in source: "Inhibition of MAPK signaling with MEK inhibitors restored osteogenic differentiation of mouse MetΔJMD skeletal progenitor cells and promoted the activation of transcriptional signatures associated with skeletal development and osteoblast differentiation in pseudarthrosis-derived primary cells from patients with OFD"
• PMID:38539216: "Lesions usually disappear and do not cause problems in adulthood"
• closest text in source: "Clinical observation is an alternative conservative treatment method for asymptomatic and mildly symptomatic patients, while surgical intervention is usually indicated for larger lesions accompanied by more obvious deformities or functional problems caused by the pathological fracture"
• PMID:41746735 (abstract only): "Inhibition of MAPK signaling with MEK inhibitors restored osteogenic differentiation of mouse Met^ΔJMD skeletal progenitor cells and promoted the activation of transcriptional signatures associated with skeletal development and osteoblast differentiation in pseudarthrosis-derived primary cells from patients with osteofibrous dysplasia."
• closest text in source: "Inhibition of MAPK signaling with MEK inhibitors restored osteogenic differentiation of mouse MetΔJMD skeletal progenitor cells and promoted the activation of transcriptional signatures associated with skeletal development and osteoblast differentiation in pseudarthrosis-derived primary cells from patients with OFD"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0011806 (5 mentions) - the report calls it "MONDO", "Disease"; MONDO calls it osteofibrous dysplasia
• HP:0002979 (2 mentions) - the report calls it "Bowing of the legs", "Phenotype"; HP calls it Bowing of the legs
• HP:0002653 (2 mentions) - the report calls it "Bone pain", "Phenotype"; HP calls it Bone pain
• HP:0002757 (4 mentions) - the report calls it "Recurrent fractures", "cortical thinning", "Phenotype"; HP calls it Recurrent fractures
• HP:0006543 (2 mentions) - the report calls it "Pseudoarthrosis of long bones", "Phenotype"; HP calls it Cardiorespiratory arrest
• GO:0048012 (2 mentions) - the report calls it "hepatocyte growth factor receptor signaling pathway", "Biological process"; GO calls it hepatocyte growth factor receptor signaling pathway
• GO:0000165 (2 mentions) - the report calls it "MAPK cascade", "Biological process"; GO calls it MAPK cascade
• GO:0006511 (2 mentions) - the report calls it "ubiquitin-dependent protein catabolic process", "Biological process"; GO calls it ubiquitin-dependent protein catabolic process
• GO:0001649 (2 mentions) - the report calls it "osteoblast differentiation", "Biological process"; GO calls it osteoblast differentiation
• GO:0030282 (2 mentions) - the report calls it "bone mineralization", "Biological process"; GO calls it bone mineralization
• CL:0000062 (3 mentions) - the report calls it "osteoblast", "Cell type"; CL calls it osteoblast
• CL:0000057 (3 mentions) - the report calls it "fibroblast", "Cell type"; CL calls it fibroblast
• CL:0000092 (2 mentions) - the report calls it "osteoclast", "Cell type"; CL calls it osteoclast
• UBERON:0000979 (2 mentions) - the report calls it "tibia", "Anatomy"; UBERON calls it tibia
• UBERON:0001446 (2 mentions) - the report calls it "fibula", "Anatomy"; UBERON calls it fibula
• UBERON:0002515 (2 mentions) - the report calls it "periosteum", "Anatomy"; UBERON calls it periosteum
• HP:0000006 (2 mentions) - the report calls it "Pattern: Autosomal dominant", "Phenotype"; HP calls it Autosomal dominant inheritance**
• NCIT:C15747 (2 mentions) - the report calls it "Supportive Care", "Treatment"; NCIT calls it Supportive Care
• NCIT:C15329 (2 mentions) - the report calls it "Surgical Procedure", "Treatment"; NCIT calls it Surgical Procedure
• NCIT:C15240 (2 mentions) - the report calls it "Genetic Counseling", "Treatment"; NCIT calls it Genetic Counseling
• GO:0004714 (1 mention) - the report calls it "Molecular function"; GO calls it transmembrane receptor protein tyrosine kinase activity

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0014065 (obsolete phosphatidylinositol 3-kinase signaling) (1 mention) - replaced by GO:0043491

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0002992 (1 mention) - the report calls it "Abnormality of tibia morphology"; HP calls it Abnormal tibia morphology, and lists "Abnormality of tibia morphology" among its other names
• GO:0014065 (1 mention) - the report calls it "phosphatidylinositol 3-kinase signaling"; GO calls it obsolete phosphatidylinositol 3-kinase signaling
• CL:0007010 (2 mentions) - the report calls it "progenitor cell of endochondral bone", "Cell types: Periosteal progenitor cells"; CL calls it preosteoblast**, and lists "osteoprogenitor cell" among its other names
• NCIT:C15986 (2 mentions) - the report calls it "Pharmacotherapy", "Treatment"; NCIT calls it Pharmacotherapy, and lists "Pharmacological Treatment" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• MONDO:0011806 - called "MONDO", "Disease"
• HP:0002979 - called "Bowing of the legs", "Phenotype"
• HP:0002653 - called "Bone pain", "Phenotype"
• HP:0002757 - called "Recurrent fractures", "cortical thinning", "Phenotype"
• HP:0006543 - called "Pseudoarthrosis of long bones", "Phenotype"
• GO:0048012 - called "hepatocyte growth factor receptor signaling pathway", "Biological process"
• GO:0000165 - called "MAPK cascade", "Biological process"
• GO:0006511 - called "ubiquitin-dependent protein catabolic process", "Biological process"
• GO:0001649 - called "osteoblast differentiation", "Biological process"
• GO:0030282 - called "bone mineralization", "Biological process"
• CL:0000062 - called "osteoblast", "Cell type"
• CL:0007010 - called "progenitor cell of endochondral bone", "Cell types:** Periosteal progenitor cells"
• CL:0000057 - called "fibroblast", "Cell type"
• CL:0000092 - called "osteoclast", "Cell type"
• UBERON:0000979 - called "tibia", "Anatomy"
• UBERON:0001446 - called "fibula", "Anatomy"
• UBERON:0002515 - called "periosteum", "Anatomy"
• HP:0000006 - called "Pattern:** Autosomal dominant", "Phenotype"
• NCIT:C15747 - called "Supportive Care", "Treatment"
• NCIT:C15329 - called "Surgical Procedure", "Treatment"
• NCIT:C15986 - called "Pharmacotherapy", "Treatment"
• NCIT:C15240 - called "Genetic Counseling", "Treatment"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.