Czech dysplasia

👪

Inheritance

1

Autosomal dominant HP:0000006

Transmitted as an autosomal dominant trait; the recurrent p.Arg275Cys allele segregated with disease in all 11 affected members of a single large family.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:17726487 SUPPORT Human Clinical

"Czech dysplasia metatarsal type is an autosomal-dominant disorder characterized by an early-onset, progressive spondyloarthropathy with normal stature."

States autosomal dominant inheritance together with the two defining features.

?

Discussions and Knowledge Gaps

1

Given that the R275C chain folds, traffics and is secreted essentially normally, how does it damage cartilage — and why does it spare the eye and palate that other COL2A1 alleles affect?

KNOWLEDGE GAP gap_r275c_cartilage_matrix_and_tissue_selectivity

Attached to

pathophysiology#Defective Type II Collagen Fibril in Cartilage Matrix

Recombinant work on this substitution (PMID:29439465) has removed several candidate explanations rather than supplying one. The mutant chain folds correctly, keeps trypsin resistance, moves from ER to Golgi normally, and provokes neither XBP-1 splicing nor caspase-3 activation, so intracellular retention, ER stress and chondrocyte apoptosis are not the route here. The authors conclude the allele "might cause a disease predominantly via extracellular interference". A 2.5 degree Celsius fall in melting temperature is the only measured abnormality, and it is slight. What is still missing is any observation from patient cartilage: fibril architecture, cross-linking, matrix composition, or how a molecule that behaves nearly normally in a recombinant system produces a severe early arthropathy. The tissue selectivity is equally unexplained — the eye and palate are type II collagen tissues and are spared by this allele while other COL2A1 alleles affect them. Both facts are why the fibril node keeps `mechanism_confidence: HYPOTHETICAL` and an INDIRECT_UNKNOWN_INTERMEDIATES edge.

Proposed experiments

Ultrastructural and biochemical analysis of R275C patient cartilage

exp_czech_r275c_fibril_ultrastructure

Examine collagen fibril diameter, packing and cross-linking in articular cartilage obtained at arthroplasty from an R275C carrier, against age-matched non-dysplastic controls, and measure the proportion of mutant chain incorporated into fibrils versus remaining soluble.

Decision criterion

Altered fibril architecture with the mutant chain incorporated would upgrade the fibril node from HYPOTHETICAL to established and confirm the extracellular-interference model. Normal fibril architecture would move the explanation to the interactions the fibril makes with other matrix components rather than to the fibril itself. An intracellular-retention result is not treated as a live branch here, because PMID:29439465 measured normal ER-to-Golgi trafficking and no unfolded-protein response for this substitution.

Comparative matrix assay across type II collagen tissues

exp_czech_r275c_tissue_selectivity

Compare mutant-chain incorporation and matrix integrity across articular cartilage, growth-plate cartilage, vitreous and palatal tissue in a knock-in model carrying the orthologous substitution, to test whether sparing of ocular and orofacial structures reflects tissue-specific tolerance.

Decision criterion

Matrix disruption confined to skeletal tissues would explain the clinical sparing structurally. Uniform disruption would mean the sparing is functional or compensatory and needs a different explanation, most likely in the differing mechanical demands placed on those matrices.

Test for aberrant disulfide bonding of the introduced cysteine

exp_czech_r275c_unpaired_cysteine_interactions

Determine, in secreted recombinant R275C collagen II and in patient-derived material, whether the introduced cysteine forms intermolecular disulfide bonds with other matrix components, using non-reducing gels and cross-linking mass spectrometry.

Decision criterion

Identified aberrant partners would give the extracellular-interference hypothesis a concrete molecular form and a candidate target. No abnormal bonding would push the explanation towards altered fibril packing driven by the reduced thermal stability alone.

Show evidence (1 reference)

PMID:29439465 SUPPORT In Vitro

"neither induce ER stress nor apoptosis and might cause a disease predominantly via extracellular interference"

The authors' own conclusion for this allele, which is what narrows the open question to the extracellular compartment.

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Pathophysiology

4

COL2A1 p.Arg275Cys Substitution in the Triple-Helical Domain

A heterozygous c.823C>T transition in exon 13 of COL2A1 replaces arginine 275 with cysteine in the triple-helical domain of the pro-alpha-1(II) collagen chain. Unlike the glycine substitutions that dominate the severe type II collagenopathies, this variant alters a non-glycine residue, and it is the only allele so far identified in molecularly confirmed cases.

COL2A1 hgnc:2200

extracellular matrix structural constituent GO:0005201 ⚠ ABNORMAL

Downstream

Defective Type II Collagen Fibril in Cartilage Matrix An unpaired cysteine substituted into the triple-helical domain of a structural collagen chain is incorporated into the heterotrimer and compromises the fibrillar matrix that chain builds.

Show evidence (2 references)

PMID:17726487 SUPPORT Human Clinical

"We identified the R275C substitution in two of the original patients reported with Czech dysplasia and three additional patients."

Establishes the R275C substitution as the molecular lesion in the original and additional Czech dysplasia patients.

PMID:19764028 SUPPORT Human Clinical

"A specific missense mutation (c.823C > T, R275C) in the exon 13 of the COL2A1 gene, coding for the triple helical domain of the alpha 1 chain of the type II collagen, has been linked to Czech dysplasia"

Locates the variant precisely in exon 13 and in the triple-helical domain of the alpha-1(II) chain.

Defective Type II Collagen Fibril in Cartilage Matrix

Type II collagen is the principal fibrillar constituent of hyaline cartilage, including articular cartilage and the vertebral growth plate. A structurally abnormal alpha-1(II) chain degrades the load-bearing collagen network of that matrix. The tissue distribution of the resulting disease follows the tissues in which type II collagen is load-bearing, which is why the vertebral bodies, the appendicular joints and the metatarsals are affected while the eye and palate — also type II collagen tissues, but affected in the other COL2A1 disorders — are spared here.

chondrocyte CL:0000138

collagen fibril organization GO:0030199 ⚠ ABNORMAL extracellular matrix organization GO:0030198 ⚠ ABNORMAL

Downstream

Early-Onset Progressive Osteoarthropathy A compromised articular cartilage matrix degenerates prematurely under ordinary joint loading, producing arthropathy decades earlier than idiopathic osteoarthritis.

Vertebral and Metatarsal Growth Abnormality The same defective cartilage matrix in the vertebral and metatarsal growth plates yields flattened vertebral bodies and selectively shortened third and fourth metatarsals.

Show evidence (4 references)

PMID:19764028 SUPPORT Human Clinical

"coding for the triple helical domain of the alpha 1 chain of the type II collagen"

Places the lesion in the structural domain of the cartilage collagen. PARTIAL because it establishes the location of the variant, not the state of the fibril.

PMID:29439465 SUPPORT In Vitro

"including Czech dysplasia metatarsal type (R75C)"

Establishes that the R75C substitution studied in this recombinant work is the Czech dysplasia allele, i.e. R275C in precursor numbering.

PMID:29439465 SUPPORT In Vitro

"suggesting slight structural differences even though these changes were not pronounced enough to loose trypsin resistance"

A 2.5 degree Celsius melting-temperature reduction with retained trypsin resistance. PARTIAL because it establishes a measurable but slight destabilization of the recombinant molecule, not a defective fibril in cartilage.

+ 1 more reference

Early-Onset Progressive Osteoarthropathy

The dominant clinical problem is a progressive arthropathy that resembles rheumatoid arthritis clinically and radiographically but is non-inflammatory and genetic. It begins early, involves the spine and the appendicular joints, and produces pain and stiffness. Weather-dependent articular pain characterised the original family but was absent in a subsequent series, so it is not a constant feature.

extracellular matrix disassembly GO:0022617 ↑ INCREASED

Show evidence (2 references)

PMID:17726487 SUPPORT Human Clinical

"All affected individuals had a similar phenotype characterized by normal height, spondyloarthropathy, short postaxial toes and absence of ocular and orofacial anomalies."

Establishes the arthropathy as a constant feature across all molecularly confirmed individuals in that series.

PMID:15266623 SUPPORT Human Clinical

"The only major difference is absence of weather dependent articular pain which characterized the family of the previous study."

Documents that weather-dependent articular pain, present in the index family, was absent in these three patients; PARTIAL because it qualifies rather than supports the general arthropathy claim.

Vertebral and Metatarsal Growth Abnormality

Growth-plate involvement produces platyspondyly and selective shortening of the third and fourth metatarsals with short corresponding toes, while overall stature remains normal. That combination — segmental growth-plate disturbance without short stature — is the radiographic signature of the disorder.

growth plate cartilage chondrocyte CL:1000217

cartilage development GO:0051216 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:18553548 SUPPORT Human Clinical

"characterized by early-onset progressive pseudorheumatoid arthritis, platyspondyly, short third and fourth metatarsals, normal height"

Establishes platyspondyly and selective metatarsal shortening alongside preserved stature.

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Pathograph

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

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Phenotypes

5

Ear 1

Sensorineural Hearing Impairment HP:0000407

Show evidence (1 reference)

PMID:18553548 SUPPORT Human Clinical

"We report on a large family with 11 patients with typical Czech dysplasia and sensorineural hearing loss. Hearing loss has hitherto not been considered as a major manifestation of Czech dysplasia."

Documents hearing loss across a large kindred while stating explicitly that it was not previously part of the phenotype, which is why no frequency band is given.

Limbs 1

Genu Valgum HP:0002857

Show evidence (1 reference)

PMID:19764028 SUPPORT Human Clinical

"Here we report on a Japanese family consisting of three patients with Czech dysplasia, each member showing valgus knees in addition to remarkably uniform manifestation of the clinical and radiological abnormalities."

Documents valgus knees in all three affected family members.

Musculoskeletal 2

Osteoarthritis VERY_FREQUENT HP:0002758

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:17726487 SUPPORT Human Clinical

"All affected individuals had a similar phenotype characterized by normal height, spondyloarthropathy, short postaxial toes and absence of ocular and orofacial anomalies."

Reports spondyloarthropathy in every affected individual in the series, supporting the VERY_FREQUENT band.

Platyspondyly VERY_FREQUENT HP:0000926

Show evidence (1 reference)

PMID:18553548 SUPPORT Human Clinical

"characterized by early-onset progressive pseudorheumatoid arthritis, platyspondyly, short third and fourth metatarsals, normal height"

Names platyspondyly among the defining features of the disorder.

Other 1

Short Metatarsals FREQUENT HP:0010743

Show evidence (1 reference)

PMID:17726487 SUPPORT Human Clinical

"Shortness of third and/or fourth toes is a frequently observed clinical feature."

The source's own word is "frequently observed", which maps to the FREQUENT band rather than a higher one.

🧬

Genetic Associations

1

COL2A1 (Heterozygous recurrent p.Arg275Cys substitution)

Gene: COL2A1 hgnc:2200 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:26443184 SUPPORT Human Clinical

"The p.(Arg275Cys) substitution is found in all patients with COL2A1-associated Czech dysplasia."

A review of over 700 COL2A1 patients reports this allele in every Czech dysplasia case, which is the strongest available support for allelic homogeneity.

PMID:18553548 SUPPORT Human Clinical

"Thus, Czech dysplasia is possibly caused exclusively by the R275C mutation, which is a unique situation among the COL2A1 disorders."

Records the exclusivity claim in the hedged form its authors used ("possibly"), which is why this item is PARTIAL rather than SUPPORT.

PMID:19764028 SUPPORT Human Clinical

"In conclusion, this report provides novel evidence for the independent occurrence of Czech dysplasia among the populations."

Refutes a single-founder explanation for the recurrent allele and supports independent recurrence.

🔬

Diagnosis

2

Targeted COL2A1 Exon 13 Sequencing

Because a single recurrent allele accounts for the molecularly confirmed cases, targeted sequencing of COL2A1 exon 13 is an efficient first-line test, with sequencing of the remaining exons reserved for cases in which R275C is not found. A negative R275C result in a patient with disproportionate short stature should prompt reconsideration of the diagnosis rather than continued pursuit of Czech dysplasia.

Molecular Analysis NCIT:C19770

Show evidence (1 reference)

PMID:17726487 SUPPORT Human Clinical

"Targeted sequencing of exon 13 of the COL2A1 gene was performed, followed by sequencing of the remaining exons in case the R275C mutation was not identified."

Describes the tiered sequencing strategy used to establish the diagnosis.

Clinical and Radiographic Differentiation from Other Type II Collagenopathies

Normal stature together with the absence of ocular and orofacial anomalies distinguishes Czech dysplasia from the other COL2A1 disorders, in which short stature and sensorial or palatal involvement are typical. In one originally reported patient, disproportionate short stature plus a different COL2A1 variant (Y1391C) reassigned the diagnosis to spondyloperipheral dysplasia.

Diagnostic Procedure NCIT:C18020

Show evidence (2 references)

PMID:17726487 SUPPORT Human Clinical

"However, the identification of the Y1391C mutation in this patient with disproportionate short stature made the diagnosis of spondyloperipheral dysplasia (SPD) more probable."

A worked example of the differential: stature plus genotype reassigned the diagnosis away from Czech dysplasia.

ORPHA:137678 SUPPORT Other

"in the absence of ophthalmologic, cleft palate, and height anomalies"

Orphanet's own definition makes the three negative features part of the disease definition rather than incidental observations, which is what makes them usable as discriminators.

📈

Progression

1

Early-onset arthropathy

Joint symptoms begin early and progress, which is what distinguishes the disorder from idiopathic osteoarthritis and drives the frequent misdiagnosis as an inflammatory arthritis.

Show evidence (1 reference)

PMID:17726487 SUPPORT Human Clinical

"Czech dysplasia metatarsal type is an autosomal-dominant disorder characterized by an early-onset, progressive spondyloarthropathy with normal stature."

Establishes early onset and progression as intrinsic to the disorder.

{ }

Source YAML

click to show

name: Czech dysplasia
creation_date: "2026-08-24T21:50:00Z"
category: Mendelian
description: >-
  Czech dysplasia (spondyloepiphyseal dysplasia with metatarsal shortening,
  OMIM 609162) is an autosomal dominant type II collagenopathy caused by the
  single recurrent COL2A1 substitution c.823C>T, p.Arg275Cys, in the
  triple-helical domain of the alpha-1 chain of type II collagen. It is defined
  as much by what it lacks as by what it has: affected individuals have normal
  height and no ophthalmological or orofacial involvement, which separates it
  from every other COL2A1 disorder. The positive features are an early-onset,
  progressive pseudorheumatoid arthropathy with joint pain and stiffness,
  platyspondyly, and short third and fourth metatarsals with correspondingly
  short toes. Sensorineural hearing loss was added to the core phenotype after
  a large family was reported. The disorder is remarkable among the type II
  collagenopathies in that a single allele appears to account for every
  molecularly confirmed case.
disease_term:
  preferred_term: spondyloepiphyseal dysplasia with metatarsal shortening
  term:
    id: MONDO:0012206
    label: spondyloepiphyseal dysplasia with metatarsal shortening
parents:
- type 2 collagenopathy
- COL2A1-related spondyloepiphyseal dysplasia
synonyms:
- Czech dysplasia
- Czech dysplasia metatarsal type
- spondyloepiphyseal dysplasia with metatarsal shortening
- SED with metatarsal shortening
- progressive pseudorheumatoid dysplasia with hypoplastic toes
- spondyloepiphyseal dysplasia with precocious osteoarthritis
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Transmitted as an autosomal dominant trait; the recurrent p.Arg275Cys allele
    segregated with disease in all 11 affected members of a single large family.
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Czech dysplasia metatarsal type is an autosomal-dominant disorder
      characterized by an early-onset, progressive spondyloarthropathy with
      normal stature.
    explanation: States autosomal dominant inheritance together with the two
      defining features.
notes: >-
  Three things about this entry are deliberate.

  First, the **allelic specificity is curated as a claim with a stated basis,
  not as a definition.** PMID:18553548 puts it as "possibly caused exclusively
  by the R275C mutation, which is a unique situation among the COL2A1
  disorders", and PMID:26443184 reports from a 700-patient COL2A1 variant review
  that "the p.(Arg275Cys) substitution is found in all patients with
  COL2A1-associated Czech dysplasia". Both are curated. Neither licenses the
  stronger statement that no other allele could produce this phenotype, and the
  entry does not make it.

  Second, the **negative features are curated as evidence-bearing content**
  rather than left out. Normal stature and the absence of ocular and orofacial
  anomalies are what separate Czech dysplasia from the rest of the type II
  collagenopathies, and PMID:17726487 shows why that matters in practice: one of
  the three originally reported Czech dysplasia patients did *not* carry R275C,
  and the Y1391C variant found instead, together with disproportionate short
  stature, reassigned the diagnosis to spondyloperipheral dysplasia. A negative
  finding did the diagnostic work there.

  Third, **module conformance is claimed at two nodes and explicitly not at the
  three in between.** The `osteoarthritis_cartilage_degradation` module names an
  intrinsic ECM defect as one of its anticipated entry routes, and the clinical
  endpoint node describes exactly the arthropathy reported here, so both ends
  are evidenced. The intermediate catabolic-chondrocyte, MMP-13/ADAMTS-5 and
  subchondral-remodeling nodes are not: no source cited here measures a
  chondrocyte phenotype, a matrix-degrading enzyme, or subchondral bone turnover
  in a Czech dysplasia patient. Declaring those would assert mechanism this
  disorder's literature has not supplied.

  A naming hazard worth recording: "progressive pseudorheumatoid dysplasia" is
  both a listed synonym of this disorder and the standard name of a
  mechanistically unrelated CCN6/WISP3 recessive disorder. The Perplexity report
  generated for this entry cited PMID:27587938, which is about the CCN6 disease,
  not this one. It is not cited anywhere in this entry.

  Research input: `research/Spondyloepiphyseal_Dysplasia_With_Metatarsal_Shortening-deep-research-perplexity.md`.
  The NEC preflight returned SKIP because MONDO records no causal gene for
  MONDO:0012206, so the manual check was run instead: the report's OMIM (609162)
  matches the MONDO xref exactly, and COL2A1 dominates its gene mentions (69 to
  1). The report supplied no usable primary citations — two PMIDs in its body,
  one of which is the wrong-disease citation above — so all references here were
  found independently in PubMed.
pathophysiology:
- name: COL2A1 p.Arg275Cys Substitution in the Triple-Helical Domain
  biological_scale: MOLECULAR
  description: >-
    A heterozygous c.823C>T transition in exon 13 of COL2A1 replaces arginine
    275 with cysteine in the triple-helical domain of the pro-alpha-1(II)
    collagen chain. Unlike the glycine substitutions that dominate the severe
    type II collagenopathies, this variant alters a non-glycine residue, and it
    is the only allele so far identified in molecularly confirmed cases.
  genes:
  - preferred_term: COL2A1
    term:
      id: hgnc:2200
      label: COL2A1
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified the R275C substitution in two of the original patients
      reported with Czech dysplasia and three additional patients.
    explanation: >-
      Establishes the R275C substitution as the molecular lesion in the original
      and additional Czech dysplasia patients.
  - reference: PMID:19764028
    reference_title: "Czech dysplasia occurring in a Japanese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A specific missense mutation (c.823C > T, R275C) in the exon 13 of the
      COL2A1 gene, coding for the triple helical domain of the alpha 1 chain of
      the type II collagen, has been linked to Czech dysplasia
    explanation: >-
      Locates the variant precisely in exon 13 and in the triple-helical domain
      of the alpha-1(II) chain.
  downstream:
  - target: Defective Type II Collagen Fibril in Cartilage Matrix
    description: >-
      An unpaired cysteine substituted into the triple-helical domain of a
      structural collagen chain is incorporated into the heterotrimer and
      compromises the fibrillar matrix that chain builds.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26443184
      reference_title: "Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutations in the COL2A1 gene cause a spectrum of rare autosomal-dominant
        conditions characterized by skeletal dysplasia, short stature, and
        sensorial defects.
      explanation: >-
        Supports COL2A1 variants acting through the collagen the gene encodes.
        PARTIAL, and the edge is typed INDIRECT_UNKNOWN_INTERMEDIATES, because no
        cited source reports a structural or biochemical study of the R275C
        protein itself.
- name: Defective Type II Collagen Fibril in Cartilage Matrix
  biological_scale: TISSUE
  description: >-
    Type II collagen is the principal fibrillar constituent of hyaline cartilage,
    including articular cartilage and the vertebral growth plate. A structurally
    abnormal alpha-1(II) chain degrades the load-bearing collagen network of that
    matrix. The tissue distribution of the resulting disease follows the tissues
    in which type II collagen is load-bearing, which is why the vertebral bodies,
    the appendicular joints and the metatarsals are affected while the eye and
    palate — also type II collagen tissues, but affected in the other COL2A1
    disorders — are spared here.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: ABNORMAL
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  mechanism_confidence: HYPOTHETICAL
  notes: >-
    Curated with `mechanism_confidence: HYPOTHETICAL` on purpose, but the reason
    is narrower than it first appears. Recombinant work on this exact
    substitution (PMID:29439465, where the allele is written R75C in mature-helix
    numbering rather than R275C in precursor numbering) has measured several of
    the properties that might have been expected to be unknown: the mutant chain
    folds correctly by circular dichroism, retains trypsin resistance, traffics
    normally from ER to Golgi, and triggers neither the unfolded-protein response
    nor apoptosis. Its melting temperature is 2.5 degrees Celsius below wild type,
    which the authors read as a slight structural difference. What remains
    unmeasured is the state of the fibril and the matrix in patient cartilage, and
    the tissue selectivity of the disease. The node stays HYPOTHETICAL for that
    reason, not for want of any biophysics.
  evidence:
  - reference: PMID:19764028
    reference_title: "Czech dysplasia occurring in a Japanese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      coding for the triple helical domain of the alpha 1 chain of the type II
      collagen
    explanation: >-
      Places the lesion in the structural domain of the cartilage collagen.
      PARTIAL because it establishes the location of the variant, not the state
      of the fibril.
  - reference: PMID:29439465
    reference_title: "Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      including Czech dysplasia metatarsal type (R75C)
    explanation: >-
      Establishes that the R75C substitution studied in this recombinant work is
      the Czech dysplasia allele, i.e. R275C in precursor numbering.
  - reference: PMID:29439465
    reference_title: "Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      suggesting slight structural differences even though these changes were not
      pronounced enough to loose trypsin resistance
    explanation: >-
      A 2.5 degree Celsius melting-temperature reduction with retained trypsin
      resistance. PARTIAL because it establishes a measurable but slight
      destabilization of the recombinant molecule, not a defective fibril in
      cartilage.
  - reference: PMID:29439465
    reference_title: "Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      demonstrating that the intracellular trafficking of these proteins from ER
      to Golgi apparatus is not affected by the mutation
    explanation: >-
      Refutes an intracellular-retention mechanism for this allele, which is why
      the pathograph routes the lesion through the extracellular matrix rather
      than through ER stress.
  downstream:
  - target: Early-Onset Progressive Osteoarthropathy
    description: >-
      A compromised articular cartilage matrix degenerates prematurely under
      ordinary joint loading, producing arthropathy decades earlier than
      idiopathic osteoarthritis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18553548
      reference_title: "Czech dysplasia: report of a large family and further delineation of the phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Czech dysplasia (OMIM 609162) is a recently delineated COL2A1 disorder
        characterized by early-onset progressive pseudorheumatoid arthritis,
        platyspondyly, short third and fourth metatarsals, normal height, and the
        absence of ophthalmological problems or cleft palate.
      explanation: >-
        Links the COL2A1 disorder to early-onset progressive arthropathy as its
        cardinal feature.
  - target: Vertebral and Metatarsal Growth Abnormality
    description: >-
      The same defective cartilage matrix in the vertebral and metatarsal growth
      plates yields flattened vertebral bodies and selectively shortened third
      and fourth metatarsals.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18553548
      reference_title: "Czech dysplasia: report of a large family and further delineation of the phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        characterized by early-onset progressive pseudorheumatoid arthritis,
        platyspondyly, short third and fourth metatarsals, normal height
      explanation: >-
        Places platyspondyly and selective metatarsal shortening alongside
        preserved stature, the growth-plate arm of the phenotype.
- name: Early-Onset Progressive Osteoarthropathy
  conforms_to: "osteoarthritis_cartilage_degradation#Joint Cartilage Degradation with Pain and Functional Impairment"
  biological_scale: ORGANISM
  description: >-
    The dominant clinical problem is a progressive arthropathy that resembles
    rheumatoid arthritis clinically and radiographically but is
    non-inflammatory and genetic. It begins early, involves the spine and the
    appendicular joints, and produces pain and stiffness. Weather-dependent
    articular pain characterised the original family but was absent in a
    subsequent series, so it is not a constant feature.
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: INCREASED
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals had a similar phenotype characterized by normal
      height, spondyloarthropathy, short postaxial toes and absence of ocular and
      orofacial anomalies.
    explanation: >-
      Establishes the arthropathy as a constant feature across all molecularly
      confirmed individuals in that series.
  - reference: PMID:15266623
    reference_title: "Czech dysplasia metatarsal type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The only major difference is absence of weather dependent articular pain
      which characterized the family of the previous study.
    explanation: >-
      Documents that weather-dependent articular pain, present in the index
      family, was absent in these three patients; PARTIAL because it qualifies
      rather than supports the general arthropathy claim.
- name: Vertebral and Metatarsal Growth Abnormality
  biological_scale: TISSUE
  description: >-
    Growth-plate involvement produces platyspondyly and selective shortening of
    the third and fourth metatarsals with short corresponding toes, while overall
    stature remains normal. That combination — segmental growth-plate disturbance
    without short stature — is the radiographic signature of the disorder.
  cell_types:
  - preferred_term: growth plate cartilage chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18553548
    reference_title: "Czech dysplasia: report of a large family and further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by early-onset progressive pseudorheumatoid arthritis,
      platyspondyly, short third and fourth metatarsals, normal height
    explanation: >-
      Establishes platyspondyly and selective metatarsal shortening alongside
      preserved stature.
phenotypes:
- name: Osteoarthritis
  category: Musculoskeletal
  description: >-
    Early-onset, progressive degenerative arthropathy, clinically
    pseudorheumatoid. Present in all reported affected individuals.
  phenotype_term:
    preferred_term: Osteoarthritis
    term:
      id: HP:0002758
      label: Osteoarthritis
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals had a similar phenotype characterized by normal
      height, spondyloarthropathy, short postaxial toes and absence of ocular and
      orofacial anomalies.
    explanation: >-
      Reports spondyloarthropathy in every affected individual in the series,
      supporting the VERY_FREQUENT band.
- name: Platyspondyly
  category: Skeletal
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  frequency: VERY_FREQUENT
  description: Flattened vertebral bodies, a cardinal radiographic feature.
  evidence:
  - reference: PMID:18553548
    reference_title: "Czech dysplasia: report of a large family and further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by early-onset progressive pseudorheumatoid arthritis,
      platyspondyly, short third and fourth metatarsals, normal height
    explanation: Names platyspondyly among the defining features of the disorder.
- name: Short Metatarsals
  category: Skeletal
  description: >-
    Shortening of the third and/or fourth metatarsals with correspondingly short
    postaxial toes. This is the feature the "metatarsal type" designation refers
    to.
  phenotype_term:
    preferred_term: Short metatarsal
    term:
      id: HP:0010743
      label: Short metatarsal
  frequency: FREQUENT
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shortness of third and/or fourth toes is a frequently observed clinical
      feature.
    explanation: >-
      The source's own word is "frequently observed", which maps to the FREQUENT
      band rather than a higher one.
- name: Sensorineural Hearing Impairment
  category: Sensory
  description: >-
    Sensorineural hearing loss was documented in all 11 affected members of a
    large Czech dysplasia family and was proposed there as an addition to the
    core phenotype. It was not part of the original phenotype definition, and no
    frequency band is asserted because the evidence rests on that single kindred.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:18553548
    reference_title: "Czech dysplasia: report of a large family and further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a large family with 11 patients with typical Czech dysplasia
      and sensorineural hearing loss. Hearing loss has hitherto not been
      considered as a major manifestation of Czech dysplasia.
    explanation: >-
      Documents hearing loss across a large kindred while stating explicitly that
      it was not previously part of the phenotype, which is why no frequency band
      is given.
- name: Genu Valgum
  category: Skeletal
  description: >-
    Valgus knee deformity was present in each affected member of the reported
    Japanese family, in addition to the otherwise uniform phenotype.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:19764028
    reference_title: "Czech dysplasia occurring in a Japanese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on a Japanese family consisting of three patients with Czech
      dysplasia, each member showing valgus knees in addition to remarkably
      uniform manifestation of the clinical and radiological abnormalities.
    explanation: Documents valgus knees in all three affected family members.
genetic:
- name: COL2A1
  gene_term:
    preferred_term: COL2A1
    term:
      id: hgnc:2200
      label: COL2A1
  association: Heterozygous recurrent p.Arg275Cys substitution
  relationship_type: CAUSATIVE
  features: >-
    Czech dysplasia is, so far, allelically homogeneous: every molecularly
    confirmed patient carries the same COL2A1 c.823C>T (p.Arg275Cys) change in
    exon 13. This is unusual among the COL2A1 disorders, where over 400 distinct
    variants are recorded and one third are glycine substitutions in the G-X-Y
    repeat. The allele has arisen independently rather than descending from a
    single European founder, since it was found in a Japanese family after the
    first 11 reported families were all of European ancestry.
  evidence:
  - reference: PMID:26443184
    reference_title: "Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The p.(Arg275Cys) substitution is found in all patients with
      COL2A1-associated Czech dysplasia.
    explanation: >-
      A review of over 700 COL2A1 patients reports this allele in every Czech
      dysplasia case, which is the strongest available support for allelic
      homogeneity.
  - reference: PMID:18553548
    reference_title: "Czech dysplasia: report of a large family and further delineation of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, Czech dysplasia is possibly caused exclusively by the R275C mutation,
      which is a unique situation among the COL2A1 disorders.
    explanation: >-
      Records the exclusivity claim in the hedged form its authors used
      ("possibly"), which is why this item is PARTIAL rather than SUPPORT.
  - reference: PMID:19764028
    reference_title: "Czech dysplasia occurring in a Japanese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, this report provides novel evidence for the independent
      occurrence of Czech dysplasia among the populations.
    explanation: >-
      Refutes a single-founder explanation for the recurrent allele and supports
      independent recurrence.
progression:
- phase: Early-onset arthropathy
  notes: >-
    Joint symptoms begin early and progress, which is what distinguishes the
    disorder from idiopathic osteoarthritis and drives the frequent
    misdiagnosis as an inflammatory arthritis.
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Czech dysplasia metatarsal type is an autosomal-dominant disorder
      characterized by an early-onset, progressive spondyloarthropathy with
      normal stature.
    explanation: Establishes early onset and progression as intrinsic to the disorder.
diagnosis:
- name: Targeted COL2A1 Exon 13 Sequencing
  description: >-
    Because a single recurrent allele accounts for the molecularly confirmed
    cases, targeted sequencing of COL2A1 exon 13 is an efficient first-line test,
    with sequencing of the remaining exons reserved for cases in which R275C is
    not found. A negative R275C result in a patient with disproportionate short
    stature should prompt reconsideration of the diagnosis rather than continued
    pursuit of Czech dysplasia.
  diagnosis_term:
    preferred_term: Molecular Analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Targeted sequencing of exon 13 of the COL2A1 gene was performed, followed by
      sequencing of the remaining exons in case the R275C mutation was not
      identified.
    explanation: Describes the tiered sequencing strategy used to establish the diagnosis.
- name: Clinical and Radiographic Differentiation from Other Type II Collagenopathies
  description: >-
    Normal stature together with the absence of ocular and orofacial anomalies
    distinguishes Czech dysplasia from the other COL2A1 disorders, in which short
    stature and sensorial or palatal involvement are typical. In one originally
    reported patient, disproportionate short stature plus a different COL2A1
    variant (Y1391C) reassigned the diagnosis to spondyloperipheral dysplasia.
  diagnosis_term:
    preferred_term: Diagnostic Procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:17726487
    reference_title: "Czech dysplasia metatarsal type: another type II collagen disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the identification of the Y1391C mutation in this patient with
      disproportionate short stature made the diagnosis of spondyloperipheral
      dysplasia (SPD) more probable.
    explanation: >-
      A worked example of the differential: stature plus genotype reassigned the
      diagnosis away from Czech dysplasia.
  - reference: ORPHA:137678
    reference_title: "Spondyloepiphyseal dysplasia with metatarsal shortening"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in the absence of ophthalmologic, cleft palate, and height anomalies
    explanation: >-
      Orphanet's own definition makes the three negative features part of the
      disease definition rather than incidental observations, which is what makes
      them usable as discriminators.
discussions:
- discussion_id: gap_r275c_cartilage_matrix_and_tissue_selectivity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Defective Type II Collagen Fibril in Cartilage Matrix
  prompt: >-
    Given that the R275C chain folds, traffics and is secreted essentially
    normally, how does it damage cartilage — and why does it spare the eye and
    palate that other COL2A1 alleles affect?
  rationale: >-
    Recombinant work on this substitution (PMID:29439465) has removed several
    candidate explanations rather than supplying one. The mutant chain folds
    correctly, keeps trypsin resistance, moves from ER to Golgi normally, and
    provokes neither XBP-1 splicing nor caspase-3 activation, so intracellular
    retention, ER stress and chondrocyte apoptosis are not the route here. The
    authors conclude the allele "might cause a disease predominantly via
    extracellular interference". A 2.5 degree Celsius fall in melting temperature
    is the only measured abnormality, and it is slight. What is still missing is
    any observation from patient cartilage: fibril architecture, cross-linking,
    matrix composition, or how a molecule that behaves nearly normally in a
    recombinant system produces a severe early arthropathy. The tissue
    selectivity is equally unexplained — the eye and palate are type II collagen
    tissues and are spared by this allele while other COL2A1 alleles affect them.
    Both facts are why the fibril node keeps `mechanism_confidence: HYPOTHETICAL`
    and an INDIRECT_UNKNOWN_INTERMEDIATES edge.
  evidence:
  - reference: PMID:29439465
    reference_title: "Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      neither induce ER stress nor apoptosis and might cause a disease
      predominantly via extracellular interference
    explanation: >-
      The authors' own conclusion for this allele, which is what narrows the open
      question to the extracellular compartment.
  proposed_experiments:
  - experiment_id: exp_czech_r275c_fibril_ultrastructure
    name: Ultrastructural and biochemical analysis of R275C patient cartilage
    description: >-
      Examine collagen fibril diameter, packing and cross-linking in articular
      cartilage obtained at arthroplasty from an R275C carrier, against
      age-matched non-dysplastic controls, and measure the proportion of mutant
      chain incorporated into fibrils versus remaining soluble.
    decision_criterion: >-
      Altered fibril architecture with the mutant chain incorporated would upgrade
      the fibril node from HYPOTHETICAL to established and confirm the
      extracellular-interference model. Normal fibril architecture would move the
      explanation to the interactions the fibril makes with other matrix
      components rather than to the fibril itself. An intracellular-retention
      result is not treated as a live branch here, because PMID:29439465 measured
      normal ER-to-Golgi trafficking and no unfolded-protein response for this
      substitution.
  - experiment_id: exp_czech_r275c_tissue_selectivity
    name: Comparative matrix assay across type II collagen tissues
    description: >-
      Compare mutant-chain incorporation and matrix integrity across articular
      cartilage, growth-plate cartilage, vitreous and palatal tissue in a knock-in
      model carrying the orthologous substitution, to test whether sparing of
      ocular and orofacial structures reflects tissue-specific tolerance.
    decision_criterion: >-
      Matrix disruption confined to skeletal tissues would explain the clinical
      sparing structurally. Uniform disruption would mean the sparing is
      functional or compensatory and needs a different explanation, most likely in
      the differing mechanical demands placed on those matrices.
  - experiment_id: exp_czech_r275c_unpaired_cysteine_interactions
    name: Test for aberrant disulfide bonding of the introduced cysteine
    description: >-
      Determine, in secreted recombinant R275C collagen II and in patient-derived
      material, whether the introduced cysteine forms intermolecular disulfide
      bonds with other matrix components, using non-reducing gels and
      cross-linking mass spectrometry.
    decision_criterion: >-
      Identified aberrant partners would give the extracellular-interference
      hypothesis a concrete molecular form and a candidate target. No abnormal
      bonding would push the explanation towards altered fibril packing driven by
      the reduced thermal stability alone.
references:
- reference: ORPHA:137678
  title: "Spondyloepiphyseal dysplasia with metatarsal shortening"
- reference: PMID:15266623
  title: "Czech dysplasia metatarsal type."
- reference: PMID:17726487
  title: "Czech dysplasia metatarsal type: another type II collagen disorder."
- reference: PMID:18553548
  title: "Czech dysplasia: report of a large family and further delineation of the phenotype."
- reference: PMID:19764028
  title: "Czech dysplasia occurring in a Japanese family."
- reference: PMID:26443184
  title: "Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies."
- reference: PMID:29439465
  title: "Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival."
- reference: PMID:31021589
  title: "Type II Collagen Disorders Overview."
  tags:
  - GeneReviews

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References & Deep Research