Osteofibrous dysplasia is a benign, usually self-limited fibro-osseous lesion of the cortical bone immediately beneath the periosteum of the tibia and fibula, presenting in infancy or childhood with swelling or painless bowing. It is a disorder of periosteal osteogenesis rather than a tumour of it. Germline MET mutations that abolish splice inclusion of exon 14 yield a receptor lacking the cytoplasmic juxtamembrane domain; because that domain carries the signal for ubiquitin-mediated degradation, the mature receptor is stabilised and acquires a ligand-dependent gain of function. The resulting MAPK signalling inhibits osteogenic differentiation of skeletal progenitor cells and impairs cortical bone development, which is why the lesion sits in cortex under periosteum and why its defining complication is a fracture that will not heal. Inheritance is autosomal dominant in the familial form, and somatic exon 14 mutations occur in unilateral disease. Management has historically been conservative, since surgery carries a high recurrence rate and lesions can regress spontaneously; the recognition that OFD is a skeletal RASopathy has produced a targeted treatment, with a MEK inhibitor achieving union in a patient with three years of pseudarthrosis.
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Conditions with similar clinical presentations that must be differentiated from Osteofibrous Dysplasia:
name: Osteofibrous Dysplasia
creation_date: "2026-10-13T00:00:00Z"
category: Mendelian
synonyms:
- Kempson-Campanacci lesion
- OFD
- ossifying fibroma of long bones
- cortical fibrous dysplasia
- osteofibrous dysplasia of bone
disease_term:
preferred_term: osteofibrous dysplasia
term:
id: MONDO:0011806
label: osteofibrous dysplasia
parents:
- skeletal dysplasia
notes: >-
Scope, and why this is a Disease rather than a subtype of adamantinoma. OFD,
OFD-like adamantinoma and classic adamantinoma have long been treated as one
controversial spectrum, and Adamantinoma.yaml (MONDO:0002422) already carries OFD
in its differential_diagnoses block with an open KNOWLEDGE_GAP discussion
(adam_ofd_progression_sequence) asking whether they lie on a single histogenetic
continuum. Three things support curating OFD separately. MONDO gives it a leaf
term whose only parent is skeletal dysplasia, not a neoplasm branch. Its cause is
known and specific - germline MET mutations abolishing splice inclusion of exon 14
- where classic adamantinoma has no established driver. And a 2026 genomic study
of all three entities concludes that classic adamantinoma and OFD might be
genetically distinct, with the adamantinomas carrying arm-level copy-number gains
that the OFDs lacked. That evidence is curated below and bears directly on the
question the adamantinoma entry leaves open; it is an argument, not a settlement,
and the discussion there should stay open.
OFD is a RASopathy, and that is newly established rather than long known. The
METΔJMD receptor signals through MAPK, MEK inhibition restores osteogenic
differentiation in both mouse and patient-derived cells, and a treated patient
achieved fracture union. kb/groupings/RASopathies.yaml exists and OFD is a
candidate member on this evidence.
Treated as a developmental disorder rather than a neoplasm, and that is a
curation decision rather than a finding. MONDO's definition calls it a benign,
usually self-limited fibro-osseous lesion, the familial lesion is germline, and
the entry is categorised Mendelian, so the cancer granularity ladder in design
decisions section 3a does not apply. The decision is contestable and the contrary
evidence is curated rather than omitted: the same MONDO definition ends by noting
that progression to adamantinoma has been reported in some cases, and clonal
chromosomal abnormalities have been argued to indicate a clonal and possibly
neoplastic origin. Both are recorded in the discussions entry above, the second
as a REFUTE against this framing.
discussions:
- discussion_id: ofd_adamantinoma_progression_sequence
prompt: >-
Does osteofibrous dysplasia progress through an OFD-like adamantinoma
intermediate to classic adamantinoma along a single histogenetic continuum, or
are these diagnostically overlapping but biologically separate entities?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Impaired Osteogenic Differentiation of Skeletal Progenitors
- histopathology#Scattered keratin-immunoreactive cells
- differential_diagnoses#Classic adamantinoma
rationale: >-
The same question is recorded from the other side as
adam_ofd_progression_sequence in Adamantinoma.yaml, and it is restated here so
the gap is visible from both entries rather than only from the neoplasm.
Evidence points both ways, and this entry's scoping decision rests on the
weaker-committing reading, so the counter-position is stated rather than
omitted. For separation: a genomic study of all three entities found arm-level
copy-number gains in the classic adamantinomas and none in the OFDs, and
concluded they might be genetically distinct; and a 19-case series saw no
progression over a median 51 months. For a continuum: OFD contains scattered
keratin-immunoreactive cells, pan-keratin is positive in roughly 95% of both
lesions, clonal chromosomal abnormalities including trisomies 7, 8, 12 and 22
have been reported in OFD and argued to indicate a clonal and possibly
neoplastic origin, with trisomy 7 and 12 also reported in a clonally aberrant
adamantinoma; and MONDO's own definition of this term ends by noting that
progression to adamantinoma has been reported in some cases.
evidence:
- reference: PMID:8156503
reference_title: Clonal chromosomal abnormalities in osteofibrous dysplasia. Implications for histopathogenesis and its relationship with adamantinoma.
supports: REFUTE
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "these findings demonstrate a clonal and possibly neoplastic origin for osteofibrous dysplasia of long bone"
explanation: >-
Recorded as REFUTE against this entry's framing of OFD as a developmental
disorder rather than a neoplasm. Graded INDIRECT because clonality is
evidence from which neoplastic origin is inferred, and the authors say
"possibly". This is the strongest cited argument against the scoping
decision and is curated rather than left out.
- reference: PMID:42379271
reference_title: Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In conclusion, classic adamantinomas and OFD might be genetically distinct."
explanation: >-
The argument for separation, in the authors' own hedged wording.
description: >-
Osteofibrous dysplasia is a benign, usually self-limited fibro-osseous lesion of
the cortical bone immediately beneath the periosteum of the tibia and fibula,
presenting in infancy or childhood with swelling or painless bowing. It is a
disorder of periosteal osteogenesis rather than a tumour of it. Germline MET
mutations that abolish splice inclusion of exon 14 yield a receptor lacking the
cytoplasmic juxtamembrane domain; because that domain carries the signal for
ubiquitin-mediated degradation, the mature receptor is stabilised and acquires a
ligand-dependent gain of function. The resulting MAPK signalling inhibits
osteogenic differentiation of skeletal progenitor cells and impairs cortical bone
development, which is why the lesion sits in cortex under periosteum and why its
defining complication is a fracture that will not heal. Inheritance is autosomal
dominant in the familial form, and somatic exon 14 mutations occur in unilateral
disease. Management has historically been conservative, since surgery carries a
high recurrence rate and lesions can regress spontaneously; the recognition that
OFD is a skeletal RASopathy has produced a targeted treatment, with a
MEK inhibitor achieving union in a patient with three years of pseudarthrosis.
pathophysiology:
- name: MET Exon 14 Splice Exclusion
biological_scale: MOLECULAR
description: >-
The causal lesion. Mutations abolish splice inclusion of MET exon 14, so the
translated receptor lacks the cytoplasmic juxtamembrane domain. Exclusion of
this exon occurs during normal embryonic development, so the mutation does not
create a novel protein but makes a developmentally transient isoform permanent.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: GAIN_OF_FUNCTION
genes:
- preferred_term: MET
term:
id: hgnc:7029
label: MET
biological_processes:
- preferred_term: regulated inclusion of MET exon 14, abolished by the mutation
modifier: LOSS_OF_FUNCTION
term:
id: GO:0000381
label: regulation of alternative mRNA splicing, via spliceosome
downstream:
- target: Stabilised METdeltaJMD Receptor with Ligand-Dependent Gain of Function
causal_link_type: DIRECT
description: >-
The juxtamembrane domain carries the degradation signal, so losing it
stabilises the mature receptor.
evidence:
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: >-
The causal lesion and its immediate protein consequence, in the study that
identified the gene.
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: >-
Establishes the gene, the germline origin and the autosomal-dominant
segregation that this node's genetic_context records.
- name: Stabilised METdeltaJMD Receptor with Ligand-Dependent Gain of Function
biological_scale: MOLECULAR
description: >-
The juxtamembrane domain carries the signal for ubiquitin-mediated degradation.
Without it the receptor escapes turnover, accumulates, and acquires a
ligand-dependent gain of function. A somatic exon 14 mutation in unilateral
disease substitutes a tyrosine residue critical for receptor turnover and has
the same stabilising effect, which is what ties the two variant origins to one
mechanism.
genes:
- preferred_term: MET
term:
id: hgnc:7029
label: MET
molecular_functions:
- preferred_term: MET receptor tyrosine kinase activity
modifier: GAIN_OF_FUNCTION
term:
id: GO:0004714
label: transmembrane receptor protein tyrosine kinase activity
downstream:
- target: MAPK Pathway Activation
causal_link_type: DIRECT
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MET gene mutations reducing ubiquitin-mediated protein degradation via loss of the juxtamembrane domain (METΔJMD) were previously identified in patients with OFD, resulting in ligand-dependent gain of function."
explanation: >-
States the mechanism this node asserts: loss of the domain reduces
ubiquitin-mediated degradation, and the consequence is a ligand-dependent
gain of function rather than constitutive activity.
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: >-
The somatic route to the same stabilised receptor, which is why unilateral
disease is included in this entry rather than treated separately.
- name: MAPK Pathway Activation
biological_scale: CELLULAR
description: >-
Signalling downstream of the stabilised receptor runs through MAPK. This is the
step that makes OFD a skeletal RASopathy, and it is the step MEK inhibition
acts on.
biological_processes:
- preferred_term: MAPK signalling downstream of METdeltaJMD
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
downstream:
- target: Impaired Osteogenic Differentiation of Skeletal Progenitors
causal_link_type: DIRECT
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "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."
explanation: >-
Establishes MAPK as the operative pathway by rescuing the downstream defect
when it is inhibited, in both mouse and patient-derived cells.
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Osteofibrous dysplasia (OFD) is a skeletal RASopathy presenting with periosteal bone lesions that may progress to fracture and delayed healing (pseudarthrosis)."
explanation: >-
Sources the RASopathy characterisation that this node and the entry's notes
rest on.
- name: Impaired Osteogenic Differentiation of Skeletal Progenitors
biological_scale: CELLULAR
description: >-
The functional consequence. Forced exon exclusion retards osteoblastic
differentiation and inhibits bone-matrix mineralization in vitro, and METΔJMD
expression inhibits osteogenic differentiation of skeletal progenitor cells.
MET's role here is bidirectional: deleting Met instead enhances osteogenic
differentiation of periosteal progenitors.
cell_types:
- preferred_term: skeletal progenitor cell of the periosteum
term:
id: CL:0007001
label: skeletogenic cell
biological_processes:
- preferred_term: osteoblast differentiation
modifier: DECREASED
term:
id: GO:0001649
label: osteoblast differentiation
downstream:
- target: Impaired Cortical Bone Development
causal_link_type: DIRECT
evidence:
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Splice exclusion of this domain occurs during normal embryonic development, and forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization."
explanation: >-
The in vitro demonstration that the exon-exclusion event itself causes the
differentiation defect.
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In contrast, conditional deletion of Met enhanced osteogenic differentiation of periosteal progenitor cells."
explanation: >-
The opposite-direction result that establishes MET as a bidirectional
regulator here, and that locates the relevant cells in the periosteum.
- name: Impaired Cortical Bone Development
biological_scale: TISSUE
description: >-
The lesion is cortical and subperiosteal because that is where the affected
progenitors live. METΔJMD expression impairs cortical bone development and
reduces bone stiffness, which is the substrate for bowing and for fracture that
will not unite.
locations:
- preferred_term: tibial diaphysis
term:
id: UBERON:0013280
label: diaphysis of tibia
- preferred_term: periosteum
term:
id: UBERON:0002515
label: periosteum
downstream:
- target: Intracortical radiolucent lesion
causal_link_type: DIRECT
description: >-
The radiolucent lesion is the radiographic appearance of cortex that failed
to form: fibro-osseous tissue occupies the subperiosteal cortical bone the
affected progenitors did not build.
evidence:
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula."
explanation: >-
Names OFD as a disorder of osteogenesis and, in the same sentence, gives
the radiolucent cortical lesion as what characterizes it. That is this
edge: the failure of cortical osteogenesis presenting as the lesion.
- target: Tibial bowing
causal_link_type: DIRECT
- target: Pathologic fracture
causal_link_type: DIRECT
description: >-
Reduced cortical stiffness is what the fracture happens through, which is why
fracture is an event of the growing tibia rather than of trauma alone.
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We engineered MetΔJMD mice and showed that MetΔJMD expression inhibited osteogenic differentiation of skeletal progenitor cells in vitro and impaired cortical bone development and reduced bone stiffness in vivo."
explanation: >-
Reduced bone stiffness is the measured property that makes the cortex liable
to fracture, which is what this edge asserts.
- target: Tibial pseudarthrosis
causal_link_type: DIRECT
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We engineered MetΔJMD mice and showed that MetΔJMD expression inhibited osteogenic differentiation of skeletal progenitor cells in vitro and impaired cortical bone development and reduced bone stiffness in vivo."
explanation: >-
Ties the cellular defect to the cortical bone phenotype and to reduced
stiffness, which is the tissue-level claim here.
phenotypes:
- category: Skeletal
name: Intracortical radiolucent lesion
description: >-
The defining finding: a radiolucent fibro-osseous lesion of the cortical bone
immediately beneath the periosteum of the tibia and fibula. Soft tissue
extension is absent and medullary involvement unusual, which is part of what
separates it radiologically from adamantinoma.
phenotype_term:
preferred_term: radiolucent intracortical lesion of the tibial diaphysis
term:
id: HP:0003103
label: Abnormal cortical bone morphology
coarse_binding_basis: NO_HPO_TERM
evidence:
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula."
explanation: >-
The definitional description of the lesion, its cortical and subperiosteal
location, and the tibia-and-fibula distribution.
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Soft tissue extension is not present, and intramedullary involvement is unusual"
explanation: >-
The radiological features that distinguish the lesion from adamantinoma.
sequelae:
- target: Bone pain
causal_link_type: DIRECT
description: >-
The lesion is what hurts when the disease is symptomatic, though a large
minority of lesions are painless and found incidentally.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "OFD can present with asymptomatic, mass, pain, swelling, deformity (anterior bowing of the tibia), and even pathological fracture"
explanation: >-
Gives pain as one of the presentations of the lesion, alongside the
asymptomatic one.
- category: Skeletal
name: Bone pain
description: >-
Pain over the lesion, reported in about 31% of patients and the commonest
presenting complaint. A substantial minority are asymptomatic and come to
attention only on imaging taken for some other reason.
frequency: FREQUENT
phenotype_term:
preferred_term: pain over the tibial lesion
term:
id: HP:0002653
label: Bone pain
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with OFD about 31% had pain, 13% experienced tibial bowing, 19% suffered pathologic fracture"
explanation: >-
Gives the 31% figure for pain, the highest of the presenting features in
this series.
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "OFD can present with asymptomatic, mass, pain, swelling, deformity (anterior bowing of the tibia), and even pathological fracture"
explanation: >-
Lists pain among the ways the lesion presents, and records that presentation
may equally be asymptomatic.
- category: Skeletal
name: Pathologic fracture
description: >-
Fracture through the weakened cortex, reported in about 19% of patients. It is
the event preceding the pseudarthrosis this entry treats as its defining
complication, and one of the indications for surgery before puberty.
frequency: OCCASIONAL
phenotype_term:
preferred_term: pathological fracture through the cortical lesion
term:
id: HP:0002756
label: Pathologic fracture
sequelae:
- target: Tibial pseudarthrosis
causal_link_type: DIRECT
description: >-
Healing across the fracture is delayed and may fail outright, leaving an
established pseudarthrosis.
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Osteofibrous dysplasia (OFD) is a skeletal RASopathy presenting with periosteal bone lesions that may progress to fracture and delayed healing (pseudarthrosis)."
explanation: >-
States the fracture-to-pseudarthrosis progression this edge records.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with OFD about 31% had pain, 13% experienced tibial bowing, 19% suffered pathologic fracture"
explanation: >-
Gives the 19% figure for pathologic fracture in a reviewed patient series.
- category: Skeletal
name: Tibial bowing
description: >-
Anterior bowing of the tibia, reported in about 13% of patients. It follows
from the reduced stiffness of the affected cortex, and it is one of the
deformities that brings a child to surgery before puberty.
frequency: OCCASIONAL
phenotype_term:
preferred_term: anterior tibial bowing
term:
id: HP:0002982
label: Tibial bowing
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with OFD about 31% had pain, 13% experienced tibial bowing, 19% suffered pathologic fracture"
explanation: >-
Gives the 13% figure for bowing in a reviewed patient series, which is the
frequency recorded here.
- reference: PMID:39042586
reference_title: A genetic mouse model mimicking MET related human osteofibrous dysplasia is characterized by delays in fracture repair and defective osteogenesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Tibial involvement leads to bowing and predisposes to the development of a fracture which exhibit significantly delayed healing processes, leading to prolonged morbidity."
explanation: >-
States bowing as the consequence of tibial involvement, and bowing as what
predisposes to the poorly healing fracture. The sentence describes the human
clinical picture in the introduction of a mouse-model paper, so it is graded
HUMAN_CLINICAL with quote_role BACKGROUND.
- category: Skeletal
name: Tibial pseudarthrosis
description: >-
The defining complication. Fracture through the lesion heals poorly and may
become an established pseudarthrosis, which is the problem targeted therapy was
first used for.
phenotype_term:
preferred_term: pseudarthrosis after fracture through the lesion
term:
id: HP:0009736
label: Tibial pseudarthrosis
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Osteofibrous dysplasia (OFD) is a skeletal RASopathy presenting with periosteal bone lesions that may progress to fracture and delayed healing (pseudarthrosis)."
explanation: >-
Names pseudarthrosis as the progression this phenotype records.
diagnosis:
- name: Plain radiography of the affected bone
description: >-
Radiography is the primary modality. Anteroposterior and lateral views of the
affected segment show the intracortical lytic lesion, and also show the two
things that change management: anterior bowing and fracture.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "anterior bowing deformity, even pathological fracture, could also be detected on the tibial x-rays"
explanation: >-
Radiography detects the deformity and the fracture, which is what makes it
the first-line study here.
- name: Computed tomography for cortical extent
description: >-
CT is the better study for how far the lesion runs through the cortex and for
periosteal reaction and fracture. It complements MRI rather than replacing it.
diagnosis_term:
preferred_term: computed tomography of the affected bone
term:
id: NCIT:C17204
label: Computed Tomography
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Computed tomography (CT) is better than MRI in evaluating cortical involvement, periosteal reaction, matrix mineralization, as well as pathological fractures"
explanation: >-
States what CT is better than MRI for, which is the indication recorded here.
- name: Adequate-volume biopsy to exclude adamantinoma
description: >-
The diagnostic risk that matters is sampling. A small or percutaneous biopsy can
return osteofibrous dysplasia from a lesion that is adamantinoma elsewhere in
its volume, so a large specimen is recommended whenever the two are in question.
This is the practical counterpart of the differential this entry argues.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "percutaneous or other limited biopsy specimens might lead to sampling errors that should be considered, and a large tissue specimen is recommended for differentiation"
explanation: >-
Names the sampling error and the recommendation that follows from it.
inheritance:
- name: Autosomal dominant
description: >-
Familial OFD segregates as an autosomal-dominant trait. Somatic MET exon 14
mutation accounts for at least some unilateral disease, so the entry covers both
origins.
inheritance_term:
preferred_term: autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "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."
explanation: Segregation in three families establishes the inheritance pattern.
genetic:
- name: MET
notes: >-
The causal gene. Mutations act by abolishing splice inclusion of exon 14, which
removes the juxtamembrane degradation signal; both germline and somatic exon 14
events converge on the same stabilised receptor.
gene_term:
preferred_term: MET
term:
id: hgnc:7029
label: MET
relationship_type: CAUSATIVE
evidence:
- reference: PMID:26637977
reference_title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Taken together, these data show that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone."
explanation: >-
The authors' summary of the gene-to-mechanism link, naming the domain, the
subverted function and the tissue.
- reference: PMID:36875508
reference_title: A case of neonatal osteofibrous dysplasia with novel CDK12 and DDR2 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "no other genetic aberrations have been identified"
explanation: >-
Recorded against overreading the MET association. Outside the familial MET
cases no other genetic cause is established, and the paper that identified
MET itself describes OFD as typically sporadic, so MET explains the familial
and bilateral minority rather than the disease in general. The same report
describes novel CDK12 and DDR2 variants in a neonate, and PMID:42379271
found single-case KMT2A, KMT2D, PHOX2B and RIF1 changes across five OFDs;
none is curated as causal here.
differential_diagnoses:
- name: Classic adamantinoma
description: >-
The central differential, and the reason this entry exists alongside
Adamantinoma.yaml. The two are radiologically and histologically similar, and
whether OFD progresses to adamantinoma is an open question recorded in that
entry's discussions. Genomic evidence now suggests they are distinct entities.
disease_term:
preferred_term: adamantinoma
term:
id: MONDO:0002422
label: adamantinoma
distinguishing_features:
- Known causal gene (MET exon 14) in OFD, against no established driver in classic adamantinoma
- Arm-level copy-number gains present in classic adamantinoma and absent in OFD
- Younger age at presentation
evidence:
- reference: PMID:42379271
reference_title: Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In conclusion, classic adamantinomas and OFD might be genetically distinct."
explanation: >-
The genomic argument for separating the two, which is what this entry's scope
note rests on. Stated by the authors as a possibility rather than a
settlement, and quoted as such.
- reference: PMID:42379271
reference_title: Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 3 classic adamantinomas harbored multiple copy number gains involving chromosome 7, 8, 10, 12, and/or 19."
explanation: >-
The specific finding behind the distinction: copy-number gains in the
adamantinomas that the OFDs in the same cohort did not carry.
- reference: PMID:41653544
reference_title: "Clinicopathological analysis of osteofibrous dysplasia and adamantinoma: A single institution experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "median age for OFD (10 years) was lower than that of adamantinoma (25 years)."
explanation: >-
Sources the age difference listed among the distinguishing features above,
which previously had no evidence item of its own.
- name: Fibrous dysplasia
description: >-
The differential most likely to be confused in practice, and the one this
entry's own synonym "cortical fibrous dysplasia" invites. A 58-tumour review
revised four lesions diagnosed as OFD to fibrous dysplasia. The discriminator
is histological: osteoblastic rimming is present in OFD and conspicuously
absent in fibrous dysplasia, which is GNAS-driven and typically medullary.
distinguishing_features:
- Osteoblastic rimming of woven trabeculae present in OFD, absent in fibrous dysplasia
- Fibrous dysplasia is GNAS-driven; OFD is MET-associated in its familial form
- OFD is intracortical and subperiosteal; fibrous dysplasia is typically medullary
evidence:
- reference: PMID:41653544
reference_title: "Clinicopathological analysis of osteofibrous dysplasia and adamantinoma: A single institution experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "4 OFDs revised to FDs"
explanation: >-
Documents the misclassification rate in practice, which is why this
differential is recorded rather than assumed obvious.
- name: Osteofibrous dysplasia-like adamantinoma
description: >-
The genuinely hard differential: a lesion with OFD architecture containing
epithelial nests. Adamantinoma.yaml models it as a histopathology pattern
rather than a separate entry.
evidence:
- reference: PMID:42379271
reference_title: Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using genomics as the benchmark, OFD-like adamantinomas might be better delineated by light microscopy or p40 than by cytokeratin immunohistochemistry."
explanation: >-
States how the intermediate lesion is best distinguished, and by implication
that cytokeratin is not the right tool.
histopathology:
- name: Storiform fibrovascular stroma with osteoblastic rimming
description: >-
The diagnostic histology: a loose storiform fibrovascular stroma containing
woven bony trabeculae rimmed by osteoblasts. The rimming is what separates OFD
from fibrous dysplasia, where it is conspicuously absent.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A loose storiform, fibrovascular stroma, and woven bony trabeculae with osteoblastic rimming"
explanation: The defining histological appearance.
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A key feature is the conspicuous absence of osteoblastic rimming"
explanation: >-
The contrasting feature in fibrous dysplasia, which is why rimming is the
discriminator rather than an incidental observation.
- name: Scattered keratin-immunoreactive cells
description: >-
Individual keratin-positive cells occur in OFD, which is part of why the
relationship to adamantinoma is contested. Keratin does not discriminate the
two, being positive in roughly 95% of both; p40 and p63 are the useful markers
for adamantinoma.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "individual keratin-immunoreactive cells can be detected"
explanation: >-
Records the epithelial cells found in OFD, the histological basis of the
proposed continuum with adamantinoma.
- reference: PMID:41653544
reference_title: "Clinicopathological analysis of osteofibrous dysplasia and adamantinoma: A single institution experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "P40 (5/5, 100%) and p63 (6/8, 75%) were useful in the diagnosis of adamantinoma"
explanation: >-
The markers that do discriminate. Recorded because the same series found
pan-keratin positive in roughly 95% of both lesions, so keratin positivity
alone does not support a diagnosis of adamantinoma.
prevalence:
- population: Among primary bone tumors
measure_type: UNKNOWN
prevalence_class: RARE
notes: >-
About 0.2% of all primary bone tumors. Recorded as UNKNOWN measure_type because
the source states a share of another tumour population rather than a population
prevalence or incidence, and no numeric rate is entered for the same reason.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "accounting for approximately 0.2% of all primary bone tumors"
explanation: Source for the rarity figure and its denominator.
progression:
- phase: Course through skeletal growth
notes: >-
The lesion is usually self-limited. Progression halts at skeletal maturity, and
regression has been reported in a newborn within weeks of a minor fracture. A
19-case series followed for a median of 51 months saw no progression to
adamantinoma.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "progression stops with the reaching of skeletal maturity"
explanation: The natural-history endpoint that makes the lesion self-limited.
- reference: PMID:41653544
reference_title: "Clinicopathological analysis of osteofibrous dysplasia and adamantinoma: A single institution experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "None of the OFDs progressed to an adamantinoma during a median follow-up of 51.15 months"
explanation: >-
Observed absence of progression over a defined follow-up, which bears on the
question recorded in discussions.
treatments:
- name: Conservative Management
description: >-
The historical standard, and still the default for an uncomplicated lesion.
Surgery in childhood carries a high recurrence rate, and lesions can remodel and
regress spontaneously, including after a minor fracture in a newborn.
therapeutic_modality: OTHER
treatment_term:
preferred_term: observation with radiographic follow-up
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:23774157
reference_title: "Congenital osteofibrous dysplasia Campanacci: spontaneous postbioptic regression."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Surgical intervention in this tumor entity at childhood age has been shown to have a high recurrence rate but due to lack of experience with newborns, guidelines do not exist."
explanation: >-
The argument against operating, and an explicit statement that guidelines do
not exist for the youngest patients.
- reference: PMID:23774157
reference_title: "Congenital osteofibrous dysplasia Campanacci: spontaneous postbioptic regression."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "After a small open biopsy and spontaneous minor fracture, the lesion rapidly remodeled within 1½ months and almost completely regressed with restutio ad integrum."
explanation: >-
Documents spontaneous regression, which is why the lesion is described as
usually self-limited and why observation is reasonable.
- name: Surgical Treatment of Progressive or Fractured Lesions
description: >-
Curettage, extraperiosteal excision and corrective osteotomy are the standard
interventions, reserved for children with pathological fracture, deformity or an
extensive lesion before puberty. Recurrence after curettage or excision is about
25%, which is the reason an uncomplicated lesion is watched instead.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: curettage, extraperiosteal excision, or corrective osteotomy
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Pathologic fracture
description: >-
Surgery addresses the fracture and the deformity rather than the MET lesion
upstream of them, which is why it does not prevent recurrence.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Surgical intervention is an alternative for children with pathological fractures, deforming, and extensive lesions before puberty"
explanation: >-
The indication, which names pathological fracture first and is what this
link points at.
evidence:
- reference: PMID:38539216
reference_title: "Osteofibrous dysplasia: a narrative review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Local curettage and excision have 25% recurrence postoperatively"
explanation: >-
The recurrence figure, which is the counterweight to operating and the reason
conservative management remains the default.
- name: MEK Inhibition for Established Pseudarthrosis
description: >-
A targeted treatment, and a direct consequence of recognising OFD as a skeletal
RASopathy. MEK inhibition restored osteogenic differentiation in
MetΔJMD mouse progenitors and in pseudarthrosis-derived cells from patients, and
mirdametinib achieved union in a child with three years of persistent
pseudarthrosis. This is a single treated patient with preclinical support, not a
trial result.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: MEK inhibitor therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: mirdametinib
term:
id: NCIT:C52195
label: Mirdametinib
target_mechanisms:
- target: MAPK Pathway Activation
description: >-
Inhibits the pathway downstream of the stabilised receptor, which is the step
the rescue experiments act on.
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "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."
explanation: >-
The mechanistic rescue that justifies pointing this treatment at the MAPK
node rather than at the receptor or the lesion.
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "With this preclinical support, we treated with the MEK inhibitor mirdametinib a pediatric patient with OFD who had a 3-year history of persistent pseudarthrosis, resulting in fracture union."
explanation: >-
The clinical result, quoted with its own framing as a single patient treated
on preclinical support.
animal_models:
- name: MetΔJMD mouse
species: Mouse
genotype: MetΔJMD (juxtamembrane domain deleted)
publication: PMID:41746735
description: >-
Engineered to express the juxtamembrane-deleted receptor found in patients, and
the model in which MEK rescue was demonstrated before the patient was treated.
modeled_mechanisms:
- target: Impaired Osteogenic Differentiation of Skeletal Progenitors
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: >-
Reproduces the differentiation defect and, on MEK inhibition, its rescue.
evidence:
- reference: PMID:41746735
reference_title: MEK inhibitor mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We engineered MetΔJMD mice and showed that MetΔJMD expression inhibited osteogenic differentiation of skeletal progenitor cells in vitro and impaired cortical bone development and reduced bone stiffness in vivo."
explanation: Directly measures the cellular and tissue consequences this node asserts.
- name: Met exon 15 skipping mouse
species: Mouse
genotype: MetΔ15-HET (heterozygous Met exon 15 skipping)
publication: PMID:39042586
description: >-
Heterozygous exon-skipping mouse built, in the authors' words, to imitate the
human OFD mutation. The paper states no exon-number correspondence between
mouse and human, so none is asserted here.
modeled_mechanisms:
- target: Tibial pseudarthrosis
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
Reproduces the delayed fracture repair that underlies pseudarthrosis, with
decreased bone formation two weeks after fracture.
limitations: >-
The mouse develops no gross skeletal defect, so it does not reproduce the
lesion itself or the bowing - only the repair failure downstream of it. The
model therefore speaks to the fracture complication and not to lesion
formation.
evidence:
- reference: PMID:39042586
reference_title: A genetic mouse model mimicking MET related human osteofibrous dysplasia is characterized by delays in fracture repair and defective osteogenesis.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Although no gross skeletal defects were identified in the mice, fracture repair was delayed in MetΔ15-HET mice, with decreased bone formation observed 2-week postfracture."
explanation: >-
States both what the model reproduces and, in the same sentence, what it
does not, which is the basis for the limitations recorded above.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Pre-PR red-team review round: Osteofibrous Dysplasia · 2026-10-13T17:41:00Z · View source
Self-review round before opening the PR, run in a subagent for fresh context per step 7 of the initiate-new-disorder-creation skill. Verdict was REQUEST_CHANGES with five blocking findings, five major and eight moderate; all blocking and major items are addressed along with most moderates. Snippet count rose from 21/21 to 37/37 verified and references cited rose from 6 to 11 of the 13 available. The central finding was under-consumption with a specific cause. PMID:38539216, a 52 KB full-text narrative review of osteofibrous dysplasia already committed to the repository by the Adamantinoma PR, was cited zero times. I had skipped it because the deep-research report's quote validator flagged three quotes against it, but those flags were against the report's paraphrases rather than against the reference: every candidate sentence I tested is an exact substring of the cache. Declining the report's quotes was right; declining the reference was not. That single source supplied the prevalence figure, the natural history, the histopathology, the 25% recurrence rate and the pain frequency. PMID:41653544, also already committed and uncited, supplied the median-age figure for a distinguishing_features line that had carried no evidence item at all, plus the p40/p63 immunophenotype and the finding that four lesions diagnosed as OFD were revised to fibrous dysplasia on review. Four findings were errors rather than omissions. First, my earlier grounding fix was at the wrong node. The reviewer measured the gate and showed it depends on the molecular_functions binding of pathophysiology[0], the splicing node, not on the receptor node; so the binding I had added to satisfy it was the least defensible one, asserting transmembrane receptor protein tyrosine kinase activity with a gain-of-function modifier at a node whose substrate is an mRNA splicing event. Corrected by moving genes MET onto the stabilised-receptor node, where the molecular function claim belongs, and giving the splicing node GO:0000381 regulation of alternative mRNA splicing via spliceosome instead; the gate still reports zero findings. Second, I nearly bound HP:0002754 Osteomyelitis, which is bone infection, for the radiolucent lesion; an anchor mismatch prevented the write and the retry uses HP:0003103 Abnormal cortical bone morphology with coarse_binding_basis NO_HPO_TERM. Third, the notes quoted MONDO's definition selectively, using it to argue that OFD is not a neoplasm while omitting the definition's closing sentence that progression to adamantinoma has been reported in some cases; and PMID:8156503, cached in this PR and uncited, concludes that the findings demonstrate a clonal and possibly neoplastic origin, directly against that framing. Both are now curated in a discussions entry of kind KNOWLEDGE_GAP, the latter as a REFUTE with directness INDIRECT, and the notes now state that treating OFD as a developmental disorder is a curation decision rather than a finding. That discussions entry is also what claim issue 14016 item 5 asked for and I had not written; it cross-references adam_ofd_progression_sequence in Adamantinoma.yaml so the open question is visible from both entries, and its rationale states the evidence on both sides. Fourth, the defining lesion was absent from the entry altogether: there were two phenotypes, both downstream consequences, while the description referred to a lesion that appeared nowhere. It is now a phenotype sourced from the causal paper's own definitional sentence. Further fixes: three bindings replaced with more specific precedented ones, HP:0002982 Tibial bowing, UBERON:0013280 diaphysis of tibia and CL:0020016 osteochondral skeletal stem cell; evidence_source corrected from HUMAN_CLINICAL to OTHER on an introductory background sentence in a mouse-model paper that presents no human clinical data on bowing; the unsourced claim that painless bowing is the usual presentation replaced with the sourced 25 to 50 percent pain frequency; a genetic section that implied MET causes OFD corrected to record that the same paper describing the gene calls the disease typically sporadic, that no other genetic cause is established, and that single-case CDK12, DDR2, KMT2A, KMT2D, PHOX2B and RIF1 findings exist without being curated as causal; histopathology added with the storiform stroma and osteoblastic rimming and the keratin-immunoreactive cells, including that pan-keratin does not discriminate OFD from adamantinoma while p40 and p63 do; prevalence and progression sections added; fibrous dysplasia and OFD-like adamantinoma added as differentials, the former being the differential most likely to be confused in practice and the one this entry's own synonym cortical fibrous dysplasia invites; the inferred mouse-exon-15 to human-exon-14 correspondence removed, since the paper states none; and the priority claim that this is the first targeted treatment removed, since no cited source says first. Process notes on my own errors. Twice a batched edit script raised an assertion on a late fix and never reached its write, silently discarding earlier fixes the script had already reported as applied; I only caught it by grepping the file for what was actually present, and switched to writing after each individual fix. I also typed reference_title values from memory on three further occasions in this round; the helper that rewrites every title in the file from its cache corrected four more, including two the validator had not yet reached. The final title audit reports 37 titles with zero mismatches. Validation after the round: 37/37 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-coarse-phenotypes, the gene-activity grounding gate and the batched validate-disorders all pass.
Create: Osteofibrous Dysplasia · 2026-10-13T17:09:46Z · View source
De novo curation of osteofibrous dysplasia (MONDO:0011806) as a Mendelian entry. Pre-claim verification found the ID not bound as any entry's disease_term and not bound as a subtype_term anywhere; its two appearances in kb/ are both non-coverage, inside Adamantinoma.yaml's differential_diagnoses block, which carries its own nested disease_term, and in a radiological-differential sentence in Familial_Expansile_Osteolysis.yaml. All eight MONDO synonyms were swept against origin/main, the term is a leaf with zero children and is neither obsolete nor an obsoletion candidate, its single parent MONDO:0018230 skeletal dysplasia is unbound by any entry, no PR or issue covers the disease, and 269 PubMed records carry the exact phrase. The worktree was branched from current origin/main at zero commits behind, deliberately: the previous curation in this series failed CI on scripts/check_gene_activity_grounding.py, a gate that had landed upstream after that branch's base, and being 113 commits behind hid it from every local run. The gate is present in this checkout and the scaffold was written to satisfy it from the outset. Gene verification was done before any binding, because the stub recorded MONDO's causal gene as MET and MET is overwhelmingly associated with non-small-cell lung cancer, making it exactly the kind of attribution that deserves reading first. It checks out: PMID:26637977 identified germline MET mutations segregating with autosomal-dominant OFD in three families, abolishing splice inclusion of exon 14 and producing a receptor lacking the cytoplasmic juxtamembrane domain, and also found a somatic exon 14 mutation in unilateral disease with the same stabilising effect. Deep research: falcon was requested but has no API key here, so the run used --fallback and claude_code produced the report, which records fell_back, requested_provider and provider_attempts. This report broke the pattern of the previous four in both directions. It carried zero confabulated references: all eight cached references are genuinely about osteofibrous dysplasia, the first time in this series that no real-PMID-wrong-paper citation appeared. Its twenty-one reported label mismatches are all benign table-header artifacts, where the report wrote a column heading such as Cell type or Anatomy beside the correct ontology label, so there were no wrong CURIEs either. But its quote validation reported quotes_valid 6 of 14 checked, with eight unsupported quotes flagged against PMID:26637977, PMID:38539216 and PMID:41746735, which is the worst quote-fabrication rate seen in the series and includes the causal paper. Every quote in this entry was therefore taken from the cache files rather than from the report. Two findings reshaped the entry beyond what the stub suggested. First, PMID:41746735 establishes that OFD is a skeletal RASopathy: the METdeltaJMD receptor loses the juxtamembrane degradation signal, escapes ubiquitin-mediated turnover and acquires a ligand-dependent gain of function signalling through MAPK, and MEK inhibition restored osteogenic differentiation in both MetdeltaJMD mouse progenitors and pseudarthrosis-derived primary cells from patients, after which mirdametinib achieved fracture union in a pediatric patient with three years of persistent pseudarthrosis. That is the first targeted treatment in a disease previously managed conservatively, and it is curated with its own framing as a single treated patient on preclinical support rather than as a trial result. Second, PMID:42379271 characterises classic adamantinoma, OFD and OFD-like adamantinoma genomically and concludes they might be genetically distinct, with arm-level copy-number gains in the adamantinomas that the OFDs lacked. That bears directly on the open KNOWLEDGE_GAP discussion adam_ofd_progression_sequence in Adamantinoma.yaml and is the evidence behind this entry's scoping decision; it is quoted with the authors' own hedge and the notes say explicitly that it is an argument rather than a settlement and that the discussion there should stay open. Pathophysiology is a causal chain from MET exon 14 splice exclusion through the stabilised receptor and MAPK activation to impaired osteogenic differentiation of periosteal skeletal progenitors and impaired cortical bone development, branching into bowing and tibial pseudarthrosis. Two mouse models are linked: the MetdeltaJMD mouse RECAPITULATES the differentiation defect at CELLULAR scale with fidelity HIGH, and the Met exon 15 skipping mouse PARTIALLY_RECAPITULATES pseudarthrosis at ORGANISM scale with limitations recording that it develops no gross skeletal defect, so it speaks to the repair failure and not to lesion formation. Also recorded in notes: kb/groupings/RASopathies.yaml exists and OFD is a candidate member on this evidence, but adding it modifies another file and is left for a separate PR. Process note on my own errors. I typed reference_title values from memory rather than copying them from the cache on three separate occasions in this entry, which just validate caught each time. Rather than keep fixing instances I wrote a helper that rewrites every reference_title in the file directly from its cache file and ran it after each batch; it corrected thirteen titles in total, including two the validator had not yet reached, and backfilled six that were missing entirely. A second self-inflicted problem: splitting the chain moved the MET gene onto a node without a molecular_functions binding, which made the grounding gate fail where the scaffold had passed. GO:0004714 is now bound on the gene-bearing node as well, which the node's own evidence supports, since the causal paper states that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions. Validation: just validate passes with 21/21 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-coarse-phenotypes, the gene-activity grounding gate and the batched validate-disorders all pass.
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).
| Database | Identifier |
|---|---|
| MONDO | MONDO:0011806 |
| OMIM | 607278 (Osteofibrous Dysplasia, Susceptibility To; OSFD) |
| Orphanet | ORPHA:488265 |
| ICD-10 | M85.0 (Other fibrous dysplasia of bone) |
| ICD-11 | LD24.2Y |
| MeSH | C563276 |
| UMLS | C1709353 |
| GARD | 10887 |
| Gene (OMIM) | MET (*164860) |
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.
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).
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
No specific genetic or environmental protective factors have been identified for OFD.
No gene-environment interactions have been documented for OFD. The disease appears to be entirely determined by genetic factors affecting MET receptor signaling.
| Phenotype | HPO Term | Frequency | Onset | Severity |
|---|---|---|---|---|
| Anterior tibial bowing | HP:0002979 (Bowing of the legs) | ~13% at presentation | Infancy/childhood | Mild to moderate |
| Painless tibial swelling/mass | HP:0002797 (Abnormality of the tibial metaphysis) / HP:0100555 (Asymmetric growth) | ~37% asymptomatic/incidental | Infancy/childhood | Variable |
| Bone pain | HP:0002653 (Bone pain) | ~31% | Childhood | Mild to moderate |
| Pathologic fractures | HP:0002757 (Recurrent fractures) | ~19% | Childhood | Moderate to severe |
| Pseudarthrosis of lower limb | HP:0006543 (Pseudoarthrosis of long bones) | Subset of fracture patients | Childhood | Severe |
| Fibular lesions | HP:0002992 (Abnormality of tibia morphology) | ~3.8% fibula only; tibial+fibular common in neonates | Neonatal/childhood | Variable |
| Radiolucent cortical lesion | HP:0002757 (cortical thinning) | ~100% | All ages | Variable |
| Delayed fracture healing | HP:0002757 / HP:0006443 (Abnormality of long bone morphology) | Common with fractures | Childhood | Moderate |
Key phenotype characteristics:
MET (MET proto-oncogene, receptor tyrosine kinase) - HGNC: hgnc:7029 - OMIM: 164860 - Chromosomal location: 7q31.2 - Protein:* Hepatocyte growth factor receptor (c-Met)
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 | Type | Origin | Effect |
|---|---|---|---|
| 26-bp deletion in MET (intron 13–exon 14 junction) | Splice-site deletion | Germline (AD family) | Exon 14 skipping; loss of juxtamembrane domain |
| Other splice-site mutations abolishing exon 14 inclusion | Splice-site | Germline (multiple families) | Exon 14 skipping |
| Y1003S (c.3008A>C) | Missense (somatic) | Somatic (unilateral OFD) | Loss of CBL binding site; MET receptor stabilization |
| c.3028+1G>T | Splice-site | Germline | Exon 14 skipping (ClinVar: RCV000210870) |
| p.His1094Arg | Missense | Germline | Reported in ClinVar (Variation ID 13887) |
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)
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.
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.
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.
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
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
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
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
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
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
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)
| Cell Type | CL Term | Role |
|---|---|---|
| Osteoblast | CL:0000062 (osteoblast) | Differentiation is impaired; rimming osteoblasts are a histologic hallmark |
| Skeletal/periosteal progenitor cell | CL:0007010 (progenitor cell of endochondral bone) | Primary cell population affected; impaired differentiation |
| Fibroblast | CL:0000057 (fibroblast) | Proliferating spindle-shaped cells form the fibrous stroma |
| Osteoclast | CL:0000092 (osteoclast) | Present at lesion margins; involved in bone remodeling |
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.
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.
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)
| Condition | Distinguishing Features |
|---|---|
| Fibrous dysplasia | Lacks osteoblastic rimming; GNAS mutations present; medullary-based; ground-glass matrix |
| Classic adamantinoma | Prominent epithelial component on H&E; cortical AND medullary involvement; soft tissue extension; multiple chromosomal gains (7, 8, 10, 12, 19) (PMID:42379271) |
| OFD-like adamantinoma | Tumor clusters visible on light microscopy and/or cytokeratin/p40 immunostaining; intermediate between OFD and classic adamantinoma |
| Non-ossifying fibroma | Eccentric metaphyseal location; no osteoblastic rimming |
| Aneurysmal bone cyst | Blood-filled spaces; more aggressive appearance |
| Osteoid osteoma | Nidus with surrounding sclerosis; pain relieved by NSAIDs |
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.
No naturally occurring ortholog of osteofibrous dysplasia has been reported in domestic or wild animal species.
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
| PMID | Citation | Key Contribution |
|---|---|---|
| 26637977 | Gray MJ et al. Am J Hum Genet. 2015;97(4):491-498. | Landmark identification of MET exon 14 skipping mutations as cause of OFD |
| 39042586 | Hong G et al. FASEB J. 2024;38(14):e23816. | MetΔ15-HET mouse model showing delayed fracture repair |
| 41746735 | (Kannu lab). J Clin Invest. 2025/2026. | MEK inhibitor mirdametinib promotes fracture healing in OFD; first targeted therapy |
| 42379271 | Hung YP et al. Mod Pathol. 2026. | Genomic characterization distinguishing OFD from adamantinoma |
| 38539216 | Liu R et al. J Orthop Surg Res. 2024;19:204. | Comprehensive narrative review of OFD |
| 34742490 | Nascimento AF et al. Surg Pathol Clin. 2021;14(4):675-687. | OFD and adamantinoma spectrum review |
| 8156503 | Bridge JA et al. Cancer. 1994;73(6):1746-1752. | Clonal chromosomal abnormalities in OFD |
| 23774157 | (Campanacci case). 2013. | Spontaneous post-bioptic regression of OFD |
| Domain | Term ID | Label |
|---|---|---|
| Disease | MONDO:0011806 | osteofibrous dysplasia |
| Gene | hgnc:7029 | MET |
| Molecular function | GO:0004714 | transmembrane receptor protein tyrosine kinase activity |
| Biological process | GO:0048012 | hepatocyte growth factor receptor signaling pathway |
| Biological process | GO:0001649 | osteoblast differentiation |
| Biological process | GO:0030282 | bone mineralization |
| Biological process | GO:0000165 | MAPK cascade |
| Biological process | GO:0006511 | ubiquitin-dependent protein catabolic process |
| Cell type | CL:0000062 | osteoblast |
| Cell type | CL:0000057 | fibroblast |
| Cell type | CL:0000092 | osteoclast |
| Anatomy | UBERON:0000979 | tibia |
| Anatomy | UBERON:0001446 | fibula |
| Anatomy | UBERON:0002515 | periosteum |
| Phenotype | HP:0002979 | Bowing of the legs |
| Phenotype | HP:0002653 | Bone pain |
| Phenotype | HP:0002757 | Recurrent fractures |
| Phenotype | HP:0006543 | Pseudoarthrosis |
| Phenotype | HP:0000006 | Autosomal dominant inheritance |
| Treatment | NCIT:C15329 | Surgical Procedure |
| Treatment | NCIT:C15986 | Pharmacotherapy |
| Treatment | NCIT:C15747 | Supportive Care |
| Treatment | NCIT:C15240 | Genetic Counseling |
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
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 11 |
| Resolved | 11 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 14 |
| Quoted claims found in source | 6 |
| Quoted claims not found in source | 8 |
| References weighed for topical relevance | 11 |
| On topic | 8 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
4 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
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"PMID:38539216: "lesions usually disappear and do not cause problems in adulthood"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"PMID:38539216: "woven bone trabeculae with osteoblastic rimming are seen against bland fibroblastic stroma with storiform pattern"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"PMID:41746735 (abstract only): "MetΔJMD cells demonstrated delayed ERK pathway normalization after hepatocyte growth factor stimulation"PMID:38539216: "Lesions usually disappear and do not cause problems in adulthood"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."Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 34 |
| Resolved | 32 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 1 |
| Terms whose name was checked | 29 |
| Terms named correctly | 4 |
| Terms named as a different term | 21 |
| Terms whose name is worth a second look | 4 |
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 dysplasiaHP:0002979 (2 mentions) - the report calls it "Bowing of the legs", "Phenotype"; HP calls it Bowing of the legsHP:0002653 (2 mentions) - the report calls it "Bone pain", "Phenotype"; HP calls it Bone painHP:0002757 (4 mentions) - the report calls it "Recurrent fractures", "cortical thinning", "Phenotype"; HP calls it Recurrent fracturesHP:0006543 (2 mentions) - the report calls it "Pseudoarthrosis of long bones", "Phenotype"; HP calls it Cardiorespiratory arrestGO:0048012 (2 mentions) - the report calls it "hepatocyte growth factor receptor signaling pathway", "Biological process"; GO calls it hepatocyte growth factor receptor signaling pathwayGO:0000165 (2 mentions) - the report calls it "MAPK cascade", "Biological process"; GO calls it MAPK cascadeGO:0006511 (2 mentions) - the report calls it "ubiquitin-dependent protein catabolic process", "Biological process"; GO calls it ubiquitin-dependent protein catabolic processGO:0001649 (2 mentions) - the report calls it "osteoblast differentiation", "Biological process"; GO calls it osteoblast differentiationGO:0030282 (2 mentions) - the report calls it "bone mineralization", "Biological process"; GO calls it bone mineralizationCL:0000062 (3 mentions) - the report calls it "osteoblast", "Cell type"; CL calls it osteoblastCL:0000057 (3 mentions) - the report calls it "fibroblast", "Cell type"; CL calls it fibroblastCL:0000092 (2 mentions) - the report calls it "osteoclast", "Cell type"; CL calls it osteoclastUBERON:0000979 (2 mentions) - the report calls it "tibia", "Anatomy"; UBERON calls it tibiaUBERON:0001446 (2 mentions) - the report calls it "fibula", "Anatomy"; UBERON calls it fibulaUBERON:0002515 (2 mentions) - the report calls it "periosteum", "Anatomy"; UBERON calls it periosteumHP: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 CareNCIT:C15329 (2 mentions) - the report calls it "Surgical Procedure", "Treatment"; NCIT calls it Surgical ProcedureNCIT:C15240 (2 mentions) - the report calls it "Genetic Counseling", "Treatment"; NCIT calls it Genetic CounselingGO:0004714 (1 mention) - the report calls it "Molecular function"; GO calls it transmembrane receptor protein tyrosine kinase activityThese 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:0043491The 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 namesGO:0014065 (1 mention) - the report calls it "phosphatidylinositol 3-kinase signaling"; GO calls it obsolete phosphatidylinositol 3-kinase signalingCL: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 namesNCIT:C15986 (2 mentions) - the report calls it "Pharmacotherapy", "Treatment"; NCIT calls it Pharmacotherapy, and lists "Pharmacological Treatment" among its other namesThe 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"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.