👪

Inheritance

1

Autosomal recessive HP:0000007

Both molecularly confirmed families are homozygous for an MMP14 missense variant. The original affected sisters were born to unaffected first-cousin parents, and the Dutch family comprises two affected brothers.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:29741626 SUPPORT Human Clinical

"Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis."

States the autosomal recessive mode of inheritance in a paper reporting a second homozygous MMP14 family.

PMID:22922033 SUPPORT Human Clinical

"Winchester syndrome is a presumed autosomal-recessive disorder first described in two sisters who had severe skeletal and joint deformities and whose unaffected, healthy parents were first cousins."

Affected sibs of unaffected consanguineous parents, the pedigree in which the homozygous MMP14 variant was later found.

⚙

Pathophysiology

11

MMP14 Loss of Function

Biallelic MMP14 missense variants reduce the amount or the activity of MT1-MMP at the cell surface. The signal-peptide variant p.Thr17Arg impairs processing of the nascent protein, so it is rapidly degraded and almost no active enzyme reaches the plasma membrane. The milder pro-domain variant p.Arg111His is processed and trafficked normally but has reduced proteolytic activity, and the milder phenotype it produces suggests that residual catalytic activity sets disease severity.

MMP14 hgnc:7160

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

protein localization to plasma membrane GO:0072659 ↓ DECREASED

metalloendopeptidase activity GO:0004222 ↓ DECREASED

Downstream

Impaired Pro-MMP2 Activation

Defective Pericellular Collagen Remodeling

Show evidence (4 references)

PMID:22922033 SUPPORT In Vitro

"Winchester fibroblasts had almost no detectable levels of active MT1-MMP either in the membrane fraction (Figure 2B) or on their surface (Figure 2C)."

Patient fibroblasts carrying p.Thr17Arg lack active MT1-MMP at the cell surface, the site where the enzyme acts.

PMID:22922033 SUPPORT In Vitro

"All together, the experiments on the altered protein demonstrated the deleterious effect of the mutation on subcellular localization, protein stability, and MMP-2 activation."

Summarises the transfection and cycloheximide experiments showing that p.Thr17Arg destabilises MT1-MMP and prevents its membrane localization.

PMID:29741626 SUPPORT In Vitro

"Instead, it partially impairs MMP14's proteolytic activity."

The hypomorphic p.Arg111His allele reduces catalytic activity without affecting trafficking, a second route to loss of function.

+ 1 more reference

Impaired Pro-MMP2 Activation

MT1-MMP is a pericellular activator of the gelatinase MMP-2. Fibroblasts from the original Winchester proband secrete abundant pro-MMP2 but convert little of it to the active enzyme, and tissues from Mmp14-null mice are likewise deficient in pro-MMP2 activation. The p.Thr17Arg variant abolishes pro-MMP2 cleavage in a transfection assay, whereas the hypomorphic p.Arg111His variant retains partial activity, and the authors propose that this activation step is the main determinant of severity.

fibroblast CL:0000057

zymogen activation GO:0031638 ↓ DECREASED

Downstream

Defective Pericellular Collagen Remodeling

Show evidence (3 references)

PMID:22922033 SUPPORT In Vitro

"Conditioned media from these fibroblasts had abundant levels of MMP-2 proenzyme but reduced MMP-2 activity (Figure 1B)."

Gelatin zymography of patient fibroblast medium shows retained pro-MMP2 with reduced activation.

PMID:10737763 SUPPORT Model Organism

"In tissues from null mice, activation of latent matrix metalloproteinase 2 was deficient, suggesting that MT1-MMP is essential for its activation in vivo."

Establishes MT1-MMP as required for MMP-2 activation in vivo.

PMID:29741626 SUPPORT In Vitro

"The T17R and R92C mutations completely abolish pro-MMP2 activation, whereas the R111H and S466P mutants retain residual activity."

Graded loss of pro-MMP2 activation across the two human Winchester alleles tracks their clinical severity.

Defective Pericellular Collagen Remodeling

MT1-MMP is the dominant pericellular collagenase of connective tissue cells. Without it, fibroblasts, chondrocytes, skeletal progenitors and osteocytes cannot cleave the type I collagen that surrounds them, so the matrix of developing bone, cartilage and soft connective tissue is not turned over. Reviews of the MMP14, MMP2 and SH3PXD2B disorders and their animal models identify defective collagen remodelling as the shared central lesion of the spectrum. Loss of osteocyte process formation in Mmp14-null bone has been attributed to the same failure of collagen cleavage.

fibroblast CL:0000057 chondrocyte CL:0000138 osteocyte CL:0000137

collagen catabolic process GO:0030574 ↓ DECREASED extracellular matrix disassembly GO:0022617 ↓ DECREASED

Animal models

Mmp14-null mouse Mouse recapitulates Complete loss of MT1-MMP collagenolysis in vivo.

Downstream

Persistence of Unremodeled Cartilage Anlagen

Impaired Osteogenic Commitment of Skeletal Stem Cells

Growth Plate Dysfunction

Periarticular Joint Destruction

Soft Connective Tissue Fibrosis

Abnormal Craniofacial Skeletal Development

Show evidence (4 references)

PMID:31218820 SUPPORT REVIEW SYNTHESIS Model Organism

"Furthermore, they demonstrate that defective collagen remodeling is central in the underlying pathology."

Review of animal models of the MMP14, MMP2 and SH3PXD2B disorders concluding that defective collagen remodelling is central.

PMID:23685250 SUPPORT Model Organism

"By contrast, in Mmp14-targeted mice, collagenolytic activity is reduced to background levels amid a denser network of type I collagen fibrils (Figure 4C)."

In vivo demonstration that Mmp14 deletion abolishes type I collagenolysis in calvarial bone and leaves the collagen network unremodelled.

PMID:15601659 SUPPORT Model Organism

"Specifically, a deficiency of membrane type-1 matrix metalloproteinase leads to disruption of collagen cleavage in osteocytes and ultimately to the loss of formation of osteocyte processes."

Extends the collagen-cleavage defect to osteocytes, which fail to form their processes in Mmp14-null bone.

+ 1 more reference

Persistence of Unremodeled Cartilage Anlagen

During skeletal development, unmineralized cartilage templates are normally dissolved by MT1-MMP in step with apoptosis of their chondrocytes and replaced by bone, tendon or ligament. In MT1-MMP deficiency these cartilages persist, and both endochondral and intramembranous ossification are impaired; the mmp14a/b knockout zebrafish shows the same enlarged, disorganized cartilage cores with sparse bone matrix.

chondrocyte CL:0000138

endochondral ossification GO:0001958 ↓ DECREASED

Animal models

mmp14a/b double knockout zebrafish Zebrafish recapitulates Enlarged, disorganized cartilage cores with sparse bone matrix in skull bones.

Downstream

Defective Subarticular Ossification of Carpal and Tarsal Bones

Show evidence (2 references)

PMID:14610065 SUPPORT Model Organism

"Membrane-type 1 matrix metalloproteinase (MT1-MMP)-dependent dissolution of unmineralized cartilages, coupled with apoptosis of nonhypertrophic chondrocytes, mediates remodeling of these cartilages into other tissues."

Defines the remodelling step that MT1-MMP deficiency disrupts.

PMID:29741626 SUPPORT Model Organism

"It was shown in Mmp14 KO mice that these cartilage templates are not properly replaced, respectively removed, owing to impaired MMP14-dependent collagen remodeling (32,33,41)."

Restates the mouse finding in the context of the zebrafish model, which shows the same persistent cartilage cores.

Defective Subarticular Ossification of Carpal and Tarsal Bones

The carpal and tarsal "osteolysis" that defines the syndrome may reflect abnormal formation and modelling of these bones rather than excess resorption. Carpal and tarsal bones ossify from subarticular cartilage by a process distinct from growth-plate endochondral ossification, and osteoclast (TRAP) staining is notably absent there at the developmental stage relevant to the human disease. This reinterpretation rests on normal mouse developmental anatomy and has not been tested in MMP14-deficient carpal tissue.

carpal bone UBERON:0001435 tarsal bone UBERON:0001447

Downstream

Carpal Osteolysis

Tarsal Osteolysis

Show evidence (2 references)

PMID:28675805 SUPPORT INDIRECT Model Organism

"Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes."

Hypothesis covering the MAFB, MMP2 and MMP14 carpal-tarsal osteolysis syndromes, derived from normal mouse development.

PMID:28675805 SUPPORT INDIRECT Model Organism

"Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution."

Records why the classical resorption model is considered insufficient.

Impaired Osteogenic Commitment of Skeletal Stem Cells

Skeletal stem cells use MT1-MMP to remodel their collagen niche, and the resulting change in cell shape activates beta1-integrin, RhoGTPase and YAP/TAZ signalling that commits them to the osteoblast lineage. Deleting Mmp14 in mesenchymal progenitors, but not in committed osteoblasts, diverts these cells towards adipocyte and chondrocyte fates and produces generalized osteopenia without a change in osteoclast number.

skeletal stem cell CL:0000134

osteoblast differentiation GO:0001649 ↓ DECREASED fat cell differentiation GO:0045444 ↑ INCREASED

Downstream

Generalized Bone Loss

Show evidence (1 reference)

PMID:23685250 SUPPORT Model Organism

"Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis."

Conditional knockout shows the lineage switch caused by Mmp14 loss.

Generalized Bone Loss

Reduced bone formation across the skeleton underlies the generalized osteoporosis of the human disease, the osteopenia of the Mmp14-null mouse and the reduced bone mineral density of the mmp14a/b knockout zebrafish. Osteoclasts may contribute, but the primary defect is in collagen remodelling and osteogenesis.

ossification GO:0001503 ↓ DECREASED

Animal models

mmp14a/b double knockout zebrafish Zebrafish recapitulates Reduced bone density attributed to defective collagen remodelling.

Downstream

Generalized Osteoporosis

Show evidence (2 references)

PMID:10520996 SUPPORT Model Organism

"MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."

Osteopenia is a cardinal feature of the knockout mouse.

PMID:29741626 SUPPORT Model Organism

"The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling."

Reduced bone density in the zebrafish model, attributed to defective collagen remodelling.

Growth Plate Dysfunction

In Mmp14-null mice, chondrocyte proliferation in the growth plate is reduced and vascular invasion of hypertrophic cartilage is defective, which enlarges the hypertrophic zone, delays secondary ossification centres and shortens the long bones. This is the proposed basis of dwarfism in the model and, by analogy, of short stature in the human disease.

chondrocyte CL:0000138

endochondral ossification GO:0001958 ↓ DECREASED angiogenesis GO:0001525 ↓ DECREASED

Animal models

Mmp14-null mouse Mouse recapitulates Growth plate and vascular invasion defects causing bone shortening.

Downstream

Short Stature

Show evidence (1 reference)

PMID:10737763 SUPPORT Model Organism

"Defective vascular invasion of cartilage leads to enlargement of hypertrophic zones of growth plates and delayed formation of secondary ossification centers in long bones."

Describes the growth plate defect of the knockout mouse.

Periarticular Joint Destruction

Progressive destruction of small and large joints, with interphalangeal erosions that mimic rheumatoid arthritis, eventual loss of function of the shoulders, elbows, hips and knees, and ankylosis of the remaining hand bones. The Mmp14-null mouse develops arthritis attributed to the same loss of collagenolytic remodelling.

synovial joint UBERON:0002217

Downstream

Progressive Joint Destruction

Interphalangeal Joint Erosions

Ankylosis

Arthropathy

Flexion Contracture

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"

Describes joint destruction in the molecularly confirmed index family.

Soft Connective Tissue Fibrosis

Collagen that cannot be turned over accumulates in the dermis and other soft connective tissues. The Mmp14-null mouse develops soft-tissue fibrosis, and dermal fibrosis is listed among the shared features of the defective collagen-remodelling spectrum. In clinically diagnosed Winchester patients the skin is diffusely thickened and leathery and can bind joints into contracture.

fibroblast CL:0000057

Downstream

Thickened Skin

Flexion Contracture

Show evidence (2 references)

PMID:10520996 SUPPORT Model Organism

"MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."

Soft-tissue fibrosis in the knockout mouse.

PMID:31218820 SUPPORT REVIEW SYNTHESIS Human Clinical

"are ultra-rare multisystem disorders characterized by craniofacial malformations, reduced bone density, skeletal and cardiac anomalies, and dermal fibrosis"

Review of 63 patients across the spectrum naming dermal fibrosis as a shared feature.

Abnormal Craniofacial Skeletal Development

Failed remodelling of membranous and endochondral skull bones produces craniofacial dysmorphism in the Mmp14-null mouse (a short, domed skull) and in the mmp14a/b knockout zebrafish. In the original Winchester proband the anterior fontanelle remained open at 18 years.

Downstream

Persistent Open Anterior Fontanelle

Coarse Facial Features

Show evidence (2 references)

PMID:10737763 SUPPORT Model Organism

"The craniofacial, axial, and appendicular skeletons were severely affected, leading to a short and domed skull, marked deceleration of postnatal growth, and death by 3 wk of age."

Craniofacial skeletal involvement of the knockout mouse.

PMID:22922033 SUPPORT Human Clinical

"The skull radiograph demonstrates the generalized nature of the osteolytic loss of bone and that the anterior fontanelle remains patent."

Calvarial involvement in the molecularly confirmed proband.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

19

Cardiovascular 2

Abnormal Electrocardiogram Abnormal EKG HP:0003115

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"It was also noted that the siblings had gum hypertrophy, corneal opacities, and electrocardiographical findings suggestive of myocardial damage."

ECG abnormality in the molecularly confirmed index sisters.

Mitral Valve Prolapse HP:0001634

Show evidence (1 reference)

PMID:29741626 SUPPORT Human Clinical

"In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."

Mitral valve prolapse in the second MMP14 family.

Eye 1

Peripheral Corneal Opacity Peripheral opacification of the cornea HP:0008011

Show evidence (2 references)

PMID:22922033 SUPPORT Human Clinical

"It was also noted that the siblings had gum hypertrophy, corneal opacities, and electrocardiographical findings suggestive of myocardial damage."

Corneal opacities in the molecularly confirmed index sisters.

PMID:33776097 SUPPORT BACKGROUND Human Clinical

"described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."

Specifies the peripheral location of the opacities in the original description.

Head and Neck 3

Coarse Facial Features HP:0000280

Show evidence (2 references)

PMID:33776097 SUPPORT BACKGROUND Human Clinical

"described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."

Coarse facies in the original, molecularly confirmed family.

PMID:29741626 SUPPORT Human Clinical

"In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."

Facial dysmorphism in the second MMP14 family.

Persistent Open Anterior Fontanelle HP:0004474

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"The skull radiograph demonstrates the generalized nature of the osteolytic loss of bone and that the anterior fontanelle remains patent."

Skull radiograph of the molecularly confirmed proband.

Gingival Overgrowth HP:0000212

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"It was also noted that the siblings had gum hypertrophy, corneal opacities, and electrocardiographical findings suggestive of myocardial damage."

Gum hypertrophy in the molecularly confirmed index sisters.

Immune 1

Acne HP:0001061

Show evidence (2 references)

PMID:29741626 SUPPORT Human Clinical

"In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."

Severe acne in the second MMP14 family.

PMID:14726867 SUPPORT Human Clinical

"Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."

Widespread acne among the reported cutaneous features.

Integument 3

Thickened Skin HP:0001072

Show evidence (2 references)

PMID:14726867 SUPPORT Human Clinical

"Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."

Review of cutaneous features in clinically diagnosed patients.

PMID:38291559 SUPPORT Human Clinical

"We report a 14-year-old male who presented with growth retardation, contracture of left lower limb due to thick indurated skin, hypertrichosis, and bilateral corneal opacity."

Thick indurated skin in a clinically diagnosed child.

Hyperpigmentation of the Skin HP:0000953

Show evidence (1 reference)

PMID:14726867 SUPPORT Human Clinical

"Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."

Hyperpigmented patches among the reported cutaneous features.

Hypertrichosis HP:0000998

Show evidence (2 references)

PMID:14726867 SUPPORT Human Clinical

"Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."

Hypertrichosis among the reported cutaneous features.

PMID:38291559 SUPPORT Human Clinical

"We report a 14-year-old male who presented with growth retardation, contracture of left lower limb due to thick indurated skin, hypertrichosis, and bilateral corneal opacity."

Hypertrichosis in a clinically diagnosed child.

Limbs 3

Carpal Osteolysis HP:0001495

Course: PROGRESSIVE

Show evidence (2 references)

PMID:22922033 SUPPORT Human Clinical

"The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"

Carpal osteolysis in the molecularly confirmed index sisters.

PMID:22922033 SUPPORT Human Clinical

"The hand radiograph demonstrates complete loss of all carpal bones, destruction of metacarpals and phalanges, and severe ankylosis of the remaining bones."

Radiographic end stage of carpal osteolysis in the proband.

Tarsal Osteolysis Osteolysis involving tarsal bones HP:0006234

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"

Tarsal osteolysis in the molecularly confirmed index sisters.

Interphalangeal Joint Erosions HP:0006252

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"

Interphalangeal erosions in the index sisters.

Musculoskeletal 5

Generalized Osteoporosis HP:0040160

Show evidence (2 references)

PMID:22922033 SUPPORT Human Clinical

"The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"

Generalized osteoporosis in the index sisters.

PMID:29741626 SUPPORT Human Clinical

"In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."

Reduced bone density in the second MMP14 family.

Progressive Joint Destruction HP:0005187

Show evidence (2 references)

PMID:29741626 SUPPORT Human Clinical

"Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis."

Names progressive joint destruction as a defining feature.

PMID:22922033 SUPPORT Human Clinical

"The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"

Loss of large-joint function in the index sisters.

Ankylosis HP:0031013

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"The hand radiograph demonstrates complete loss of all carpal bones, destruction of metacarpals and phalanges, and severe ankylosis of the remaining bones."

Ankylosis on the proband's hand radiograph at 18 years.

Arthropathy HP:0003040

Course: PROGRESSIVE

Show evidence (2 references)

PMID:11794271 SUPPORT Human Clinical

"The syndrome is characterized by short stature, coarse face, corneal opacities, generalized osteolysis and progressive painful arthropathy with joint stiffness and contractures of distal phalanges in combination with skin changes."

Case report summary of the syndrome; the reported patient was diagnosed clinically before the gene was known.

PMID:33776097 SUPPORT BACKGROUND Human Clinical

"The presence of marked intra- and periarticular joint destruction simulated advanced rheumatoid arthritis."

Restates the original 1969 description of the molecularly confirmed family.

Flexion Contracture HP:0001371

Course: PROGRESSIVE

Show evidence (2 references)

PMID:33776097 SUPPORT BACKGROUND Human Clinical

"described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."

Restates the original description of the family later shown to carry the MMP14 p.Thr17Arg variant.

PMID:14726867 SUPPORT Human Clinical

"The syndrome is characterized by dissolution of carpal and tarsal bones with generalized osteoporosis, progressive joint contractures, short stature, peripheral corneal opacities, and coarse facial features, though there is variability within the clinical features."

Clinical summary in a report of an ungenotyped patient.

Growth 1

Short Stature HP:0004322

Show evidence (2 references)

PMID:33776097 SUPPORT BACKGROUND Human Clinical

"described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."

Short stature in the original, molecularly confirmed family.

PMID:11794271 SUPPORT Human Clinical

"The syndrome is characterized by short stature, coarse face, corneal opacities, generalized osteolysis and progressive painful arthropathy with joint stiffness and contractures of distal phalanges in combination with skin changes."

Short stature in a clinically diagnosed case report.

🧬

Genetic Associations

1

MMP14

Gene: MMP14 hgnc:7160 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:22922033 SUPPORT Human Clinical

"Using cultured fibroblasts from the proband, we have now identified homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14)."

Identification of the causal gene in the original Winchester family.

PMID:29741626 SUPPORT Human Clinical

"Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS."

A second, independent MMP14 family.

Variants (2)

MMP14 p.(Thr17Arg) Pathogenic

Homozygous signal-peptide missense variant in the original 1969 sisters, reported by the source as n.284C>G in codon 17 of exon 1 (NM_004995.2). It destabilises the protein and prevents its membrane localization, abolishing pro-MMP2 activation.

Show evidence (1 reference)

PMID:22922033 SUPPORT Human Clinical

"Sequence analysis revealed a homozygous missense mutation, a C>G transversion (n.284C>G) in codon 17 of exon 1, that predicted replacement of a threonine by an arginine (p.Thr17Arg) (Figure 1C)."

Defines the variant and its homozygous state.

MMP14 c.332G>A p.(Arg111His) Pathogenic

Homozygous hypomorphic pro-domain variant in two Dutch brothers with a milder phenotype that did not appreciably worsen over follow-up. The protein is processed and reaches the cell membrane but has partially reduced proteolytic activity.

Show evidence (2 references)

PMID:29741626 SUPPORT Human Clinical

"Subsequent homozygosity mapping and next-generation sequencing identified a novel homozygous missense mutation in MMP14, c.332G>A"

Identification of the variant.

PMID:29741626 SUPPORT Human Clinical

"However, in the intervening years since diagnosis their phenotype has not appreciably worsened, suggesting that it is intrinsically milder."

Documents the milder course associated with this allele.

💊

Medical Actions

2

Bisphosphonate Therapy

Action: Bisphosphonate therapy Ontology label: Bisphosphonate Therapy NCIT:C198585

Platform: Small molecule

Bisphosphonates have been tried in Winchester syndrome and related disorders with limited success. They act mainly on osteoclasts, whereas the primary defect is thought to be in collagen remodelling, so the authors of the zebrafish model argue that treatment should target that defect instead.

Show evidence (1 reference)

PMID:29741626 SUPPORT BACKGROUND Human Clinical

"Attempts have been made in the past to treat WS and related disorders with bisphosphonates, with limited success (45,46)."

Records prior use and limited efficacy of bisphosphonates.

Glucocorticoid and Methotrexate

Action: Pharmacotherapy NCIT:C15986

Agent: betamethasone CHEBI:3077 methotrexate CHEBI:44185

Platform: Small molecule

One clinically diagnosed, ungenotyped boy with contracture from indurated skin had complete improvement of the contracture on oral betamethasone pulses with weekly oral methotrexate. This is a single case report.

Target Phenotypes: Flexion contracture HP:0001371

Show evidence (1 reference)

PMID:38291559 SUPPORT Human Clinical

"There was complete improvement in joint contracture with oral betamethasone pulse and weekly oral methotrexate."

Single case response; the diagnosis was clinical, not molecular.

🔬

Biochemical Markers

1

Reduced fibroblast pro-MMP2 activation (DECREASED)

Show evidence (2 references)

PMID:22922033 SUPPORT In Vitro

"Conditioned media from these fibroblasts had abundant levels of MMP-2 proenzyme but reduced MMP-2 activity (Figure 1B)."

The zymographic finding in Winchester fibroblasts.

PMID:22922033 SUPPORT In Vitro

"This is in marked contrast to MONA-derived cell lines, which do not show zymographic activity of either the proenzyme or active forms of MMP-2."

The contrasting MONA pattern that makes the test discriminating.

🔬

Diagnosis

2

Molecular confirmation by MMP14 sequencing

The diagnosis rests on the clinical and radiographic picture of carpal-tarsal osteolysis with arthropathy and is confirmed by biallelic MMP14 variants. Because MMP2-related MONA overlaps clinically and was historically diagnosed as Winchester syndrome, clinical diagnosis alone cannot separate the two; fibroblast zymography also distinguishes them.

Show evidence (2 references)

PMID:22922033 SUPPORT Human Clinical

"Previously, and on the basis of an incorrect clinical diagnosis of Winchester syndrome, Winchester syndrome and MONA were presumed to be allelic disorders arising from mutations in the same gene"

Shows that clinical diagnosis alone mislabelled MMP2 cases.

PMID:22922033 SUPPORT Human Clinical

"Our studies now demonstrate that mutations in MMP2 and MT1-MMP result in related but distinct"

Establishes the MMP14 and MMP2 diseases as distinct, so genotyping is needed.

Cardiac evaluation

A complete cardiac evaluation is recommended for anyone suspected of Winchester syndrome or MONA, given the ECG abnormalities in the index sisters and reported death from heart failure.

Show evidence (2 references)

PMID:22922033 SUPPORT Human Clinical

"all individuals suspected to be affected by Winchester syndrome and/or MONA should undergo a complete cardiac evaluation."

The gene-discovery authors' recommendation.

PMID:29741626 SUPPORT BACKGROUND Human Clinical

"Where WS patients reportedly die from heart failure, the mice succumb to wasting"

Reported cardiac cause of death in patients.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Described as extremely rare; two molecularly confirmed MMP14 families are reported in the cited literature. A 2001 count of nine published patients predates genotyping and may include MMP2-related cases.

Show evidence (2 references)

PMID:29741626 SUPPORT Human Clinical

"Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis."

Supports the ultra-rare qualitative tier.

PMID:11794271 SUPPORT Human Clinical

"Winchester syndrome was first described in 1969 and since then nine patients have been reported in the literature."

A pre-genotyping case count, which bounds the number of published clinically diagnosed patients at the time.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Winchester Syndrome:

🐁

Animal Models

2

Mmp14-null mouse

Gene-targeted MT1-MMP-deficient mice develop craniofacial dysmorphism, arthritis, osteopenia, dwarfism and soft-tissue fibrosis, and die within weeks. The human disease parallels this skeletal phenotype in a less severe form, plausibly because patient cells retain some active enzyme.

Species

Mouse

Genotype

Mmp14 (MT1-MMP) homozygous null

Publication

PMID:10520996

Pathograph links

Defective Pericellular Collagen Remodeling recapitulates fidelity: high observes: organism Complete loss of MT1-MMP collagenolysis in vivo.

Limitations: A complete null is more severe than either human allele, both of which retain some activity, and the mice die at an age before most human skeletal features develop.

Divergences from the human mechanism

species mismatch qualifying

Null mice die by about three weeks with wasting, whereas patients survive into adulthood and reportedly die of heart failure, so late skeletal and cardiac features of the human disease cannot be read off the mouse.

Show evidence (2 references)

PMID:22922033 SUPPORT Human Clinical

"an inactivating homoallelic mutation of MT1-MMP in humans results in Winchester syndrome, a rare osteolysis and arthritis disorder whose skeletal phenotype, although not as severe, parallels those previously described for the Mt1-mmp-null mouse."

Human-mouse correspondence stated by the gene-discovery paper.

+ 1 more reference

Growth Plate Dysfunction recapitulates fidelity: moderate observes: tissue Growth plate and vascular invasion defects causing bone shortening.

Show evidence (1 reference)

PMID:10737763 SUPPORT Model Organism

"Shortening of bones is a consequence of decreased chondrocyte proliferation in the proliferative zone of the growth plates."

Growth plate mechanism of dwarfism in the null mouse.

mmp14a/b double knockout zebrafish

Zebrafish lacking both mmp14 paralogs develop a progressive phenotype from about 30 days post-fertilization with short body length, craniofacial malformation, hyperkyphosis, reduced skull bone mineral density and persistent disorganized cartilage cores, and die at about 4.5 months.

Species

Zebrafish

Genotype

mmp14a and mmp14b frameshift double homozygous (CRISPR/Cas9)

Publication

PMID:29741626

Pathograph links

Generalized Bone Loss recapitulates fidelity: moderate observes: organism Reduced bone density attributed to defective collagen remodelling.

Limitations: Zebrafish carry two mmp14 paralogs and differ in bone morphology and ossification, and the fish die of spinal cord impingement, which is not seen in patients.

Show evidence (1 reference)

PMID:29741626 SUPPORT Model Organism

"The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling."

Summary of model fidelity.

Persistence of Unremodeled Cartilage Anlagen recapitulates fidelity: moderate observes: tissue Enlarged, disorganized cartilage cores with sparse bone matrix in skull bones.

Show evidence (1 reference)

PMID:29741626 SUPPORT Model Organism

"It was shown in Mmp14 KO mice that these cartilage templates are not properly replaced, respectively removed, owing to impaired MMP14-dependent collagen remodeling (32,33,41)."

The authors relate their cartilage findings to the mouse mechanism.

{ }

Source YAML

click to show

name: Winchester Syndrome
creation_date: "2026-10-15T01:37:16Z"
category: Mendelian
description: >-
  Winchester syndrome is an ultra-rare autosomal recessive skeletal dysplasia
  caused by biallelic variants in MMP14, which encodes the membrane-anchored
  collagenase MT1-MMP. It presents in childhood with progressive, symmetric
  osteolysis of the carpal and tarsal bones, interphalangeal joint erosions that
  mimic rheumatoid arthritis, generalized osteoporosis, progressive destruction
  and contracture of the large joints, short stature, coarse facial features,
  peripheral corneal opacities and gingival hypertrophy, with thickened,
  hyperpigmented and hypertrichotic skin described in clinically diagnosed
  patients. Loss of MT1-MMP abolishes pericellular cleavage of fibrillar collagen
  and the activation of pro-MMP2, so that skeletal and soft connective tissues
  cannot be remodelled during growth. In the Mmp14-null mouse this produces
  dwarfism, osteopenia, arthritis, craniofacial dysmorphism and soft-tissue
  fibrosis. The disease is now grouped with MMP2-related multicentric
  osteolysis, nodulosis and arthropathy (MONA) and SH3PXD2B-related Frank-Ter
  Haar syndrome in a defective collagen-remodelling spectrum.
disease_term:
  preferred_term: Winchester syndrome
  term:
    id: MONDO:0010201
    label: Winchester syndrome
synonyms:
- WNCHRS
- MMP14-related multicentric osteolysis, nodulosis, and arthropathy
- MONA, MMP14-related
parents:
- Defective Collagen Remodelling Spectrum
notes: >-
  The name "Winchester syndrome" has been applied to two genetically distinct
  diseases, and the literature cannot be used without checking which one a
  report describes. The two sisters described by Winchester in 1969 carry a
  homozygous MMP14 p.Thr17Arg variant, and MONDO:0010201 (OMIM 277950) is the
  MMP14 disease. Before that gene was found, several families diagnosed
  clinically as Winchester syndrome were shown to carry biallelic MMP2 variants;
  those patients have MMP2-related MONA (MONDO:0009809), a related but distinct
  disease, and their reports are not used as evidence here. The MMP14-related
  disease is distinguished in the laboratory by patient fibroblasts that secrete
  abundant pro-MMP2 but activate little of it, whereas MMP2-deficient MONA cells
  show neither form.


  Only two MMP14 families are molecularly confirmed in the cited literature: the
  original sisters (p.Thr17Arg) and two Dutch brothers with a milder,
  hypomorphic p.Arg111His allele who were first reported as Borrone
  dermato-cardio-skeletal syndrome. The cutaneous phenotype (thickened leathery
  skin, hyperpigmented and hypertrichotic patches) and several other features
  are documented in reports of clinically diagnosed Winchester syndrome that
  predate or lack genotyping; those items are cited as such and could include
  MMP2-related cases.


  MONDO also lists "nodulosis arthropathy osteolysis syndrome", "NOA syndrome"
  and "Al-Qeel Sewairi syndrome" among the synonyms of this term. Those names
  belong to the MMP2-related MONA phenotype and are not carried here. The
  GeneReviews chapter "Multicentric Osteolysis Nodulosis and Arthropathy"
  defines MONA by biallelic MMP2 variants or reduced MMP2
  activity and is therefore not the clinical baseline for this MMP14 disease;
  no GeneReviews chapter covers MMP14-related Winchester syndrome.
references:
- reference: PMID:22922033
  title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
- reference: PMID:29741626
  title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
- reference: PMID:31218820
  title: "Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling."
- reference: PMID:10520996
  title: "MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover."
- reference: PMID:10737763
  title: "Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I."
- reference: PMID:14610065
  title: "MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth."
- reference: PMID:23685250
  title: "MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis."
- reference: PMID:28675805
  title: "Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders."
inheritance:
- name: Autosomal recessive
  description: >-
    Both molecularly confirmed families are homozygous for an MMP14 missense
    variant. The original affected sisters were born to unaffected first-cousin
    parents, and the Dutch family comprises two affected brothers.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis."
    explanation: >-
      States the autosomal recessive mode of inheritance in a paper reporting a
      second homozygous MMP14 family.
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Winchester syndrome is a presumed autosomal-recessive disorder first described in two sisters who had severe skeletal and joint deformities and whose unaffected, healthy parents were first cousins."
    explanation: >-
      Affected sibs of unaffected consanguineous parents, the pedigree in which
      the homozygous MMP14 variant was later found.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Described as extremely rare; two molecularly confirmed MMP14 families are
    reported in the cited literature. A 2001 count of nine published patients
    predates genotyping and may include MMP2-related cases.
  evidence:
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis."
    explanation: Supports the ultra-rare qualitative tier.
  - reference: PMID:11794271
    reference_title: "Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Winchester syndrome was first described in 1969 and since then nine patients have been reported in the literature."
    explanation: >-
      A pre-genotyping case count, which bounds the number of published
      clinically diagnosed patients at the time.
pathophysiology:
- name: MMP14 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic MMP14 missense variants reduce the amount or the activity of
    MT1-MMP at the cell surface. The signal-peptide variant p.Thr17Arg impairs
    processing of the nascent protein, so it is rapidly degraded and almost no
    active enzyme reaches the plasma membrane. The milder pro-domain variant
    p.Arg111His is processed and trafficked normally but has reduced
    proteolytic activity, and the milder phenotype it produces suggests that
    residual catalytic activity sets disease severity.
  genes:
  - preferred_term: MMP14
    term:
      id: hgnc:7160
      label: MMP14
  molecular_functions:
  - preferred_term: metalloendopeptidase activity
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Winchester fibroblasts had almost no detectable levels of active MT1-MMP either in the membrane fraction (Figure 2B) or on their surface (Figure 2C)."
    explanation: >-
      Patient fibroblasts carrying p.Thr17Arg lack active MT1-MMP at the cell
      surface, the site where the enzyme acts.
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All together, the experiments on the altered protein demonstrated the deleterious effect of the mutation on subcellular localization, protein stability, and MMP-2 activation."
    explanation: >-
      Summarises the transfection and cycloheximide experiments showing that
      p.Thr17Arg destabilises MT1-MMP and prevents its membrane localization.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Instead, it partially impairs MMP14's proteolytic activity."
    explanation: >-
      The hypomorphic p.Arg111His allele reduces catalytic activity without
      affecting trafficking, a second route to loss of function.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we hypothesize that MMP14's catalytic activity is the prime determinant of disease severity."
    explanation: >-
      The authors' interpretation linking residual enzyme activity to the
      milder phenotype of the p.Arg111His family. Stated as a hypothesis.
  downstream:
  - target: Impaired Pro-MMP2 Activation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22922033
      reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We demonstrate that the resulting hydrophobic-region signal-peptide substitution (p.Thr17Arg) decreases MT1-MMP membrane localization with consequent impairment of pro-MMP2 activation"
      explanation: >-
        States the causal step from loss of membrane MT1-MMP to failed pro-MMP2
        activation in patient cells.
  - target: Defective Pericellular Collagen Remodeling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10520996
      reference_title: "MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."
      explanation: >-
        In the knockout mouse, loss of MT1-MMP removes an essential
        collagenolytic activity; the edge is drawn from mouse data.
- name: Impaired Pro-MMP2 Activation
  biological_scale: MOLECULAR
  description: >-
    MT1-MMP is a pericellular activator of the gelatinase MMP-2. Fibroblasts
    from the original Winchester proband secrete abundant pro-MMP2 but convert
    little of it to the active enzyme, and tissues from Mmp14-null mice are
    likewise deficient in pro-MMP2 activation. The p.Thr17Arg variant abolishes
    pro-MMP2 cleavage in a transfection assay, whereas the hypomorphic
    p.Arg111His variant retains partial activity, and the authors propose that
    this activation step is the main determinant of severity.
  biological_processes:
  - preferred_term: zymogen activation
    term:
      id: GO:0031638
      label: zymogen activation
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Conditioned media from these fibroblasts had abundant levels of MMP-2 proenzyme but reduced MMP-2 activity (Figure 1B)."
    explanation: >-
      Gelatin zymography of patient fibroblast medium shows retained pro-MMP2
      with reduced activation.
  - reference: PMID:10737763
    reference_title: "Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In tissues from null mice, activation of latent matrix metalloproteinase 2 was deficient, suggesting that MT1-MMP is essential for its activation in vivo."
    explanation: Establishes MT1-MMP as required for MMP-2 activation in vivo.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The T17R and R92C mutations completely abolish pro-MMP2 activation, whereas the R111H and S466P mutants retain residual activity."
    explanation: >-
      Graded loss of pro-MMP2 activation across the two human Winchester
      alleles tracks their clinical severity.
  downstream:
  - target: Defective Pericellular Collagen Remodeling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29741626
      reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "MMP14 hydrolyzes intact fibrillar collagen and activates downstream effectors, including the gelatinase matrix metalloproteinase 2 (MMP2) that in turn can further degrade fragmented collagen fibrils"
      explanation: >-
        Describes the two-step collagen degradation in which MT1-MMP cleaves
        fibrillar collagen and activated MMP-2 degrades the fragments, so failed
        MMP-2 activation also impairs collagen turnover.
- name: Defective Pericellular Collagen Remodeling
  biological_scale: CELLULAR
  description: >-
    MT1-MMP is the dominant pericellular collagenase of connective tissue
    cells. Without it, fibroblasts, chondrocytes, skeletal progenitors and
    osteocytes cannot cleave the type I collagen that surrounds them, so the
    matrix of developing bone, cartilage and soft connective tissue is not
    turned over. Reviews of the MMP14, MMP2 and SH3PXD2B disorders and their
    animal models identify defective collagen remodelling as the shared central
    lesion of the spectrum. Loss of osteocyte process formation in Mmp14-null
    bone has been attributed to the same failure of collagen cleavage.
  biological_processes:
  - preferred_term: collagen catabolic process
    term:
      id: GO:0030574
      label: collagen catabolic process
    modifier: DECREASED
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  evidence:
  - reference: PMID:31218820
    reference_title: "Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Furthermore, they demonstrate that defective collagen remodeling is central in the underlying pathology."
    explanation: >-
      Review of animal models of the MMP14, MMP2 and SH3PXD2B disorders
      concluding that defective collagen remodelling is central.
  - reference: PMID:23685250
    reference_title: "MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By contrast, in Mmp14-targeted mice, collagenolytic activity is reduced to background levels amid a denser network of type I collagen fibrils (Figure 4C)."
    explanation: >-
      In vivo demonstration that Mmp14 deletion abolishes type I collagenolysis
      in calvarial bone and leaves the collagen network unremodelled.
  - reference: PMID:15601659
    reference_title: "The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Specifically, a deficiency of membrane type-1 matrix metalloproteinase leads to disruption of collagen cleavage in osteocytes and ultimately to the loss of formation of osteocyte processes."
    explanation: >-
      Extends the collagen-cleavage defect to osteocytes, which fail to form
      their processes in Mmp14-null bone.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Whereas our observations as well as previously published work do support a role for osteoclasts in the WS bone phenotype, the major problem seems to be defective collagen remodeling."
    explanation: >-
      The zebrafish knockout study's conclusion that collagen remodelling,
      rather than osteoclast activity, is the primary defect.
  downstream:
  - target: Persistence of Unremodeled Cartilage Anlagen
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14610065
      reference_title: "MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The MT1-MMP deficiency disrupts this process and uncouples apoptotic demise of chondrocytes and cartilage degradation"
      explanation: >-
        Loss of MT1-MMP-dependent cartilage dissolution leaves unmineralized
        cartilage in place in the knockout mouse.
  - target: Impaired Osteogenic Commitment of Skeletal Stem Cells
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23685250
      reference_title: "MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "By effecting ECM remodeling, MT1-MMP regulates stem cell shape, thereby activating a β1-integrin/RhoGTPase signaling cascade and triggering the nuclear localization of the transcriptional coactivators YAP and TAZ, which serve to control SSC lineage commitment."
      explanation: >-
        Places matrix remodelling upstream of the integrin/YAP/TAZ signal that
        commits skeletal stem cells to the osteoblast lineage.
  - target: Growth Plate Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Periarticular Joint Destruction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10520996
      reference_title: "MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."
      explanation: Attributes the arthritis of the knockout to lost collagenolysis.
  - target: Soft Connective Tissue Fibrosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10520996
      reference_title: "MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."
      explanation: Attributes soft-tissue fibrosis of the knockout to lost collagenolysis.
  - target: Abnormal Craniofacial Skeletal Development
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10520996
      reference_title: "MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."
      explanation: Attributes craniofacial dysmorphism of the knockout to lost collagenolysis.
- name: Persistence of Unremodeled Cartilage Anlagen
  biological_scale: TISSUE
  description: >-
    During skeletal development, unmineralized cartilage templates are normally
    dissolved by MT1-MMP in step with apoptosis of their chondrocytes and
    replaced by bone, tendon or ligament. In MT1-MMP deficiency these cartilages
    persist, and both endochondral and intramembranous ossification are
    impaired; the mmp14a/b knockout zebrafish shows the same enlarged,
    disorganized cartilage cores with sparse bone matrix.
  biological_processes:
  - preferred_term: endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:14610065
    reference_title: "MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Membrane-type 1 matrix metalloproteinase (MT1-MMP)-dependent dissolution of unmineralized cartilages, coupled with apoptosis of nonhypertrophic chondrocytes, mediates remodeling of these cartilages into other tissues."
    explanation: Defines the remodelling step that MT1-MMP deficiency disrupts.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "It was shown in Mmp14 KO mice that these cartilage templates are not properly replaced, respectively removed, owing to impaired MMP14-dependent collagen remodeling (32,33,41)."
    explanation: >-
      Restates the mouse finding in the context of the zebrafish model, which
      shows the same persistent cartilage cores.
  downstream:
  - target: Defective Subarticular Ossification of Carpal and Tarsal Bones
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28675805
      reference_title: "Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Thus, abnormal bone formation in areas of subarticular ossification may explain the site-specific distribution of the carpal-tarsal osteolysis phenotype."
      explanation: >-
        Proposes, from normal mouse forepaw development, that the carpal and
        tarsal bones form by a distinct subarticular endochondral ossification
        that would be the site most affected by failed cartilage remodelling.
        A hypothesis, not a demonstration in MMP14-deficient tissue.
- name: Defective Subarticular Ossification of Carpal and Tarsal Bones
  biological_scale: TISSUE
  description: >-
    The carpal and tarsal "osteolysis" that defines the syndrome may reflect
    abnormal formation and modelling of these bones rather than excess
    resorption. Carpal and tarsal bones ossify from subarticular cartilage by a
    process distinct from growth-plate endochondral ossification, and osteoclast
    (TRAP) staining is notably absent there at the developmental stage relevant
    to the human disease. This reinterpretation rests on normal mouse
    developmental anatomy and has not been tested in MMP14-deficient carpal
    tissue.
  locations:
  - preferred_term: carpal bone
    term:
      id: UBERON:0001435
      label: carpal bone
  - preferred_term: tarsal bone
    term:
      id: UBERON:0001447
      label: tarsal bone
  evidence:
  - reference: PMID:28675805
    reference_title: "Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes."
    explanation: >-
      Hypothesis covering the MAFB, MMP2 and MMP14 carpal-tarsal osteolysis
      syndromes, derived from normal mouse development.
  - reference: PMID:28675805
    reference_title: "Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution."
    explanation: Records why the classical resorption model is considered insufficient.
  downstream:
  - target: Carpal Osteolysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Tarsal Osteolysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Osteogenic Commitment of Skeletal Stem Cells
  biological_scale: CELLULAR
  description: >-
    Skeletal stem cells use MT1-MMP to remodel their collagen niche, and the
    resulting change in cell shape activates beta1-integrin, RhoGTPase and
    YAP/TAZ signalling that commits them to the osteoblast lineage. Deleting
    Mmp14 in mesenchymal progenitors, but not in committed osteoblasts, diverts
    these cells towards adipocyte and chondrocyte fates and produces
    generalized osteopenia without a change in osteoclast number.
  cell_types:
  - preferred_term: skeletal stem cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  - preferred_term: fat cell differentiation
    term:
      id: GO:0045444
      label: fat cell differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:23685250
    reference_title: "MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis."
    explanation: Conditional knockout shows the lineage switch caused by Mmp14 loss.
  downstream:
  - target: Generalized Bone Loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23685250
      reference_title: "MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective osteogenesis is not confined to cranial tissues, as osteopenia is apparent throughout the skeleton of adult Mmp14f/f/Dermo1-Cre mice with no apparent changes in osteoclast number"
      explanation: >-
        Progenitor-targeted Mmp14 deletion produces skeleton-wide osteopenia
        from failed bone formation rather than increased resorption.
- name: Generalized Bone Loss
  biological_scale: TISSUE
  description: >-
    Reduced bone formation across the skeleton underlies the generalized
    osteoporosis of the human disease, the osteopenia of the Mmp14-null mouse
    and the reduced bone mineral density of the mmp14a/b knockout zebrafish.
    Osteoclasts may contribute, but the primary defect is in collagen
    remodelling and osteogenesis.
  biological_processes:
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: DECREASED
  evidence:
  - reference: PMID:10520996
    reference_title: "MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."
    explanation: Osteopenia is a cardinal feature of the knockout mouse.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling."
    explanation: Reduced bone density in the zebrafish model, attributed to defective collagen remodelling.
  downstream:
  - target: Generalized Osteoporosis
    causal_link_type: DIRECT
- name: Growth Plate Dysfunction
  biological_scale: TISSUE
  description: >-
    In Mmp14-null mice, chondrocyte proliferation in the growth plate is
    reduced and vascular invasion of hypertrophic cartilage is defective, which
    enlarges the hypertrophic zone, delays secondary ossification centres and
    shortens the long bones. This is the proposed basis of dwarfism in the
    model and, by analogy, of short stature in the human disease.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:10737763
    reference_title: "Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Defective vascular invasion of cartilage leads to enlargement of hypertrophic zones of growth plates and delayed formation of secondary ossification centers in long bones."
    explanation: Describes the growth plate defect of the knockout mouse.
  downstream:
  - target: Short Stature
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10737763
      reference_title: "Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Shortening of bones is a consequence of decreased chondrocyte proliferation in the proliferative zone of the growth plates."
      explanation: >-
        States that the growth plate defect causes bone shortening in the
        model; the extension to human short stature is by analogy.
- name: Periarticular Joint Destruction
  biological_scale: TISSUE
  description: >-
    Progressive destruction of small and large joints, with interphalangeal
    erosions that mimic rheumatoid arthritis, eventual loss of function of the
    shoulders, elbows, hips and knees, and ankylosis of the remaining hand
    bones. The Mmp14-null mouse develops arthritis attributed to the same loss
    of collagenolytic remodelling.
  locations:
  - preferred_term: synovial joint
    term:
      id: UBERON:0002217
      label: synovial joint
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"
    explanation: Describes joint destruction in the molecularly confirmed index family.
  downstream:
  - target: Progressive Joint Destruction
    causal_link_type: DIRECT
  - target: Interphalangeal Joint Erosions
    causal_link_type: DIRECT
  - target: Ankylosis
    causal_link_type: DIRECT
  - target: Arthropathy
    causal_link_type: DIRECT
  - target: Flexion Contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Soft Connective Tissue Fibrosis
  biological_scale: TISSUE
  description: >-
    Collagen that cannot be turned over accumulates in the dermis and other soft
    connective tissues. The Mmp14-null mouse develops soft-tissue fibrosis, and
    dermal fibrosis is listed among the shared features of the defective
    collagen-remodelling spectrum. In clinically diagnosed Winchester patients
    the skin is diffusely thickened and leathery and can bind joints into
    contracture.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:10520996
    reference_title: "MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."
    explanation: Soft-tissue fibrosis in the knockout mouse.
  - reference: PMID:31218820
    reference_title: "Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "are ultra-rare multisystem disorders characterized by craniofacial malformations, reduced bone density, skeletal and cardiac anomalies, and dermal fibrosis"
    explanation: Review of 63 patients across the spectrum naming dermal fibrosis as a shared feature.
  downstream:
  - target: Thickened Skin
    causal_link_type: DIRECT
  - target: Flexion Contracture
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38291559
      reference_title: "A child with Winchester syndrome responding to oral betamethasone and methotrexate."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report a 14-year-old male who presented with growth retardation, contracture of left lower limb due to thick indurated skin, hypertrichosis, and bilateral corneal opacity."
      explanation: >-
        A clinically diagnosed, ungenotyped patient whose limb contracture is
        attributed to indurated skin.
- name: Abnormal Craniofacial Skeletal Development
  biological_scale: TISSUE
  description: >-
    Failed remodelling of membranous and endochondral skull bones produces
    craniofacial dysmorphism in the Mmp14-null mouse (a short, domed skull) and
    in the mmp14a/b knockout zebrafish. In the original Winchester proband the
    anterior fontanelle remained open at 18 years.
  evidence:
  - reference: PMID:10737763
    reference_title: "Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The craniofacial, axial, and appendicular skeletons were severely affected, leading to a short and domed skull, marked deceleration of postnatal growth, and death by 3 wk of age."
    explanation: Craniofacial skeletal involvement of the knockout mouse.
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The skull radiograph demonstrates the generalized nature of the osteolytic loss of bone and that the anterior fontanelle remains patent."
    explanation: Calvarial involvement in the molecularly confirmed proband.
  downstream:
  - target: Persistent Open Anterior Fontanelle
    causal_link_type: DIRECT
  - target: Coarse Facial Features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Skeletal
  name: Carpal Osteolysis
  description: >-
    Progressive, bilateral and symmetric dissolution of the carpal bones, the
    defining radiographic feature; at 18 years the original proband had lost all
    carpal bones.
  phenotype_term:
    preferred_term: Carpal osteolysis
    term:
      id: HP:0001495
      label: Carpal osteolysis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"
    explanation: Carpal osteolysis in the molecularly confirmed index sisters.
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hand radiograph demonstrates complete loss of all carpal bones, destruction of metacarpals and phalanges, and severe ankylosis of the remaining bones."
    explanation: Radiographic end stage of carpal osteolysis in the proband.
- category: Skeletal
  name: Tarsal Osteolysis
  description: Progressive, symmetric dissolution of the tarsal bones.
  phenotype_term:
    preferred_term: Osteolysis involving tarsal bones
    term:
      id: HP:0006234
      label: Osteolysis involving tarsal bones
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"
    explanation: Tarsal osteolysis in the molecularly confirmed index sisters.
- category: Skeletal
  name: Generalized Osteoporosis
  description: >-
    Generalized loss of bone density. Reduced bone density was also present in
    the milder p.Arg111His family.
  phenotype_term:
    preferred_term: Generalized osteoporosis
    term:
      id: HP:0040160
      label: Generalized osteoporosis
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"
    explanation: Generalized osteoporosis in the index sisters.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."
    explanation: Reduced bone density in the second MMP14 family.
- category: Skeletal
  name: Interphalangeal Joint Erosions
  description: Erosions of the interphalangeal joints resembling rheumatoid arthritis.
  phenotype_term:
    preferred_term: Interphalangeal joint erosions
    term:
      id: HP:0006252
      label: Interphalangeal joint erosions
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"
    explanation: Interphalangeal erosions in the index sisters.
- category: Skeletal
  name: Progressive Joint Destruction
  description: >-
    Progressive destruction of the large joints with eventual loss of function
    of the shoulders, elbows, hips and knees.
  phenotype_term:
    preferred_term: Progressive joint destruction
    term:
      id: HP:0005187
      label: Progressive joint destruction
  evidence:
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis."
    explanation: Names progressive joint destruction as a defining feature.
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The children suffered from progressive bilateral and symmetric osteolysis of the carpals and tarsals, interphalangeal joint erosions mimicking rheumatoid arthritis, generalized osteoporosis, and eventual loss of function of the larger joints, including the shoulder, elbow, hip, and knee joints"
    explanation: Loss of large-joint function in the index sisters.
- category: Skeletal
  name: Ankylosis
  description: Ankylosis of the remaining hand bones after carpal dissolution.
  phenotype_term:
    preferred_term: Ankylosis
    term:
      id: HP:0031013
      label: Ankylosis
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hand radiograph demonstrates complete loss of all carpal bones, destruction of metacarpals and phalanges, and severe ankylosis of the remaining bones."
    explanation: Ankylosis on the proband's hand radiograph at 18 years.
- category: Skeletal
  name: Arthropathy
  description: >-
    Progressive painful arthropathy with joint stiffness, simulating advanced
    rheumatoid arthritis.
  phenotype_term:
    preferred_term: Progressive painful arthropathy
    term:
      id: HP:0003040
      label: Arthropathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11794271
    reference_title: "Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The syndrome is characterized by short stature, coarse face, corneal opacities, generalized osteolysis and progressive painful arthropathy with joint stiffness and contractures of distal phalanges in combination with skin changes."
    explanation: >-
      Case report summary of the syndrome; the reported patient was diagnosed
      clinically before the gene was known.
  - reference: PMID:33776097
    reference_title: "Anaesthesia management for Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The presence of marked intra- and periarticular joint destruction simulated advanced rheumatoid arthritis."
    explanation: Restates the original 1969 description of the molecularly confirmed family.
- category: Skeletal
  name: Flexion Contracture
  description: >-
    Progressive flexion contractures of large and small joints, including the
    distal phalanges.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33776097
    reference_title: "Anaesthesia management for Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."
    explanation: >-
      Restates the original description of the family later shown to carry the
      MMP14 p.Thr17Arg variant.
  - reference: PMID:14726867
    reference_title: "Progressive multilayered banded skin in Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The syndrome is characterized by dissolution of carpal and tarsal bones with generalized osteoporosis, progressive joint contractures, short stature, peripheral corneal opacities, and coarse facial features, though there is variability within the clinical features."
    explanation: Clinical summary in a report of an ungenotyped patient.
- category: Growth
  name: Short Stature
  description: Postnatal short stature.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:33776097
    reference_title: "Anaesthesia management for Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."
    explanation: Short stature in the original, molecularly confirmed family.
  - reference: PMID:11794271
    reference_title: "Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The syndrome is characterized by short stature, coarse face, corneal opacities, generalized osteolysis and progressive painful arthropathy with joint stiffness and contractures of distal phalanges in combination with skin changes."
    explanation: Short stature in a clinically diagnosed case report.
- category: Craniofacial
  name: Coarse Facial Features
  description: >-
    Coarsened facial features; the milder p.Arg111His brothers had dysmorphic
    facial features.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: PMID:33776097
    reference_title: "Anaesthesia management for Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."
    explanation: Coarse facies in the original, molecularly confirmed family.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."
    explanation: Facial dysmorphism in the second MMP14 family.
- category: Craniofacial
  name: Persistent Open Anterior Fontanelle
  description: The anterior fontanelle remained patent at 18 years in the original proband.
  phenotype_term:
    preferred_term: Persistent open anterior fontanelle
    term:
      id: HP:0004474
      label: Persistent open anterior fontanelle
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The skull radiograph demonstrates the generalized nature of the osteolytic loss of bone and that the anterior fontanelle remains patent."
    explanation: Skull radiograph of the molecularly confirmed proband.
- category: Ophthalmologic
  name: Peripheral Corneal Opacity
  description: Peripheral opacities of the cornea.
  phenotype_term:
    preferred_term: Peripheral corneal opacities
    term:
      id: HP:0008011
      label: Peripheral opacification of the cornea
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was also noted that the siblings had gum hypertrophy, corneal opacities, and electrocardiographical findings suggestive of myocardial damage."
    explanation: Corneal opacities in the molecularly confirmed index sisters.
  - reference: PMID:33776097
    reference_title: "Anaesthesia management for Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "described a new syndrome characterised by short stature, joint stiffening with severe contractures, peripheral corneal opacities, coarsened facial features, dissolution of the carpal and tarsal bones, and generalised osteoporosis."
    explanation: Specifies the peripheral location of the opacities in the original description.
- category: Oral
  name: Gingival Overgrowth
  description: Gingival (gum) hypertrophy.
  phenotype_term:
    preferred_term: Gingival hypertrophy
    term:
      id: HP:0000212
      label: Gingival overgrowth
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was also noted that the siblings had gum hypertrophy, corneal opacities, and electrocardiographical findings suggestive of myocardial damage."
    explanation: Gum hypertrophy in the molecularly confirmed index sisters.
- category: Cardiovascular
  name: Abnormal Electrocardiogram
  description: >-
    Electrocardiographic findings suggestive of myocardial damage in the index
    sisters. Cardiac evaluation is recommended for suspected patients, and death
    from heart failure has been reported.
  phenotype_term:
    preferred_term: Electrocardiographic findings suggestive of myocardial damage
    term:
      id: HP:0003115
      label: Abnormal EKG
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was also noted that the siblings had gum hypertrophy, corneal opacities, and electrocardiographical findings suggestive of myocardial damage."
    explanation: ECG abnormality in the molecularly confirmed index sisters.
- category: Cardiovascular
  name: Mitral Valve Prolapse
  description: Reported in the two brothers homozygous for the hypomorphic p.Arg111His allele.
  phenotype_term:
    preferred_term: Mitral valve prolapse
    term:
      id: HP:0001634
      label: Mitral valve prolapse
  evidence:
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."
    explanation: Mitral valve prolapse in the second MMP14 family.
- category: Dermatologic
  name: Thickened Skin
  description: >-
    Diffusely thickened, leathery skin, which in one reported adult developed
    into progressive restrictive banding. Documented in clinically diagnosed,
    ungenotyped patients.
  phenotype_term:
    preferred_term: Thickened leathery skin
    term:
      id: HP:0001072
      label: Thickened skin
  evidence:
  - reference: PMID:14726867
    reference_title: "Progressive multilayered banded skin in Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."
    explanation: Review of cutaneous features in clinically diagnosed patients.
  - reference: PMID:38291559
    reference_title: "A child with Winchester syndrome responding to oral betamethasone and methotrexate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 14-year-old male who presented with growth retardation, contracture of left lower limb due to thick indurated skin, hypertrichosis, and bilateral corneal opacity."
    explanation: Thick indurated skin in a clinically diagnosed child.
- category: Dermatologic
  name: Hyperpigmentation of the Skin
  description: >-
    Patches of hyperpigmented, hypertrichotic leathery skin in annular or linear
    distribution, documented in clinically diagnosed patients.
  phenotype_term:
    preferred_term: Hyperpigmented skin patches
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:14726867
    reference_title: "Progressive multilayered banded skin in Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."
    explanation: Hyperpigmented patches among the reported cutaneous features.
- category: Dermatologic
  name: Hypertrichosis
  description: Hypertrichosis, diffuse or within patches of thickened skin.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  evidence:
  - reference: PMID:14726867
    reference_title: "Progressive multilayered banded skin in Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."
    explanation: Hypertrichosis among the reported cutaneous features.
  - reference: PMID:38291559
    reference_title: "A child with Winchester syndrome responding to oral betamethasone and methotrexate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 14-year-old male who presented with growth retardation, contracture of left lower limb due to thick indurated skin, hypertrichosis, and bilateral corneal opacity."
    explanation: Hypertrichosis in a clinically diagnosed child.
- category: Dermatologic
  name: Acne
  description: Severe or widespread acne.
  phenotype_term:
    preferred_term: Acne
    term:
      id: HP:0001061
      label: Acne
  evidence:
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2007, we reported two Dutch brothers with an autosomal recessive disorder consisting of dysmorphic facial features, mitral valve prolapse, severe acne and reduced bone density (1)."
    explanation: Severe acne in the second MMP14 family.
  - reference: PMID:14726867
    reference_title: "Progressive multilayered banded skin in Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic heterogeneity of cutaneous features are also reported to date of diffusely thickened leathery skin, hypertrichosis, patches of hyperpigmented, hypertrichotic leathery skin in annular or linear distribution, widespread acne, subcutaneous nodules, and gingival hypertrophy."
    explanation: Widespread acne among the reported cutaneous features.
biochemical:
- name: Reduced fibroblast pro-MMP2 activation
  presence: DECREASED
  notes: >-
    Gelatin zymography of conditioned medium from patient fibroblasts shows
    abundant pro-MMP2 with reduced active MMP-2. MMP2-deficient MONA fibroblasts
    show neither the proenzyme nor the active form, so the pattern separates
    the two diseases.
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Conditioned media from these fibroblasts had abundant levels of MMP-2 proenzyme but reduced MMP-2 activity (Figure 1B)."
    explanation: The zymographic finding in Winchester fibroblasts.
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This is in marked contrast to MONA-derived cell lines, which do not show zymographic activity of either the proenzyme or active forms of MMP-2."
    explanation: The contrasting MONA pattern that makes the test discriminating.
genetic:
- name: MMP14
  gene_term:
    preferred_term: MMP14
    term:
      id: hgnc:7160
      label: MMP14
  relationship_type: CAUSATIVE
  notes: >-
    MMP14 encodes membrane type-1 matrix metalloproteinase (MT1-MMP). Two
    homozygous missense alleles are reported: p.Thr17Arg in the signal peptide
    in the original family, and the hypomorphic p.Arg111His in the pro-domain in
    a milder family.
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using cultured fibroblasts from the proband, we have now identified homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14)."
    explanation: Identification of the causal gene in the original Winchester family.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS."
    explanation: A second, independent MMP14 family.
  variants:
  - name: MMP14 p.(Thr17Arg)
    description: >-
      Homozygous signal-peptide missense variant in the original 1969 sisters,
      reported by the source as n.284C>G in codon 17 of exon 1 (NM_004995.2). It
      destabilises the protein and prevents its membrane localization,
      abolishing pro-MMP2 activation.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22922033
      reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequence analysis revealed a homozygous missense mutation, a C>G transversion (n.284C>G) in codon 17 of exon 1, that predicted replacement of a threonine by an arginine (p.Thr17Arg) (Figure 1C)."
      explanation: Defines the variant and its homozygous state.
  - name: MMP14 c.332G>A p.(Arg111His)
    description: >-
      Homozygous hypomorphic pro-domain variant in two Dutch brothers with a
      milder phenotype that did not appreciably worsen over follow-up. The
      protein is processed and reaches the cell membrane but has partially
      reduced proteolytic activity.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:29741626
      reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subsequent homozygosity mapping and next-generation sequencing identified a novel homozygous missense mutation in MMP14, c.332G>A"
      explanation: Identification of the variant.
    - reference: PMID:29741626
      reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, in the intervening years since diagnosis their phenotype has not appreciably worsened, suggesting that it is intrinsically milder."
      explanation: Documents the milder course associated with this allele.
diagnosis:
- name: Molecular confirmation by MMP14 sequencing
  description: >-
    The diagnosis rests on the clinical and radiographic picture of
    carpal-tarsal osteolysis with arthropathy and is confirmed by biallelic
    MMP14 variants. Because MMP2-related MONA overlaps clinically and was
    historically diagnosed as Winchester syndrome, clinical diagnosis alone
    cannot separate the two; fibroblast zymography also distinguishes them.
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, and on the basis of an incorrect clinical diagnosis of Winchester syndrome, Winchester syndrome and MONA were presumed to be allelic disorders arising from mutations in the same gene"
    explanation: Shows that clinical diagnosis alone mislabelled MMP2 cases.
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our studies now demonstrate that mutations in MMP2 and MT1-MMP result in related but distinct"
    explanation: Establishes the MMP14 and MMP2 diseases as distinct, so genotyping is needed.
- name: Cardiac evaluation
  description: >-
    A complete cardiac evaluation is recommended for anyone suspected of
    Winchester syndrome or MONA, given the ECG abnormalities in the index
    sisters and reported death from heart failure.
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all individuals suspected to be affected by Winchester syndrome and/or MONA should undergo a complete cardiac evaluation."
    explanation: The gene-discovery authors' recommendation.
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Where WS patients reportedly die from heart failure, the mice succumb to wasting"
    explanation: Reported cardiac cause of death in patients.
differential_diagnoses:
- name: Multicentric osteolysis, nodulosis, and arthropathy (MMP2-related)
  description: >-
    The MMP2 disease overlaps closely and several MMP2 families were reported as
    Winchester syndrome. Both belong to the defective collagen-remodelling
    spectrum with Frank-Ter Haar syndrome.
  distinguishing_features:
  - Biallelic MMP2 rather than MMP14 variants.
  - Fibroblasts lack both pro-MMP2 and active MMP-2 on zymography, whereas MMP14-deficient cells secrete pro-MMP2 that is poorly activated.
  disease_term:
    preferred_term: multicentric osteolysis, nodulosis, and arthropathy
    term:
      id: MONDO:0009809
      label: multicentric osteolysis, nodulosis, and arthropathy
  evidence:
  - reference: PMID:22922033
    reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This is in marked contrast to MONA-derived cell lines, which do not show zymographic activity of either the proenzyme or active forms of MMP-2."
    explanation: The laboratory discriminator between the two diseases.
  - reference: PMID:31218820
    reference_title: "Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "These autosomal recessive syndromes are caused by homozygous mutation or deletion of respectively SH3PXD2B (SH3 and PX Domains 2B), MMP14 (matrix metalloproteinase 14), or MMP2."
    explanation: Assigns each syndrome of the spectrum to its own gene.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Bisphosphonates have been tried in Winchester syndrome and related
    disorders with limited success. They act mainly on osteoclasts, whereas the
    primary defect is thought to be in collagen remodelling, so the authors of
    the zebrafish model argue that treatment should target that defect instead.
  treatment_term:
    preferred_term: Bisphosphonate therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:29741626
    reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Attempts have been made in the past to treat WS and related disorders with bisphosphonates, with limited success (45,46)."
    explanation: Records prior use and limited efficacy of bisphosphonates.
- name: Glucocorticoid and Methotrexate
  description: >-
    One clinically diagnosed, ungenotyped boy with contracture from indurated
    skin had complete improvement of the contracture on oral betamethasone
    pulses with weekly oral methotrexate. This is a single case report.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: betamethasone
      term:
        id: CHEBI:3077
        label: betamethasone
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  evidence:
  - reference: PMID:38291559
    reference_title: "A child with Winchester syndrome responding to oral betamethasone and methotrexate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was complete improvement in joint contracture with oral betamethasone pulse and weekly oral methotrexate."
    explanation: Single case response; the diagnosis was clinical, not molecular.
animal_models:
- name: Mmp14-null mouse
  species: Mouse
  genotype: Mmp14 (MT1-MMP) homozygous null
  publication: PMID:10520996
  description: >-
    Gene-targeted MT1-MMP-deficient mice develop craniofacial dysmorphism,
    arthritis, osteopenia, dwarfism and soft-tissue fibrosis, and die within
    weeks. The human disease parallels this skeletal phenotype in a less severe
    form, plausibly because patient cells retain some active enzyme.
  modeled_mechanisms:
  - target: Defective Pericellular Collagen Remodeling
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: Complete loss of MT1-MMP collagenolysis in vivo.
    limitations: >-
      A complete null is more severe than either human allele, both of which
      retain some activity, and the mice die at an age before most human
      skeletal features develop.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Null mice die by about three weeks with wasting, whereas patients
        survive into adulthood and reportedly die of heart failure, so late
        skeletal and cardiac features of the human disease cannot be read off
        the mouse.
    evidence:
    - reference: PMID:22922033
      reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "an inactivating homoallelic mutation of MT1-MMP in humans results in Winchester syndrome, a rare osteolysis and arthritis disorder whose skeletal phenotype, although not as severe, parallels those previously described for the Mt1-mmp-null mouse."
      explanation: Human-mouse correspondence stated by the gene-discovery paper.
    - reference: PMID:22922033
      reference_title: "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The low level of active MT1-MMP present at the surface of patient-derived fibroblasts provides evidence of at least partial activity of the enzyme and might explain the differences in skeletal findings and survival between affected humans and engineered Mt1-mmp-null mice."
      explanation: Explains the severity gap between the null mouse and patients.
  - target: Growth Plate Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Growth plate and vascular invasion defects causing bone shortening.
    evidence:
    - reference: PMID:10737763
      reference_title: "Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Shortening of bones is a consequence of decreased chondrocyte proliferation in the proliferative zone of the growth plates."
      explanation: Growth plate mechanism of dwarfism in the null mouse.
- name: mmp14a/b double knockout zebrafish
  species: Zebrafish
  genotype: mmp14a and mmp14b frameshift double homozygous (CRISPR/Cas9)
  publication: PMID:29741626
  description: >-
    Zebrafish lacking both mmp14 paralogs develop a progressive phenotype from
    about 30 days post-fertilization with short body length, craniofacial
    malformation, hyperkyphosis, reduced skull bone mineral density and
    persistent disorganized cartilage cores, and die at about 4.5 months.
  modeled_mechanisms:
  - target: Generalized Bone Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reduced bone density attributed to defective collagen remodelling.
    limitations: >-
      Zebrafish carry two mmp14 paralogs and differ in bone morphology and
      ossification, and the fish die of spinal cord impingement, which is not
      seen in patients.
    evidence:
    - reference: PMID:29741626
      reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling."
      explanation: Summary of model fidelity.
  - target: Persistence of Unremodeled Cartilage Anlagen
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Enlarged, disorganized cartilage cores with sparse bone matrix in skull bones.
    evidence:
    - reference: PMID:29741626
      reference_title: "Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "It was shown in Mmp14 KO mice that these cartilage templates are not properly replaced, respectively removed, owing to impaired MMP14-dependent collagen remodeling (32,33,41)."
      explanation: The authors relate their cartilage findings to the mouse mechanism.

📚

References & Deep Research

References

8

PMID:22922033

Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome.

No top-level findings curated for this source.

PMID:29741626

Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype.

No top-level findings curated for this source.

PMID:31218820

Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling.

No top-level findings curated for this source.

PMID:10520996

MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.

No top-level findings curated for this source.

PMID:10737763

Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.

No top-level findings curated for this source.

PMID:14610065

MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth.

No top-level findings curated for this source.

PMID:23685250

MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis.

No top-level findings curated for this source.

PMID:28675805

Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders.

No top-level findings curated for this source.

Deep Research

1

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.

Evaluations and curation notes (1)

Create: Winchester_Syndrome · 2026-10-15T02:20:11Z · View source

Created the MMP14-related Winchester syndrome entry (MONDO:0010201) from the curation stub, which is removed in the same change. Scope: restricted to the MMP14 disease. Families with biallelic MMP2 variants that were reported as Winchester syndrome before 2012 belong to MMP2-related MONA (MONDO:0009809, a separate stub) and were not used as evidence. Molecularly confirmed MMP14 evidence comes from Evans 2012 (PMID:22922033, original sisters, p.Thr17Arg) and de Vos 2018 (PMID:29741626, Dutch brothers, hypomorphic p.Arg111His). Cutaneous features and some clinical features are cited from reports of clinically diagnosed, ungenotyped patients (PMID:14726867, 11794271, 38291559, 33776097), and each such item says so. Mechanism chain: MMP14 loss of function, impaired pro-MMP2 activation, defective pericellular collagen remodelling, then branches to persistent cartilage anlagen, carpal-tarsal subarticular ossification defect (hypothesis from PMID:28675805), skeletal stem cell osteogenic commitment (PMID:23685250), growth plate dysfunction (PMID:10737763), joint destruction, soft-tissue fibrosis and craniofacial skeletal development. 12 of 19 phenotypes are causally connected; corneal opacity, gingival overgrowth, ECG abnormality, mitral valve prolapse, hyperpigmentation, hypertrichosis and acne have no sourced mechanism and are left unconnected. Deep research: the OpenScientist report (research/Winchester_Syndrome-deep-research-openscientist.md) resolved 20/20 references with no unresolved terms, but just preflight-dr returned WARN (MMP2 mentioned 45 times against 27 for MMP14). On reading, the report conflates MMP2-related MONA with Winchester syndrome: most of its citations (for example PMID:34466312, 37842447, 26601801, 37025869, 33101055, 37710205, 39502084) describe MMP2 patients. Its corneal-imaging source PMID:39502084 is an MMP2 patient. Its treatment table NCIT codes were mislabelled (C15682, C15329, C15300) and were not used. Only report leads that were independently confirmed as MMP14 or Mmp14-model sources were used. GeneReviews: just check-genereviews --online reports NO_CHAPTER. The MONA chapter is defined by MMP2 and is noted, not tagged, as it is not this disease's baseline. Validation: just validate, validate-terms, count-verified-snippets (90/90), check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys, check-block-scalar-comments, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading all pass.

OpenScientist ▸

Winchester Syndrome: A Comprehensive Disease Characterization Report

openscientist-autonomous 20 citations 2026-10-15T02:17:14.460272

Winchester Syndrome: A Comprehensive Disease Characterization Report

Disease: Winchester Syndrome MONDO ID: MONDO:0010201 · OMIM: #277950 · Category: Mendelian (autosomal recessive) Report type: Disease knowledge-base characterization (multi-iteration autonomous literature synthesis) Evidence basis: Human clinical case reports/series, model-organism (mouse) studies, in vitro functional assays. No patient-level dataset was provided; this report is synthesized from primary literature (PMIDs cited inline).

Summary

Winchester syndrome is an ultra-rare, autosomal recessive "vanishing bone" skeletal dysplasia caused by biallelic loss-of-function mutations in MMP14 (MT1-MMP, membrane type-1 matrix metalloproteinase). The defining molecular lesion abolishes the cell-surface activation of pro-MMP2 and cripples pericellular remodeling of type I and type IV collagen. Because MT1-MMP is the master pericellular collagenase required to model skeletal and extraskeletal connective tissue, its loss produces a slow, relentless destruction of bone and a reactive fibrosis of soft tissue. Clinically, this manifests as progressive carpal and tarsal osteolysis ("disappearing bones"), generalized osteoporosis, destructive arthropathy with joint contractures, short stature, coarse facial features, peripheral corneal opacities, gingival hypertrophy, thickened leathery skin, and — in a substantial subset — congenital cardiac anomalies (PMID: 22922033, PMID: 14726867).

Winchester syndrome does not stand alone. Landmark nosological work places it within a unified "defective collagen-remodeling spectrum" (DECORS) together with Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA/Torg-Winchester, caused by MMP2) and Frank-Ter Haar syndrome (caused by SH3PXD2B). The three gene products — SH3PXD2B, MMP14, and MMP2 — physically and functionally cooperate in a single collagen-degradation axis, which is why the three disorders share craniofacial malformation, reduced bone density, skeletal and cardiac anomalies, and dermal fibrosis (PMID: 31218820). The mechanism is strongly corroborated by mouse genetics: Mmp14-null mice reproduce the human phenotype (dwarfism, osteopenia, arthritis, soft-tissue fibrosis) through ablated collagenolysis, and Mmp2-null mice reproduce the bone-density and osteocyte-network defects (PMID: 10520996, PMID: 16959767).

The disease is strongly associated with consanguinity, has been reported across many ethnicities (Indian, Egyptian, Pakistani, Finnish, Iranian, Japanese), and is frequently misdiagnosed as juvenile idiopathic arthritis (JIA) or rheumatoid arthritis — a dangerous error that leads to inappropriate immunosuppression. Diagnosis rests on characteristic radiographic osteolysis confirmed by MMP-2 zymography or molecular testing of MMP14/MMP2. No disease-modifying or curative therapy exists; care is supportive and multidisciplinary (physiotherapy, analgesia, orthopedic correction, and ophthalmologic/cardiac surveillance) (PMID: 34466312, PMID: 37842447).

1. Disease Information

Overview. Winchester syndrome is a Mendelian, autosomal recessive skeletal dysplasia belonging to the "idiopathic / inherited osteolysis" group of disorders. It is characterized by the spontaneous dissolution (osteolysis) of bones — most prominently the carpals and tarsals — together with generalized osteoporosis, progressive joint contractures, short stature, coarse facies, corneal opacities, and characteristic skin changes (PMID: 14726867). It is sometimes grouped under the colloquial term "disappearing bone disease," although that label also covers non-heritable entities such as Gorham-Stout disease (PMID: 21995273).

Key identifiers.

Resource	Identifier
MONDO	MONDO:0010201
OMIM	#277950 (Winchester syndrome)
Causal gene	MMP14 (MT1-MMP); closely related MONA = MMP2
Spectrum	DECORS (defective collagen-remodeling spectrum)

Synonyms / alternative names. Winchester syndrome; Torg-Winchester syndrome; (closely related / historically conflated) Multicentric Osteolysis, Nodulosis and Arthropathy (MONA), Torg syndrome, Nodulosis-Arthropathy-Osteolysis (NAO) syndrome, Multicentric Osteolysis with Arthropathy (MOA). Historically, Winchester syndrome and Torg/MONA were considered variants of a single entity; molecular work now separates classic Winchester syndrome (MMP14) from MONA (MMP2), while uniting them mechanistically (PMID: 24637309, PMID: 31218820).

Source of information. The evidence base is aggregated from individual patient case reports and small consanguineous-family case series rather than large registries or EHR datasets — a direct consequence of the disease's extreme rarity.

2. Etiology

Primary cause — genetic. Classic Winchester syndrome is caused by homozygous (biallelic) loss-of-function mutations in MMP14. Evans et al. (2012) identified homozygous MMP14 mutations in the original Winchester sisters and demonstrated that the resulting signal-peptide substitution p.Thr17Arg decreases MT1-MMP membrane localization, with consequent impairment of pro-MMP2 activation (PMID: 22922033):

"we have now identified homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14). We demonstrate that the resulting hydrophobic-region signal-peptide substitution (p.Thr17Arg) decreases MT1-MMP membrane localization with consequent impairment of pro-MMP2 activation."

The closely allied MONA/Torg phenotype is caused by biallelic MMP2 mutations; MMP2 encodes a gelatinase that cleaves type IV collagen, a major basement-membrane component (PMID: 24637309).

Genetic risk factors. The overwhelming risk determinant is inheritance of two pathogenic alleles, almost always in the setting of parental consanguinity. There are no established susceptibility loci or polygenic contributions; this is a monogenic Mendelian disorder.

Environmental risk factors. None established. There is no evidence that toxins, infections, diet, occupational exposure, age, or sex trigger or modify disease onset. The only "non-genetic" risk amplifier is the population-structural factor of consanguineous mating, which raises homozygosity.

Protective factors. None identified at the genetic or environmental level. Because the disorder is fully penetrant recessive, the only "protective" state is being a heterozygous carrier (clinically unaffected).

Gene–environment interactions. No gene–environment interaction has been described. The phenotype appears driven essentially entirely by genotype, with variable expressivity attributable to genetic/allelic background rather than environment.

3. Phenotypes

Winchester syndrome is a multisystem disorder. The cardinal features, drawn primarily from Sidwell et al. (2004) and corroborated across the MONA/Winchester case series, are summarized below (PMID: 14726867):

"characterized by dissolution of carpal and tarsal bones with generalized osteoporosis, progressive joint contractures, short stature, peripheral corneal opacities, and coarse facial features."

Phenotype	Type	HPO suggestion	Onset	Severity / progression	Frequency
Carpal/tarsal osteolysis ("vanishing bone")	Radiographic/clinical sign	HP:0010656 (carpal) / HP:0008369 (tarsal)	Childhood	Progressive	Cardinal/near-universal
Generalized osteoporosis / reduced bone density	Radiographic	HP:0000939	Childhood	Progressive	Very frequent
Progressive joint contractures	Physical manifestation	HP:0001371	Childhood	Progressive	Very frequent
Destructive arthropathy (pain, swelling, stiffness)	Clinical sign	HP:0001387	Childhood	Progressive	Frequent
Short stature / dwarfism	Physical manifestation	HP:0004322	Childhood	Stable–progressive	Frequent
Coarse facial features	Physical manifestation	HP:0000280	Childhood	Progressive	Frequent
Peripheral corneal opacities	Clinical sign (ocular)	HP:0007957	Childhood	Slowly progressive	Frequent
Gingival hypertrophy	Clinical sign	HP:0000212	Childhood	Progressive	Variable
Thickened, leathery skin / dermal fibrosis	Physical manifestation	HP:0000974 (thick skin)	Childhood	Progressive	Variable
Hypertrichosis / hirsutism	Physical manifestation	HP:0000998	Childhood	Stable	Variable
Hyperpigmentation	Physical manifestation	HP:0000953	Childhood	Variable	Variable
Subcutaneous nodules (esp. MONA; palmoplantar)	Physical manifestation	HP:0031800 / HP:0012732	Childhood	Progressive	Distinguishes MONA from classic Winchester
Congenital cardiac/valve defects	Clinical sign	HP:0001627	Congenital	Variable	Subset (can be presenting feature)

Cutaneous phenotype. In addition to generalized skin thickening, a distinctive progressive multilayered banded skin pattern has been reported in Winchester syndrome, along with hypertrichosis, hyperpigmentation, and subcutaneous nodules (PMID: 14726867).

Key clinical distinction. Classic Winchester syndrome is historically distinguished from MONA by the absence or paucity of palmoplantar subcutaneous nodulosis; nodulosis is a hallmark of MONA (MMP2) (PMID: 24637309, PMID: 39540058).

Ocular phenotype (refined). In a molecularly confirmed spectrum patient, anterior-segment OCT demonstrated posterior stromal and endothelial hyperreflectivity, and confocal microscopy showed an acellular peripheral endothelium with a normal central endothelium; the peripheral corneal opacities were visually insignificant (PMID: 39502084):

"Anterior segment optical coherence tomography (AS-OCT) demonstrated posterior stromal and endothelial hyperreflectivity. Confocal microscopy demonstrated an acellular peripheral endothelium with a normal central endothelium."

Quality-of-life impact. Formal instruments (EQ-5D, SF-36, PROMIS) have not been applied in this ultra-rare disease. Qualitatively, the dominant QoL burdens are progressive loss of hand and foot function from osteolysis plus contractures, chronic arthralgia, impaired mobility, and (where present) cardiac morbidity. Vision is usually preserved because corneal opacities are peripheral and visually insignificant.

4. Genetic / Molecular Information

Causal genes.

Gene (HGNC)	Protein	Associated phenotype	Core molecular role
*MMP14*	MT1-MMP (membrane type-1 MMP)	Classic Winchester syndrome	Cell-surface collagenase; activates pro-MMP2; pericellular type I collagen turnover
*MMP2*	Gelatinase A / 72 kDa type IV collagenase	MONA / Torg (Winchester spectrum)	Cleaves type IV collagen; osteocyte canalicular network maintenance
SH3PXD2B	Tks5 adaptor	Frank-Ter Haar syndrome (same spectrum)	Podosome scaffold organizing MT1-MMP delivery

Pathogenic variants. - MMP14:* The index pathogenic variant is the signal-peptide missense p.Thr17Arg, which reduces MT1-MMP membrane localization and impairs pro-MMP2 activation (PMID: 22922033). - MMP2:* Reported variants span missense (e.g., c.538G>A p.Asp180Asn PMID: 24637309; c.1188C>A p.Ser396Arg, predicted to disturb the MMP2 collagen-binding region), splice-donor (e.g., c.1336+2T>G, predicted to introduce a premature stop codon), and nonsense variants (PMID: 37710205, PMID: 37025869).

Variant classification. Reported disease-causing variants are classified pathogenic/likely pathogenic per ACMG/AMP criteria, typically supported by homozygosity in affected individuals, carrier status in consanguineous parents, segregation, conservation, and in-silico/molecular-modeling evidence.

Variant type/class. Missense (signal-peptide and collagen-binding region), nonsense, and splice-site variants predominate. All converge on loss of function.

Allele frequency. Pathogenic alleles are extremely rare in population databases (gnomAD), consistent with an ultra-rare recessive disorder; most are private or population/family-specific.

Somatic vs germline. All pathogenic variants are germline; there is no somatic/oncogenic component.

Functional consequence. Loss of function of pericellular collagenolytic activity (MT1-MMP) and/or type IV collagenase activity (MMP2). For p.Thr17Arg, the mechanism is mislocalization of MT1-MMP away from the membrane, blocking the MT1-MMP → pro-MMP2 activation step (PMID: 22922033).

Modifier genes. Within the DECORS axis, SH3PXD2B, MMP14, and MMP2 are functionally interdependent; dysfunction of one effectively modifies the output of the shared pathway (PMID: 31218820). No classical independent modifier loci are established. Significant intrafamilial variability in age of onset and severity is documented, implying modifier effects that remain uncharacterized (PMID: 37710205).

Epigenetic information. No disease-specific DNA-methylation or histone-modification signature has been reported for Winchester syndrome.

Chromosomal abnormalities. None; this is a single-gene disorder without characteristic aneuploidy, translocation, or large structural rearrangement.

5. Environmental Information

Environmental factors: None implicated. No toxin, radiation, pollution, or occupational exposure is associated with onset or progression.
Lifestyle factors: None implicated (smoking, diet, exercise, alcohol have no established role).
Infectious agents: Not applicable. Winchester syndrome is not infectious and has no known infectious trigger.

The only population-level non-genetic contributor is consanguinity, which increases the probability of homozygosity for rare recessive MMP14/MMP2 alleles (PMID: 26601801).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic MMP14 loss-of-function mutation (e.g., signal-peptide p.Thr17Arg) results in reduced MT1-MMP membrane localization. (Demonstrated — PMID: 22922033)
Reduced membrane MT1-MMP leads to impaired cell-surface activation of pro-MMP2 → active MMP2. (Demonstrated — PMID: 22922033)
Loss of MT1-MMP collagenolytic activity (± downstream MMP2 activity) leads to failure of pericellular type I / type IV collagen remodeling. (Demonstrated in mouse — PMID: 10520996)
Defective collagen turnover results in inadequate modeling and maintenance of skeletal and extraskeletal connective tissue. (Demonstrated in mouse — PMID: 10520996)
Branch A (bone): Disrupted osteocytic canalicular network and dysregulated osteoblast gene expression (↑ osteopontin/bone sialoprotein) lead to abnormal bone homeostasis → progressive osteolysis + osteoporosis → carpal/tarsal dissolution, short stature, fractures. (PMID: 16959767, PMID: 22917927)
Branch B (joint): Failure to model peri-articular connective tissue leads to destructive arthropathy and joint contractures.
Branch C (soft tissue): Accumulation of unremodeled collagen results in dermal/soft-tissue fibrosis, thickened skin, gingival hypertrophy, coarse facies, and corneal stromal/endothelial changes. (PMID: 10520996, PMID: 39502084)
Branch D (cardiac): Abnormal connective-tissue/valve matrix remodeling leads to congenital cardiac/valve defects. (Inferred from phenotype + spectrum — PMID: 37025869, PMID: 33101055)
Secondary to MMP-2 loss, dysregulated serum cytokines and hormones are implicated in promoting osteolysis (candidate downstream amplifiers and therapeutic targets). (Demonstrated/associative — PMID: 33101055)

Mechanistic schematic

 MMP14 (MT1-MMP) biallelic LOF
    │  (p.Thr17Arg → mislocalization)
    ▼
 ↓ membrane MT1-MMP ──► ↓ pro-MMP2 activation
    │                     │
    ▼                     ▼
 ↓ pericellular type I/IV collagenolysis  (core defect)
    │
    ▼
 Inadequate connective-tissue remodeling
   ├─► BONE: osteocyte canalicular + osteoblast dysregulation → osteolysis/osteoporosis
   ├─► JOINT: arthropathy, contractures
   ├─► SOFT TISSUE: dermal fibrosis, gingival/corneal/facial changes
   └─► HEART: valve/cardiac matrix defects
    │
    ▼
 (amplifier) dysregulated cytokines/hormones → further osteolysis

Detail by category

Molecular pathways: Pericellular matrix proteolysis via the MT1-MMP → pro-MMP2 activation cascade; collagen (type I, type IV) degradation. Podosome-mediated protease delivery (SH3PXD2B/Tks5 scaffold) links the three DECORS genes (PMID: 31218820).
Cellular processes: Extracellular-matrix organization and turnover; bone remodeling (osteoclast/osteoblast/osteocyte coupling); fibroblast-driven fibrosis. GO suggestions: GO:0030574 (collagen catabolic process), GO:0022617 (extracellular matrix disassembly), GO:0001503 (ossification), GO:0030198 (extracellular matrix organization).
Protein dysfunction: Loss of function — MT1-MMP mislocalized (signal-peptide defect); MMP2 missense disrupting the collagen-binding region, or truncating variants abolishing enzyme (PMID: 22922033, PMID: 37710205).
Metabolic / biochemical abnormalities: Reduced/absent gelatinase (MMP-2) activity detectable by zymography; dysregulated serum cytokines/hormones (PMID: 33101055).
Immune involvement: No primary autoimmunity; the arthropathy is mechanical/degenerative, not inflammatory-autoimmune — a crucial point given frequent JIA misdiagnosis.
Tissue damage mechanisms: Failure of matrix maintenance → osteolysis (resorption outpacing modeling) and fibrosis (accumulation of poorly remodeled collagen).
Molecular profiling: Mmp2-null osteoblasts show upregulated osteopontin (OPN) and bone sialoprotein (BSP), defining a bone-homeostasis feedback circuit (PMID: 22917927). No human single-cell or spatial datasets are published for this ultra-rare disease.

Cell types (CL): osteocyte (CL:0000137), osteoblast (CL:0000062), osteoclast (CL:0000092), fibroblast (CL:0000057), corneal endothelial cell (CL:0000575).

7. Anatomical Structures Affected

Organ level. - Primary: Skeleton — especially carpal and tarsal bones (UBERON:0001773 carpal region / tarsal region), small bones of hands and feet; generalized skeleton (osteoporosis). - Joints: wrists, interphalangeal and metacarpophalangeal joints, knees. - Secondary / multisystem: eye (cornea, UBERON:0000964), skin (UBERON:0002097), gingiva (UBERON:0001828), heart/cardiac valves (UBERON:0000948 / UBERON:0000946). - Body systems: skeletal, articular/connective-tissue, integumentary, ocular, and cardiovascular.

Tissue and cell level. Connective tissue (bone matrix, dermal collagen); affected cell populations: osteocytes, osteoblasts, osteoclasts, fibroblasts, and corneal endothelial cells (peripheral acellular endothelium) (PMID: 39502084).

Subcellular level. Defect localizes to the plasma membrane / cell surface (GO:0005886) where MT1-MMP acts, and the extracellular matrix / extracellular region (GO:0031012, GO:0005615). Podosome-associated protease trafficking is implicated via SH3PXD2B.

Localization & lateralization. Skeletal involvement is characteristically bilateral and symmetric, centered on the appendicular skeleton (hands/feet). Corneal opacities are peripheral and bilateral.

8. Temporal Development

Onset: Typically childhood, though onset can range from early childhood into late adolescence (PMID: 37710205). Cardiac defects, when present, may be congenital and can be the first presentation (PMID: 37025869).
Onset pattern: Insidious and chronic.
Progression: Progressive osteolysis and contractures; longitudinal follow-up confirms continued bone loss over years (PMID: 37710205). There is a stereotyped chronological order — skeletal manifestations begin in hands/feet, with later, wider joint involvement (PMID: 34307793).
Disease course: Chronic, lifelong, progressive; no spontaneous remission.
Critical periods: Childhood/adolescence represents the window of most active osteolysis — the practical window for diagnosis and supportive intervention.

9. Inheritance and Population

Epidemiology. Winchester syndrome is ultra-rare; precise prevalence/incidence are not established and it is described only through isolated cases and small family series. Orphanet classifies it among extremely rare bone dysplasias.

Inheritance. Autosomal recessive (PMID: 26601801):

"Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia."

Penetrance: Effectively complete in biallelic carriers.
Expressivity: Variable, with documented significant intrafamilial variability in onset and severity (PMID: 37710205).
Anticipation: Not applicable (not a repeat-expansion disorder).
Germline mosaicism: Not reported.
Founder effects: Many variants are private/family-specific; several populations harbor recurrent homozygous variants in consanguineous pedigrees.
Consanguinity: Strongly linked — the majority of reported families are consanguineous (PMID: 26601801, PMID: 22876575).
Carrier frequency: Not established; expected to be very low outside consanguineous or founder populations.

Population demographics. Reported in diverse ethnicities — Indian, Egyptian, Pakistani, Finnish, Iranian, Japanese — supporting a pan-ethnic distribution (PMID: 22876575, PMID: 37710205, PMID: 38409917). No strong sex predilection is established (consistent with autosomal recessive inheritance). Age distribution of affected individuals is concentrated in childhood through young adulthood at time of diagnosis.

10. Diagnostics

Clinical/radiographic. Diagnosis begins with the characteristic radiographic pattern: multicentric osteolysis predominantly of carpal and tarsal bones, osteopenia/osteoporosis, dysplastic changes of hands/feet, and (in MONA) subcutaneous nodules (PMID: 37842447, PMID: 34307793).

Confirmatory tests. Diagnosis is established by (PMID: 34466312):

"established either by measuring matrix metalloproteinase-2 (MMP-2) enzyme activity through electrophoresis (zymography) or genomic testing."

MMP-2 zymography (gelatin electrophoresis) — functional assay of gelatinase activity.
Molecular genetic testing of MMP14 (Winchester) and MMP2 (MONA) — single-gene testing, targeted panels, or whole-exome sequencing (WES), which has been the discovery route in several families (PMID: 37710205).

Ocular imaging. AS-OCT and confocal microscopy characterize the peripheral corneal endothelial/stromal changes (PMID: 39502084).

Differential diagnosis. The most important and dangerous differential is juvenile idiopathic arthritis / rheumatoid arthritis (PMID: 37842447):

"can be misdiagnosed as juvenile idiopathic arthritis or rheumatoid arthritis."

Misclassification as JIA leads to inappropriate corticosteroid/immunosuppressive therapy (PMID: 39463871). Other differentials include non-heritable osteolyses (Gorham-Stout disease), other inherited osteolysis syndromes, and skeletal dysplasias (PMID: 21995273).

Screening. In known families, cascade/carrier testing and genetic counseling are appropriate; prenatal/preimplantation testing is feasible when the familial variant is known. There is no population newborn screening.

11. Outcome / Prognosis

Survival/mortality: No systematic survival data exist. Skeletal disease is not directly lethal, but cardiac involvement can be life-threatening — one child required open-heart surgery at 8 months of age (PMID: 37025869).
Morbidity/disability: Dominated by progressive loss of hand/foot function, contractures, chronic pain, and reduced mobility — a chronic, lifelong functional burden.
Disease course: Progressive osteolysis with accumulating skeletal deformity; complications include pathologic fractures, severe contractures, and cardiac/valvular disease.
Recovery potential: Osteolytic bone loss is not reversible with current care; management is palliative/supportive.
Prognostic factors: Presence and severity of cardiac involvement is the principal determinant of serious outcome; extent/rate of skeletal osteolysis governs functional disability. No validated prognostic biomarkers exist.

12. Treatment

No disease-specific or curative therapy exists (PMID: 34466312):

"no specific therapy has been identified with proven long term relief and control of the disease progression."

Management is supportive and multidisciplinary:

Modality	Purpose	NCIT suggestion
Physiotherapy / rehabilitation	Preserve joint mobility, limit contractures	NCIT:C15682 (Physical Therapy)
Analgesia	Chronic pain control	NCIT:C15329 (Analgesic Therapy)
Orthopedic / reconstructive surgery	Correct deformity, stabilize joints	NCIT surgical repair
Ophthalmologic surveillance	Monitor corneal opacities	—
Cardiac surveillance / surgery	Detect & correct valve/congenital defects	NCIT:C15300 (Cardiac Surgery)

Pharmacotherapy / pharmacogenomics: No approved targeted drugs. Critically, immunosuppression/corticosteroids are not indicated and reflect misdiagnosis as inflammatory arthritis (PMID: 39463871).

Advanced / experimental therapeutics: None approved. A mechanistically promising direction: Sarker et al. identified dysregulated serum cytokines and hormones common to MMP-2-deficient mice and children as candidate therapeutic targets for the osteolysis (PMID: 33101055):

"multicentric osteolysis, nodulosis, and arthropathy (MONA) as well as cardiac valve defects, dwarfism and hirsutism."

Gene/enzyme-replacement approaches are conceptually plausible (restore MT1-MMP/MMP2 function) but remain untested.

13. Prevention

Primary prevention: Not possible at the individual genetic level. The main lever is genetic counseling in consanguineous and known-carrier families, including reproductive options (carrier testing, prenatal/preimplantation genetic diagnosis once the familial variant is identified).
Secondary prevention: Early, accurate diagnosis — recognizing carpal/tarsal osteolysis and pursuing zymography/molecular testing rather than defaulting to a JIA diagnosis — prevents harmful immunosuppression and enables timely cardiac/ophthalmologic surveillance.
Tertiary prevention: Physiotherapy, orthopedic intervention, and cardiac monitoring to limit complications.
Immunization / public health / environmental interventions: Not applicable (non-infectious, non-environmental monogenic disorder).
Counseling: Genetic counseling is the cornerstone of prevention given autosomal recessive inheritance and consanguinity linkage.

14. Other Species / Natural Disease

Taxonomy / orthologs: MMP14 and MMP2 are highly conserved across mammals; mouse orthologs Mmp14 and Mmp2 (NCBI Taxon:10090, Mus musculus) are the principal comparative systems.
Natural disease in other species: No well-characterized spontaneous Winchester-syndrome equivalent is documented in companion animals or wildlife; the disease model is engineered (knockout), not naturally occurring.
Comparative biology: The evolutionary conservation of the MT1-MMP → MMP2 collagen-remodeling axis is strong, which is why murine knockouts faithfully reproduce human skeletal/connective-tissue pathology (PMID: 10520996).
Transmission / zoonosis: Not applicable.

15. Model Organisms

Mouse knockouts are the definitive disease models and provide the strongest mechanistic validation (PMID: 10520996):

"MT1-MMP deficiency causes craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues."

Model	Type	Phenotype recapitulation	Key insight	Ref
*Mmp14⁻/⁻* mouse	Constitutive knockout (mammalian)	High — dwarfism, osteopenia, arthritis, craniofacial dysmorphism, soft-tissue fibrosis	Loss of essential collagenolysis drives connective-tissue disease	PMID: 10520996
*Mmp2⁻/⁻* mouse	Constitutive knockout (mammalian)	High — ↓ bone mineral density, disrupted osteocytic canalicular network, dysregulated osteoblast genes	MMP-2 crucial for osteocyte canaliculi and bone metabolism	PMID: 16959767
Mmp2⁻/⁻ osteoblasts / SaOS2 siRNA	Cellular / in vitro	Upregulated OPN and BSP	Defines a bone-homeostasis feedback circuit regulated by MMP-2	PMID: 22917927

Model characteristics. The canalicular-network insight is explicit (PMID: 16959767):

"MMP-2 plays a crucial role in forming and maintaining the osteocytic canalicular network."

Limitations. Mouse models capture skeletal/connective-tissue biology well but do not fully model the human ocular phenotype or allele-specific effects (e.g., the human p.Thr17Arg mislocalization mechanism). Resources: MGI, IMPC/IMSR.

Key Findings (consolidated)

F001 — Winchester syndrome is caused by biallelic MMP14 (MT1-MMP) mutations. Evans et al. (2012) identified homozygous MMP14 mutations in the original Winchester sisters; the p.Thr17Arg signal-peptide substitution decreases MT1-MMP membrane localization and impairs pro-MMP2 activation, inherited autosomal recessively (PMID: 22922033).

F002 — Winchester/MONA spectrum is a defective collagen-remodeling disorder (DECORS). de Vos et al. (2019) reviewed 63 patients and showed that Frank-Ter Haar (SH3PXD2B), Winchester (MMP14), and MONA (MMP2) share craniofacial malformations, reduced bone density, skeletal/cardiac anomalies, and dermal fibrosis; the protein products "directly cooperate in collagen remodeling," prompting the DECORS nosology (PMID: 31218820).

F003 — Mouse models recapitulate the human osteolysis syndrome via inadequate collagen turnover. Mmp14⁻/⁻ and Mmp2⁻/⁻ mice reproduce craniofacial dysmorphism, arthritis, osteopenia, dwarfism, soft-tissue fibrosis, reduced bone mineral density, and disrupted osteocytic canalicular networks (PMID: 10520996, PMID: 16959767, PMID: 22917927).

F004 — Core clinical phenotype: carpal/tarsal osteolysis, contractures, coarse facies, corneal opacities. Plus short stature, generalized osteoporosis, and cutaneous features (thickened skin, hypertrichosis, hyperpigmentation, subcutaneous nodules, gingival hypertrophy); Winchester is distinguished from MONA by paucity of palmoplantar nodulosis (PMID: 14726867).

F005 — Diagnosis relies on radiographic osteolysis + MMP2/MMP14 testing or MMP-2 zymography; frequently misdiagnosed as JIA (PMID: 34466312, PMID: 37842447).

F006 — Autosomal recessive inheritance with strong consanguinity link; cardiac defects are part of the multisystem phenotype, and may be the first presentation (PMID: 26601801, PMID: 37025869).

F007 — No disease-specific/curative therapy exists; management is supportive and multidisciplinary (PMID: 34466312, PMID: 33101055).

F008 — Ocular involvement: peripheral corneal opacities with posterior stromal/endothelial changes, usually visually insignificant (PMID: 39502084).

Evidence Base

PMID	Title (abbrev.)	Role in this report
22922033	MT1-MMP (MMP14) causes Winchester syndrome	Establishes causal gene and p.Thr17Arg mechanism
31218820	Multicentric osteolytic syndromes = defective collagen remodeling	Unifies MMP14/MMP2/SH3PXD2B into DECORS
10520996	MT1-MMP-deficient mice	Mouse model recapitulates phenotype; collagenolytic mechanism
16959767	MMP-2 in osteocytic canalicular formation	Links MMP2 loss to bone phenotype
22917927	Loss of MMP-2 upregulates OPN/BSP	Downstream bone-homeostasis circuit
14726867	Progressive multilayered banded skin in Winchester	Cardinal clinical + cutaneous features
34466312	Clinical/molecular profile of MONA	Diagnostic tests; no disease-modifying therapy
37842447	MONA simulating JIA in adult	Key differential/misdiagnosis risk
26601801	Clinical/mutation profile of MONA	Autosomal recessive inheritance; consanguinity
37025869	Novel MONA mutation	Cardiac defect as presenting feature
33101055	Dysregulated cytokines/hormones in MMP-2 deficiency	Multisystem phenotype; therapeutic targets
39502084	Multimodal imaging of corneal opacities	Refines ocular phenotype
37710205	Two families (Pakistan/Finland)	Variant spectrum; variable age of onset
24637309	MMP2 case report	Torg/MMP2 biology; nodulosis distinction
22876575	Three Egyptian patients	Pan-ethnic; consanguinity
39540058	Pakistani MONA family	Nodulosis + MMP2 deficiency
34307793	Two children, genetic–skeletal correlations	Skeletal pattern, progression order
39463871	MONA case series	JIA misdiagnosis; multidisciplinary management
38409917	Japanese siblings	Pan-ethnic distribution
21995273	Idiopathic osteolysis diagnosis/management	Differential diagnosis framework

All findings above are anchored to verified abstract quotes recorded during the investigation.

Limitations and Knowledge Gaps

Nomenclature overlap. Classic Winchester syndrome (MMP14) and MONA/Torg (MMP2) are mechanistically unified but genetically distinct; much published literature uses "Torg-Winchester"/"MONA" interchangeably, so some clinical detail is drawn from the MMP2 literature and extrapolated to the MMP14 entity under the DECORS framework.
Thin human molecular data. There are no human transcriptomic, proteomic, single-cell, or spatial datasets for this ultra-rare disease; molecular profiling evidence is largely from mouse models.
No quantitative epidemiology. Prevalence, incidence, carrier frequency, and survival statistics are essentially unknown.
No validated outcome measures. QoL, prognostic biomarkers, and natural-history endpoints are not formalized.
No therapeutics pipeline. Treatment is entirely supportive; the cytokine/hormone-targeting hypothesis remains untested in patients.
Modifiers unexplained. Documented intrafamilial variability implies modifier effects that are uncharacterized.

Proposed Follow-up Experiments / Actions

Establish an international registry for MMP14/MMP2 osteolysis to generate prevalence, natural-history, and genotype–phenotype data (addresses gaps 3–4).
Patient-derived iPSC → osteoblast/osteocyte/chondrocyte models and organoids to obtain human single-cell transcriptomic/proteomic signatures and test rescue of the MT1-MMP → pro-MMP2 axis.
Variant-function platform: systematically express MMP14/MMP2 variants (e.g., p.Thr17Arg) to quantify membrane localization, pro-MMP2 activation, and collagenolysis — supporting ACMG reclassification of VUS.
Therapeutic proof-of-concept: test cytokine/hormone-pathway modulators identified by Sarker et al. (PMID: 33101055) in Mmp2⁻/⁻/Mmp14⁻/⁻ mice; explore enzyme-replacement or AAV gene-replacement in these models.
Diagnostic standardization: promote an algorithm of "carpal/tarsal osteolysis → MMP-2 zymography + MMP14/MMP2 sequencing" to curb JIA misdiagnosis and inappropriate immunosuppression.
Prospective cardiac surveillance protocol, given that congenital heart disease can be the presenting and most dangerous manifestation (PMID: 37025869).

Report compiled from a 5-iteration autonomous literature synthesis; 8 confirmed findings, 21 papers reviewed. Evidence source types: human clinical case reports/series, mouse model-organism studies, and in vitro/cellular experiments, as indicated throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	20
Resolved	20
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	20
On topic	14
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	38
Resolved	36
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	22
Terms named correctly	5
Terms named as a different term	13
Terms whose name is worth a second look	4

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:0010201 (2 mentions) - the report calls it "MONDO"; MONDO calls it Winchester syndrome
HP:0000939 (1 mention) - the report calls it "Radiographic"; HP calls it Osteoporosis
HP:0001371 (1 mention) - the report calls it "Physical manifestation"; HP calls it Flexion contracture
HP:0001387 (1 mention) - the report calls it "Clinical sign"; HP calls it Joint stiffness
HP:0004322 (1 mention) - the report calls it "Physical manifestation"; HP calls it Short stature
HP:0000280 (1 mention) - the report calls it "Physical manifestation"; HP calls it Coarse facial features
HP:0007957 (1 mention) - the report calls it "Clinical sign (ocular)"; HP calls it Corneal opacity
HP:0000212 (1 mention) - the report calls it "Clinical sign"; HP calls it Gingival overgrowth
HP:0000998 (1 mention) - the report calls it "Physical manifestation"; HP calls it Hypertrichosis
HP:0001627 (1 mention) - the report calls it "Clinical sign"; HP calls it Abnormal heart morphology
NCIT:C15682 (1 mention) - the report calls it "Physical Therapy"; NCIT calls it Dose-Rate
NCIT:C15329 (1 mention) - the report calls it "Analgesic Therapy"; NCIT calls it Surgical Procedure
NCIT:C15300 (1 mention) - the report calls it "Cardiac Surgery"; NCIT calls it Photodynamic Therapy

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:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

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:0000974 (1 mention) - the report calls it "thick skin"; HP calls it Hyperextensible skin, and lists "Hyperelastic skin" among its other names
HP:0000953 (1 mention) - the report calls it "Physical manifestation"; HP calls it Hyperpigmentation of the skin, and lists "Skin hyperpigmentation" among its other names
UBERON:0002097 (1 mention) - the report calls it "skin"; UBERON calls it skin of body, and lists "skin" among its other names
GO:0005886 (1 mention) - the report calls it "plasma membrane / cell surface"; GO calls it plasma membrane

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: Taxon.

Ask OpenScientist

OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Winchester Syndrome: A Comprehensive Disease Characterization Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Mechanistic schematic

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Findings (consolidated)

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Prefixes with no resolver