Metaphyseal Chondrodysplasia, Schmid Type (MCDS) is an autosomal dominant skeletal dysplasia caused by heterozygous pathogenic variants in COL10A1, encoding type X collagen. The disease mechanism centers on misfolding and intracellular retention of mutant collagen X in hypertrophic chondrocytes, triggering endoplasmic reticulum stress and an unfolded protein response that disrupts chondrocyte differentiation and growth plate architecture. Clinical features manifest in early childhood with progressive short stature, genu varum, coxa vara, waddling gait, and characteristic metaphyseal irregularities on radiography. There are no extraskeletal manifestations.
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name: Metaphyseal Chondrodysplasia, Schmid Type
creation_date: '2026-03-04T18:10:30Z'
updated_date: '2026-04-19T00:06:00Z'
category: Mendelian
description: >
Metaphyseal Chondrodysplasia, Schmid Type (MCDS) is an autosomal dominant skeletal
dysplasia caused by heterozygous pathogenic variants in COL10A1, encoding type X
collagen. The disease mechanism centers on misfolding and intracellular retention of
mutant collagen X in hypertrophic chondrocytes, triggering endoplasmic reticulum stress
and an unfolded protein response that disrupts chondrocyte differentiation and growth
plate architecture. Clinical features manifest in early childhood with progressive short
stature, genu varum, coxa vara, waddling gait, and characteristic metaphyseal
irregularities on radiography. There are no extraskeletal manifestations.
disease_term:
preferred_term: metaphyseal chondrodysplasia, Schmid type
term:
id: MONDO:0007983
label: Schmid metaphyseal chondrodysplasia
parents:
- Skeletal Dysplasia
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >
MCDS is inherited in an autosomal dominant pattern. Approximately half of affected
individuals have an affected parent and half have a de novo COL10A1 pathogenic variant.
Each child of an affected individual has a 50% chance of inheriting the variant.
evidence:
- reference: PMID:8220429
reference_title: "A type X collagen mutation causes Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0).
explanation: >-
Demonstrates autosomal dominant segregation with high LOD score in a large kindred.
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Approximately half of individuals diagnosed with SMCD have an affected parent (the heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed). Approximately half of individuals diagnosed with SMCD have the disorder as the result of a de novo COL10A1 pathogenic variant.
explanation: >-
GeneReviews summary of inheritance pattern including de novo rate and variable expressivity.
prevalence:
- population: Global
percentage: Unknown
notes: >-
MCDS is described as rare with an estimated incidence of approximately 3-6 per
million. The Schmid type is the most common form of metaphyseal chondrodysplasia.
evidence:
- reference: PMID:30209734
reference_title: "Schmid Type Metaphyseal Chondrodysplasia with a Novel COL10A1 Mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Schmid type metaphyseal chondrodysplasia (SMCD) is a rare skeletal dysplasia, characterized by short stature, short limbs, bowing of the legs, and radiographic features of metaphyseal irregularities with fraying and splaying, more severe at the knee.
explanation: >-
Explicitly describes MCDS as a rare skeletal dysplasia.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The Schmid type of metaphyseal chondrodysplasia is the most common.
explanation: >-
Confirms MCDS is the most common subtype of metaphyseal chondrodysplasia, though still rare overall.
progression:
- phase: Onset
age_range: 1-3 years
notes: >-
Clinical and radiographic features are typically absent at birth and manifest in
early childhood (by age two years) with progressive short stature, short limbs,
genu varum, and waddling gait. Hand and vertebral involvement, when present,
can resolve with age.
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait.
explanation: >-
GeneReviews details the postnatal onset and progressive course.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age.
explanation: >-
Confirms early childhood onset and progressive short stature in a clinical cohort.
pathophysiology:
- name: Collagen X Misfolding and ER Stress
description: >
COL10A1 mutations, predominantly in the NC1 domain, cause misfolding and
intracellular retention of mutant collagen X in hypertrophic chondrocytes. This
triggers endoplasmic reticulum stress and activation of all three canonical
UPR sensors (IRE1, ATF6, PERK). ER stress is a central and sufficient pathogenic
factor, as demonstrated by knock-in mouse models and transgenic lines expressing
unrelated ER stress-inducing proteins under the collagen X promoter.
genes:
- preferred_term: COL10A1
term:
id: hgnc:2185
label: COL10A1
molecular_functions:
- preferred_term: extracellular matrix structural constituent conferring tensile strength
term:
id: GO:0030020
label: extracellular matrix structural constituent conferring tensile strength
cell_types:
- preferred_term: Hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
biological_processes:
- preferred_term: Response to ER Stress
term:
id: GO:0034976
label: response to endoplasmic reticulum stress
- preferred_term: ER Unfolded Protein Response
term:
id: GO:0030968
label: endoplasmic reticulum unfolded protein response
- preferred_term: Protein Folding
term:
id: GO:0006457
label: protein folding
evidence:
- reference: PMID:15695517
reference_title: "Misfolding of collagen X chains harboring Schmid metaphyseal chondrodysplasia mutations results in aberrant disulfide bond formation, intracellular retention, and activation of the unfolded protein response."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our data provide the first clear evidence for misfolding of SMCD collagen X mutants, and we propose that solvent exposure of the NC1 thiol may trigger the recognition and degradation of mutant collagen X chains.
explanation: >-
First demonstration of collagen X misfolding with MCDS mutations in cell models.
- reference: PMID:15695517
reference_title: "Misfolding of collagen X chains harboring Schmid metaphyseal chondrodysplasia mutations results in aberrant disulfide bond formation, intracellular retention, and activation of the unfolded protein response."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In cells expressing mutant collagen X, we detected significantly increased amounts of the spliced form of X-box DNA-binding protein mRNA and up-regulation of BiP, two key markers for the unfolded protein response.
explanation: >-
Demonstrates UPR activation with XBP1 splicing and BiP upregulation.
- reference: PMID:19834559
reference_title: "Targeted induction of endoplasmic reticulum stress induces cartilage pathology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our data demonstrate that triggering ER stress per se in hypertrophic chondrocytes is sufficient to induce the essential features of the cartilage pathology associated with MCDS and confirm that ER stress is a central pathogenic factor in the disease mechanism.
explanation: >-
Demonstrates ER stress sufficiency by reproducing MCDS phenotype with unrelated ER stress-inducing protein in hypertrophic chondrocytes.
- reference: PMID:17403716
reference_title: "COL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Misfolded FCdel alpha1(X) chains were retained within the endoplasmic reticulum of hypertrophic chondrocytes, activating the unfolded protein response. Our findings provide strong in vivo evidence for a gain-of-function effect that is linked to the activation of endoplasmic reticulum-stress response and altered chondrocyte differentiation, as a possible molecular pathogenesis for MCDS.
explanation: >-
In vivo confirmation of ER retention and UPR activation in transgenic mouse model.
- reference: PMID:30543055
reference_title: "Mesencephalic astrocyte-derived neurotropic factor is an important factor in chondrocyte ER homeostasis."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
MANF plays a cytoprotective role in several soft tissues and is upregulated in conditions resulting from intracellular retention of mutant protein, including two skeletal diseases, metaphyseal chondrodysplasia, Schmid type (MCDS) and multiple epiphyseal dysplasia (MED).
explanation: >-
MANF upregulation in MCDS reflects a chondroprotective response to ER stress, further supporting ER stress as a central pathogenic axis.
- reference: PMID:29522813
reference_title: "Paradoxical roles of ATF6α and ATF6β in modulating disease severity caused by mutations in collagen X."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
disease severity in vivo is increased by ATF6α ablation and decreased by ATF6β ablation.
explanation: >-
Demonstrates paradoxical roles of ATF6 paralogs in modulating MCDS severity, with ATF6-alpha protective and ATF6-beta exacerbating.
downstream:
- target: PERK-Mediated Disruption of Chondrocyte Differentiation
- name: PERK-Mediated Disruption of Chondrocyte Differentiation
description: >
The PERK arm of the UPR is the dominant pathogenic pathway in MCDS. PERK-mediated
phosphorylation of eIF2-alpha leads to preferential translation of ATF4 and CHOP.
ATF4 directly transactivates Sox9, reverting hypertrophic chondrocytes toward a
proliferative-like state, while CHOP inhibits C/EBP-beta, a master regulator of
chondrocyte differentiation. This disrupted differentiation program, rather than
chondrocyte death, is responsible for the expanded hypertrophic zone.
cell_types:
- preferred_term: Hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
biological_processes:
- preferred_term: PERK-Mediated UPR
term:
id: GO:0036499
label: PERK-mediated unfolded protein response
- preferred_term: Growth Plate Chondrocyte Differentiation
term:
id: GO:0003418
label: growth plate cartilage chondrocyte differentiation
modifier: DECREASED
evidence:
- reference: PMID:30024379
reference_title: "Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9.
explanation: >-
Identifies PERK/ATF4/Sox9 axis as the dominant pathogenic pathway in MCDS.
- reference: PMID:26372225
reference_title: "XBP1-Independent UPR Pathways Suppress C/EBP-beta Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation.
explanation: >-
Demonstrates that MCDS pathology is driven by PERK/CHOP-mediated disruption of C/EBP-beta, independent of IRE1/XBP1.
- reference: PMID:26372225
reference_title: "XBP1-Independent UPR Pathways Suppress C/EBP-beta Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS.
explanation: >-
XBP1 deletion does not modify MCDS severity, confirming the IRE1/XBP1 pathway is dispensable for pathogenesis.
- reference: PMID:26587667
reference_title: "Label-Free Quantitative Proteomics Reveals Survival Mechanisms Developed by Hypertrophic Chondrocytes under ER Stress."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
ER stress is triggered in hypertrophic chondrocytes (HCs) in a mouse model (13del) of metaphyseal chondrodysplasia type Schmid (MCDS) caused by misfolded mutant collagen X proteins, but the HCs do not undergo apoptosis; rather chondrocyte differentiation is altered, causing skeletal abnormality.
explanation: >-
Proteomics confirms ER-stressed hypertrophic chondrocytes survive rather than undergoing apoptosis, with altered differentiation as the pathogenic outcome.
downstream:
- target: Impaired VEGF-Mediated Vascular Invasion
- name: Impaired VEGF-Mediated Vascular Invasion
description: >
Disrupted hypertrophic chondrocyte differentiation reduces osteoclast
recruitment and VEGF-mediated vascular invasion of the growth plate,
slowing the transition from cartilage to bone.
cell_types:
- preferred_term: Hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
biological_processes:
- preferred_term: Angiogenesis
term:
id: GO:0001525
label: angiogenesis
modifier: DECREASED
- preferred_term: Endochondral Ossification
term:
id: GO:0001958
label: endochondral ossification
modifier: DECREASED
evidence:
- reference: PMID:19834559
reference_title: "Targeted induction of endoplasmic reticulum stress induces cartilage pathology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Hypertrophic chondrocyte differentiation and osteoclast recruitment were significantly reduced indicating that the hypertrophic zone was expanded due to a decreased rate of VEGF-mediated vascular invasion of the growth plate.
explanation: >-
Demonstrates reduced osteoclast recruitment and VEGF-mediated vascular invasion as a direct consequence of ER stress in hypertrophic chondrocytes.
downstream:
- target: Hypertrophic Zone Expansion
- name: Hypertrophic Zone Expansion
description: >
Impaired vascular clearance of the hypertrophic zone leads to accumulation
of undegraded hypertrophic chondrocytes and expansion of the hypertrophic
zone, resulting in metaphyseal abnormalities and impaired longitudinal
bone growth.
cell_types:
- preferred_term: Hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
biological_processes:
- preferred_term: Endochondral Ossification
term:
id: GO:0001958
label: endochondral ossification
modifier: DECREASED
evidence:
- reference: PMID:19834559
reference_title: "Targeted induction of endoplasmic reticulum stress induces cartilage pathology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mice expressing the collagen X mutation had shortened limbs and an expanded hypertrophic zone.
explanation: >-
Hypertrophic zone expansion is a hallmark finding in the knock-in mouse model.
- reference: PMID:16088909
reference_title: "Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our findings suggest that COL10A1 mutations result in a uniform pattern of growth plate abnormalities.
explanation: >-
Supports growth plate dysfunction as a uniform consequence of COL10A1 mutations in human patients.
- name: Functional Haploinsufficiency
description: >
Across mutation classes, functional haploinsufficiency of collagen X is considered
a proximate cause of the clinical phenotype. Nonsense mutations may undergo
nonsense-mediated mRNA decay, directly reducing collagen X levels. Missense and
frameshift mutations can also act through a gain-of-function mechanism, as
misfolded mutant chains are retained intracellularly, reducing functional
extracellular collagen X and additionally triggering ER stress.
cell_types:
- preferred_term: Hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
biological_processes:
- preferred_term: Cartilage Development
term:
id: GO:0051216
label: cartilage development
evidence:
- reference: PMID:15880705
reference_title: "Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Thus for both classes of mutations, functional haploinsufficiency is the most probable cause of the clinical phenotype in SMCD.
explanation: >-
Review concluding that haploinsufficiency is the common proximate mechanism regardless of mutation class.
- reference: PMID:17403716
reference_title: "COL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We show that nonsense/frame-shift mutations can elicit a gain-of-function effect, affecting chondrocyte differentiation in the growth plate.
explanation: >-
Demonstrates that some nonsense/frameshift mutations also exert gain-of-function effects via ER stress, in addition to haploinsufficiency.
animal_models:
- species: Mouse
genotype: Col10a1 p.N617K knock-in
category: knock-in model
genes:
- preferred_term: COL10A1
term:
id: hgnc:2185
label: COL10A1
description: >-
A knock-in mouse model carrying the Col10a1 p.Asn617Lys mutation (equivalent
to a human MCDS-causing NC1 domain missense variant) recapitulates the human
phenotype with shortened limbs and expanded growth plate hypertrophic zone.
Hypertrophic chondrocytes exhibit ER stress with UPR activation and reduced
osteoclast recruitment.
associated_phenotypes:
- Shortened limbs
- Expanded hypertrophic zone
- ER stress in hypertrophic chondrocytes
evidence:
- reference: PMID:19834559
reference_title: "Targeted induction of endoplasmic reticulum stress induces cartilage pathology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We generated a knock-in mouse model of an MCDS-causing mutation (COL10A1 p.Asn617Lys) to investigate pathogenic mechanisms linking genotype and phenotype. Mice expressing the collagen X mutation had shortened limbs and an expanded hypertrophic zone.
explanation: >-
Establishes the Col10a1 N617K knock-in mouse as a model of MCDS.
- reference: PMID:22859705
reference_title: "Hypertrophic chondrocytes have a limited capacity to cope with increases in endoplasmic reticulum stress without triggering the unfolded protein response."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Embryos homozygous for the Col10a1p.N617K mutation displayed a delayed secretion of mutant collagen X accompanied by a UPR at E14.5, delayed ossification of the primary center at E15.5, and an expanded HZ at E17.5.
explanation: >-
Characterizes the developmental timing of UPR onset and pathology in the N617K model, demonstrating gene dosage effects.
- species: Mouse
genotype: FCdel transgenic (p.P620fsX621)
category: transgenic model
genes:
- preferred_term: COL10A1
term:
id: hgnc:2185
label: COL10A1
description: >-
Transgenic mice carrying the mouse equivalent of a human MCDS frameshift mutation
(p.P620fsX621) display disproportionate shortening of limbs and early-onset coxa
vara. The hypertrophic zone expansion is transgene-dosage dependent, with misfolded
chains retained in the ER.
associated_phenotypes:
- Disproportionate shortening of limbs
- Early onset coxa vara
- Dosage-dependent hypertrophic zone expansion
evidence:
- reference: PMID:17403716
reference_title: "COL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Unlike Col10a1 null mutants, transgenic mice (FCdel) bearing the mouse equivalent of a human MCDS p.P620fsX621 mutation, displayed typical characteristics of MCDS with disproportionate shortening of limbs and early onset coxa vara.
explanation: >-
FCdel mice phenocopy MCDS, distinguishing gain-of-function from null allele effects.
- species: Mouse
genotype: Col10a1 p.Y632X knock-in
category: knock-in model
genes:
- preferred_term: COL10A1
term:
id: hgnc:2185
label: COL10A1
description: >-
A knock-in model of the Col10a1 p.Y632X premature stop codon produces a relatively
severe form of MCDS. Despite the premature stop, mutant mRNA is stable and truncated
protein is translated and retained intracellularly, triggering ER stress. Carbamazepine
treatment alleviates disease severity in this model.
associated_phenotypes:
- Severe MCDS phenotype
- ER stress and UPR activation
- Responsive to carbamazepine
evidence:
- reference: PMID:30010889
reference_title: "Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
a gene-targeted mouse model of the Col10a1 p.Y632X mutation was generated. In this model, the mutant mRNA showed no instability, and in mice heterozygous for the mutation, mutant and wild-type mRNAs were present at equal concentrations. The protein was translated from the mutant allele and retained within the cell, triggering increased ER stress and a UPR. The mutation produced a relatively severe form of MCDS.
explanation: >-
Establishes the Y632X knock-in as a model of severe MCDS with confirmed ER stress mechanism.
- species: Medaka fish
genotype: col10a1-delta-633a (5bp deletion, frameshift)
category: knockout/knockin model
genes:
- preferred_term: COL10A1
term:
id: hgnc:2185
label: COL10A1
description: >-
A medaka (Oryzias latipes) MCDS model with a 5bp deletion in col10a1 disrupting
the trimerization domain. Heterozygotes recapitulate key MCDS features and
revealed early cell polarity defects as a cause for dysregulated matrix secretion
and deformed skeletal structures. Carbamazepine rescued polarity impairment and
skeletal defects.
associated_phenotypes:
- Cell polarity disruption
- Dysregulated matrix secretion
- Skeletal deformity
- Responsive to carbamazepine
evidence:
- reference: PMID:38510140
reference_title: "A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
col10a1Δ633a heterozygotes recapitulated key features of MCDS and revealed early cell polarity defects as cause for dysregulated matrix secretion and deformed skeletal structures. Carbamazepine, an ER stress-reducing drug, rescued this polarity impairment and alleviated skeletal defects in col10a1Δ633a heterozygotes.
explanation: >-
Medaka model demonstrating cell polarity disruption as a downstream consequence of ER stress in MCDS.
genetic:
- name: COL10A1 Pathogenic Variants
association: Causative
gene_term:
preferred_term: COL10A1
term:
id: hgnc:2185
label: COL10A1
notes: >
Heterozygous pathogenic variants in COL10A1 cause MCDS. Most mutations cluster in
the NC1 (non-collagenous) domain. Missense, nonsense, and frameshift mutations are
all represented. Type X collagen expression is restricted to hypertrophic
chondrocytes during endochondral ossification.
evidence:
- reference: PMID:8220429
reference_title: "A type X collagen mutation causes Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0).
explanation: >-
Original identification of COL10A1 as the causal gene.
- reference: PMID:15880705
reference_title: "Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Schmid metaphyseal chondrodysplasia (SMCD) is a dominantly inherited cartilage disorder caused by mutations in the gene for the hypertrophic cartilage extracellular matrix structural protein, collagen X (COL10A1).
explanation: >-
Comprehensive review consolidating the causal gene-disease relationship and mutation spectrum.
- reference: PMID:30010889
reference_title: "Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mutations, mostly in the region of the COL10A1 gene encoding the C-terminal non-collagenous domain, cause the dwarfism metaphyseal chondrodysplasia type Schmid (MCDS).
explanation: >-
Background statement from a mouse model study confirming NC1 domain as the primary mutation hotspot.
- reference: PMID:8220429
reference_title: "A type X collagen mutation causes Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The expression of type X collagen is restricted to hypertrophic chondrocytes in regions undergoing endochondral ossification, such as growth plates.
explanation: >-
Establishes the tissue-restricted expression pattern of COL10A1.
- reference: PMID:41454937
reference_title: "Clinical, Molecular Characteristics, and Genotype-Phenotype Relationships of Metaphyseal Chondrodysplasia Type Schmid."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genotype-phenotype analysis of 124 cases previously reported and 4 new cases revealed that NC1 domain mutations were associated with an earlier onset of MCDS than non-NC1 mutations (median 12 vs. 72 months, P = 0.0014). Patients carrying a missense mutation in COL10A1 showed significantly lower height Z-scores (- 3.62 ± 1.95 vs. - 1.99 ± 1.28, P = 0.013) at first and more metaphyseal irregularities in the distal radius/ulna than those with truncating mutations (P = 0.019).
explanation: >-
Large genotype-phenotype analysis demonstrating NC1 domain mutations associate with earlier onset and missense mutations with more severe short stature.
- reference: CGGV:assertion_5529304a-e8aa-4e44-a544-6864b8afe78a-2024-06-28T160000.000Z
reference_title: "COL10A1 / Schmid metaphyseal chondrodysplasia (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "COL10A1 | HGNC:2185 | Schmid metaphyseal chondrodysplasia | MONDO:0007983 | AD | Definitive"
explanation: ClinGen classifies the COL10A1-Schmid metaphyseal chondrodysplasia gene-disease relationship as definitive with autosomal dominant inheritance.
phenotypes:
- name: Short Stature
category: Clinical
description: >
Progressive short stature developing by age two years is a hallmark feature.
Adult height is typically more than 3.5 standard deviations below the mean,
although a wide spectrum overlapping normal height has been reported.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years.
explanation: >-
GeneReviews confirms progressive short stature as the cardinal growth phenotype.
- reference: PMID:16088909
reference_title: "Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones.
explanation: >-
Confirms short stature in a clinical cohort with molecularly confirmed MCDS.
- name: Short Lower Limbs
category: Clinical
description: >
Short lower limbs are part of the early phenotype and are often evident when
the disorder first becomes clinically apparent in early childhood.
phenotype_term:
preferred_term: Short lower limbs
term:
id: HP:0006385
label: Short lower limbs
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait.
explanation: >-
GeneReviews identifies short limbs as part of the characteristic early phenotype.
- reference: PMID:25542771
reference_title: "Case of mild Schmid-type metaphyseal chondrodysplasia with novel sequence variation involving an unusual mutational site of the COL10A1 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature with short legs, bowing of the long bones, coxa vara, and waddling gait.
explanation: >-
Independent clinical series confirms lower-limb shortening as a defining feature.
- name: Genu Varum
category: Clinical
description: >
Bow legs are a prominent lower-limb deformity that typically emerges in early
childhood and can progress to angular deformity.
phenotype_term:
preferred_term: Genu varum
term:
id: HP:0002970
label: Genu varum
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait.
explanation: >-
Lists genu varum as one of the early clinical manifestations.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities.
explanation: >-
Confirms genu varum as a uniform feature in a cohort of 12 children.
- name: Coxa Vara
category: Clinical
description: >
Coxa vara is a characteristic hip deformity that contributes to waddling gait
and proximal femoral deformity.
phenotype_term:
preferred_term: Coxa vara
term:
id: HP:0002812
label: Coxa vara
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs.
explanation: >-
Coxa vara listed among the characteristic radiographic findings.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara.
explanation: >-
Documents coxa vara in 8 of 12 children and its clinical consequence.
- name: Waddling Gait
category: Clinical
description: >
Waddling gait is a common early manifestation and in one cohort was a
consequence of coxa vara in eight of 12 children.
phenotype_term:
preferred_term: Waddling gait
term:
id: HP:0002515
label: Waddling gait
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait.
explanation: >-
Waddling gait listed as one of the early presenting features.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moderate short stature and a waddling gait associated with pain are the most common clinical presentations.
explanation: >-
Confirms waddling gait as one of the most common clinical presentations.
- name: Metaphyseal Widening
category: Radiographic
description: >
Widened growth plates and physes are characteristic radiographic abnormalities.
phenotype_term:
preferred_term: Metaphyseal widening
term:
id: HP:0003016
label: Metaphyseal widening
evidence:
- reference: PMID:16088909
reference_title: "Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones.
explanation: >-
Widened growth plates confirmed in molecularly characterized cohort.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease.
explanation: >-
Independent cohort confirms growth plate widening as a major radiographic feature.
- name: Metaphyseal Irregularity
category: Radiographic
description: >
Metaphyseal irregularities including splaying, flaring, and cupping are
pronounced around the hips and knees.
phenotype_term:
preferred_term: Metaphyseal irregularity
term:
id: HP:0003025
label: Metaphyseal irregularity
evidence:
- reference: PMID:16088909
reference_title: "Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographs showed metaphyseal changes which were most pronounced at the hips and knees.
explanation: >-
Documents metaphyseal irregularity distribution.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease.
explanation: >-
Confirms metaphyseal irregularity as the most striking radiological feature.
- name: Flared Metaphyses
category: Radiographic
description: >
Diffuse metaphyseal flaring, especially around the knees, is a hallmark
radiographic finding.
phenotype_term:
preferred_term: Flared metaphysis
term:
id: HP:0003015
label: Flared metaphysis
evidence:
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease.
explanation: >-
Metaphyseal flaring described as a striking radiological feature.
- name: Bowing of the Long Bones
category: Radiographic
description: >
Bowing of the long bones is a defining skeletal deformity; femoral bowing is
specifically reported in radiographic series.
phenotype_term:
preferred_term: Bowing of the long bones
term:
id: HP:0006487
label: Bowing of the long bones
evidence:
- reference: PMID:16088909
reference_title: "Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones.
explanation: >-
Bowing of the long bones confirmed as a defining feature.
- reference: PMID:15578582
reference_title: "Hand involvement in Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographic findings include anterior cupping, sclerosis and splaying of the ribs, diffuse metaphyseal flaring, and irregularity that is most pronounced at the knees, coxa vara, and femoral bowing.
explanation: >-
Registry radiographs specifically document femoral bowing as part of the skeletal phenotype.
- name: Anterior Rib Cupping
category: Radiographic
description: >
Anterior cupping with sclerosis and splaying of the ribs is a recurrent
radiographic feature.
phenotype_term:
preferred_term: Anterior rib cupping
term:
id: HP:0000907
label: Anterior rib cupping
evidence:
- reference: PMID:15578582
reference_title: "Hand involvement in Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographic findings include anterior cupping, sclerosis and splaying of the ribs, diffuse metaphyseal flaring, and irregularity that is most pronounced at the knees, coxa vara, and femoral bowing.
explanation: >-
Registry radiographs identify anterior rib cupping with associated rib sclerosis and splaying.
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs.
explanation: >-
GeneReviews independently lists anterior rib cupping among the characteristic radiographic findings.
- name: Platyspondyly
category: Radiographic
description: >
Spinal involvement is uncommon; one registry review found mild platyspondyly,
vertebral body abnormalities, and end-plate irregularity in 9.1% (3/33) of cases.
phenotype_term:
preferred_term: Platyspondyly
term:
id: HP:0000926
label: Platyspondyly
evidence:
- reference: PMID:10929364
reference_title: "Schmid type metaphyseal chondrodysplasia: a spondylometaphyseal dysplasia identical to the \"Japanese\" type."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found that in 9.1% (3/33) of cases reviewed there was definite radiographic evidence of spinal involvement comprising mild platyspondyly, vertebral body abnormalities, and end-plate irregularity.
explanation: >-
Registry review quantifies platyspondyly as an uncommon but real component of MCDS.
- reference: PMID:41454937
reference_title: "Clinical, Molecular Characteristics, and Genotype-Phenotype Relationships of Metaphyseal Chondrodysplasia Type Schmid."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The four patients presented with short stature or waddling gait, flattened vertebrae, and irregular femoral epiphyses.
explanation: >-
Recent series also reported flattened vertebrae, providing contemporary support for vertebral flattening in MCDS.
- name: Arthralgia
category: Clinical
description: >
Joint pain, particularly in the knees and hips, is common and may limit
physical activity.
phenotype_term:
preferred_term: Arthralgia
term:
id: HP:0002829
label: Arthralgia
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Joint pain in the knees and hips is common and may limit physical activity.
explanation: >-
GeneReviews documents arthralgia as a common clinical feature.
- name: Delayed Gross Motor Development
category: Clinical
description: >
Early motor milestones may be delayed because of orthopedic complications.
phenotype_term:
preferred_term: Delayed gross motor development
term:
id: HP:0002194
label: Delayed gross motor development
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal.
explanation: >-
GeneReviews documents delayed gross motor milestones as a secondary consequence of orthopedic burden.
- name: Short Tubular Bones of the Hand
category: Radiographic
description: >
Mild hand involvement is not universal but was found in 47% (7/15) of one
registry series, with shortening of the tubular bones and metaphyseal cupping
of the metacarpals and proximal phalanges.
phenotype_term:
preferred_term: Short tubular bones of the hand
term:
id: HP:0001248
label: Short tubular bones of the hand
evidence:
- reference: PMID:15578582
reference_title: "Hand involvement in Schmid metaphyseal chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found hand involvement in 47% (7/15) of cases included in our analysis. These changes were subtle and consisted of shortening of the tubular bones and metaphyseal cupping of the proximal phalanges and metacarpals.
explanation: >-
Provides explicit frequency data and defines the hand radiographic pattern in MCDS.
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mild hand involvement often includes shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges.
explanation: >-
GeneReviews corroborates the characteristic hand involvement pattern described in registry studies.
diagnosis:
- name: Clinical-Radiographic and Molecular Diagnosis
description: >
Diagnosis is based on characteristic clinical features (progressive short stature,
genu varum, waddling gait developing in early childhood) and radiographic findings
(metaphyseal irregularities, widened growth plates, coxa vara). Confirmation is by
identification of a heterozygous pathogenic variant in COL10A1. Facial features and
head size are normal, and there are no extraskeletal manifestations.
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of SMCD is established in a proband with characteristic clinical and radiographic features and/or identification of a heterozygous pathogenic variant in COL10A1 by molecular genetic testing.
explanation: >-
GeneReviews diagnostic criteria combining clinical, radiographic, and molecular testing.
- reference: PMID:16088909
reference_title: "Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report the clinical and radiographic findings in 10 patients with MCDS and COL10A1 mutations.
explanation: >-
Supports integrated clinical-radiographic evaluation with molecular confirmation.
treatments:
- name: Corrective Osteotomy
description: >
Corrective osteotomy (guided growth surgery or valgus osteotomy) may be considered
in late childhood or adolescence for progressive or symptomatic varus deformity,
significant coxa vara, or deteriorating function. Recurrence of deformities with
growth is not uncommon.
treatment_term:
preferred_term: corrective osteotomy
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
corrective osteotomy by guided growth surgery or valgus osteotomy may be considered in late childhood / adolescence in those with progressive or symptomatic varus deformity, significant coxa vara, triangular fragment in the interior femoral neck, or poor or deteriorating function
explanation: >-
GeneReviews management recommendations for surgical intervention.
- reference: PMID:30027601
reference_title: "Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases.
explanation: >-
Describes orthopedic surgical experience including risk of deformity recurrence.
- reference: PMID:16088909
reference_title: "Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations--findings in 10 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Six patients had lower limb deformities, which necessitated orthopedic surgeries in all of them.
explanation: >-
Confirms orthopedic surgery needed in patients with significant deformity.
- name: Physical Therapy and Supportive Care
description: >
Management includes physiotherapy, occupational therapy, joint-friendly exercise,
weight management, and psychosocial support. Mobility devices may be needed.
Obesity and physical activities causing excessive joint strain should be avoided.
treatment_term:
preferred_term: physical therapy
term:
id: MAXO:0000011
label: physical therapy
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Management of orthopedic complications by an orthopedist, physiotherapist, occupational therapist, and pain specialist as indicated; joint-friendly exercise, weight management; mobility device as needed
explanation: >-
GeneReviews management recommendations for supportive care.
- name: Genetic Counseling
description: >
Genetic counseling is recommended given autosomal dominant inheritance with 50%
recurrence risk. Prenatal testing and preimplantation genetic testing are available
once the familial COL10A1 variant is identified.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:31633898
reference_title: "Schmid Metaphyseal Chondrodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Once the COL10A1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for SMCD and preimplantation genetic testing are possible.
explanation: >-
GeneReviews genetic counseling section.
- name: Carbamazepine (Preclinical)
description: >
Carbamazepine, which stimulates intracellular proteolysis and alleviates ER stress,
reduced disease severity in a mouse model of MCDS. The drug reduced ER stress in
the growth plate, restored growth plate architecture, increased bone growth, and
corrected hip distortion within two weeks of treatment. This remains preclinical.
treatment_term:
preferred_term: carbamazepine therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:30010889
reference_title: "Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
treatment of the mice with carbamazepine (CBZ), a drug which stimulates intracellular proteolysis and alleviates ER stress, effectively reduced the disease severity in this model of MCDS caused by a premature stop codon in the Col10a1 gene. Specifically, the drug reduced ER stress in the growth plate, restored growth plate architecture toward the wild-type state, significantly increased bone growth and within 2 weeks of treatment corrected the MCDS-induced hip distortion.
explanation: >-
Preclinical evidence of carbamazepine efficacy in MCDS mouse model.
- name: PERK Inhibition (Preclinical)
description: >
Chemical inhibition of the PERK signaling pathway prevented differentiation
defects and ameliorated chondrodysplasia in a mouse model, suggesting that
titrated ISR inhibition may be a therapeutic strategy for MCDS. This remains
preclinical.
treatment_term:
preferred_term: PERK pathway inhibition
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:30024379
reference_title: "Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress-induced skeletal disorders.
explanation: >-
Preclinical evidence of PERK pathway inhibition as a therapeutic approach.
notes: >-
MCDS shows considerable intrafamilial phenotypic variability despite shared
COL10A1 variants. The disorder has no extraskeletal manifestations. Spinal changes
(platyspondyly) are present in approximately 9% of cases, supporting reclassification
as a spondylometaphyseal dysplasia in some patients. MCDS and the Japanese-type
spondylometaphyseal chondrodysplasia are now considered identical type X
collagenopathies.
references:
- reference: PMID:31633898
title: "Schmid Metaphyseal Chondrodysplasia."
tags:
- GeneReviews
findings: []
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Metaphyseal Chondrodysplasia, Schmid Type. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
MCDS is a growth-plate disorder caused by pathogenic COL10A1 variants—usually in the NC1 trimerization domain—that disrupt collagen X assembly, leading to intracellular retention of mutant collagen X in hypertrophic chondrocytes and triggering endoplasmic reticulum (ER) stress with activation of the unfolded protein response (UPR) and integrated stress response (ISR). These stress programs alter terminal chondrocyte differentiation rather than primarily inducing apoptosis, producing expansion of the hypertrophic zone, impaired VEGF-mediated vascular invasion, reduced osteoclast recruitment, and delayed endochondral ossification. A major mechanistic emphasis is PERK→eIF2α→ATF4/CHOP signaling, which can drive aberrant differentiation (including SOX9 dysregulation), while IRE1/XBP1 appears partly redundant for disease severity in at least one mouse genetic context. Recent 2024 work extends the phenotype to include cell polarity disruption in chondrocytes/osteoblasts, with rescue by pharmacologic ER-stress reduction in a fish model. (rajpar2009targetedinductionof pages 1-2, cameron2011transcriptionalprofilingof pages 1-2, wang2018inhibitingtheintegrated pages 1-2, cameron2015xbp1independentuprpathways pages 1-2, tan2024acollagen10a1mutation media 7b4c3afa)
Key disrupted biological processes supported by the evidence base include: - Response to ER stress / unfolded protein response with induction of chaperones, foldases, and ERAD machinery (cameron2011transcriptionalprofilingof pages 1-2, patterson2014mechanismsandmodels pages 3-4). - Integrated stress response / PERK-eIF2α signaling influencing cell fate/differentiation through ATF4/CHOP and downstream effectors including SOX9 and FGF21 (wang2018inhibitingtheintegrated pages 1-2). - Regulation of chondrocyte differentiation / hypertrophic maturation, including disruption of C/EBPβ-mediated programs and suppression of RUNX2-associated pathways (cameron2015xbp1independentuprpathways pages 1-2). - Angiogenesis/vascular invasion at growth plate (VEGF-mediated) and osteoclast recruitment required for endochondral ossification (rajpar2009targetedinductionof pages 1-2). - Establishment/maintenance of cell polarity (2024 model) as a downstream phenotype potentially linking ER stress to tissue architecture (tan2024acollagen10a1mutation media 7b4c3afa).
Evidence limitation note: within the retrieved corpus, 2023–2024 mechanistic primary literature specifically on MCDS is limited mainly to the 2024 medaka model plus the 2024 GeneReviews-style synthesis; much of the UPR/ISR mechanistic detail still relies on landmark mouse-model studies (2009–2018). (rajpar2009targetedinductionof pages 1-2, wang2018inhibitingtheintegrated pages 1-2, tan2024acollagen10a1mutation media 7b4c3afa)
The medaka model provides direct visual support for (i) disorganized chondrocyte stacking and polarity defects, (ii) ER ultrastructural stress changes, and (iii) rescue with carbamazepine treatment. (tan2024acollagen10a1mutation media 7b4c3afa, tan2024acollagen10a1mutation media 2ad256bd, tan2024acollagen10a1mutation media c648ae69)
Schmid metaphyseal chondrodysplasia is driven primarily by COL10A1 variants that impair type X collagen folding/trimerization in hypertrophic chondrocytes, causing intracellular retention in the rough ER and activation of UPR/ISR pathways (PERK/ATF4/CHOP; ATF6 cleavage; IRE1/XBP1 splicing). The stress response rewires hypertrophic differentiation programs—often manifesting as persistence of proliferative-like gene expression and/or SOX9-driven reversion—while not necessarily inducing early apoptosis. Reduced terminal differentiation impairs VEGF-driven vascular invasion and osteoclast recruitment at the chondro-osseous junction, expanding the hypertrophic zone and slowing endochondral ossification, leading to short stature and characteristic metaphyseal deformities. Recent model systems show that polarity defects may be an additional downstream cellular phenotype linking ER stress to disrupted growth plate architecture. (rajpar2009targetedinductionof pages 1-2, cameron2011transcriptionalprofilingof pages 1-2, wang2018inhibitingtheintegrated pages 1-2, tan2024acollagen10a1mutation media 7b4c3afa)
| Entity type | Preferred label | Ontology ID | Role in MCDS | Key supporting evidence (paper + mechanism) | PMID/DOI | URL | Year |
|---|---|---|---|---|---|---|---|
| Gene | COL10A1 | HGNC:2186 | Causal gene; encodes type X collagen misfolded in ER | Ho 2007: Human/mouse mutations exhibit gain-of-function retention (ho2007col10a1nonsenseand pages 1-2) | 10.1093/hmg/ddm067 | https://doi.org/10.1093/hmg/ddm067 | 2007 |
| GO Biological Process | Cellular response to ER stress / UPR | GO:0034976 / GO:0030968 | Core pathogenic response driving cartilage dysplasia | Cameron 2011: Transcriptomics identify adaptive UPR disrupting hypertrophy (cameron2011transcriptionalprofilingof pages 1-2) | 10.1371/journal.pone.0024600 | https://doi.org/10.1371/journal.pone.0024600 | 2011 |
| Gene | EIF2AK3 (PERK) / ATF4 / DDIT3 (CHOP) | HGNC:3255 / 786 / 2726 | Drives aberrant dedifferentiation via ISR | Wang 2018: PERK/ATF4 transactivates SOX9; CHOP suppresses CEBPB (wang2018inhibitingtheintegrated pages 1-2) | 10.7554/eLife.37673 | https://doi.org/10.7554/eLife.37673 | 2018 |
| Gene | ERN1 (IRE1) / XBP1 | HGNC:3449 / 12811 | UPR branch activated but pathologically redundant | Cameron 2015: Cartilage-specific Xbp1 deletion does not alter disease severity (cameron2015xbp1independentuprpathways pages 1-2) | 10.1371/journal.pgen.1005505 | https://doi.org/10.1371/journal.pgen.1005505 | 2015 |
| Gene | ATF6 | HGNC:788 | UPR sensor driving chaperone and ERAD expression | Briggs 2020: Review highlighting ATF6 activation by BiP dissociation (briggs2020newdevelopmentsin pages 3-5) | 10.12688/f1000research.22275.1 | https://doi.org/10.12688/f1000research.22275.1 | 2020 |
| Gene | HSPA5 (BiP), CRELD2, SYVN1, WFS1 | HGNC:5238, 24652, 16790, 12762 | Highly induced chaperones and ERAD regulators | Forouhan 2018: UPR markers significantly upregulated in Y632X mice (forouhan2018carbamazepinereducesdisease pages 7-9, cameron2011transcriptionalprofilingof pages 1-2) | 10.1093/hmg/ddy253 | https://doi.org/10.1093/hmg/ddy253 | 2018 |
| Gene | FGF21 | HGNC:3689 | Paracrine factor promoting cell-autonomous survival | Wang 2018: Transactivated by CHOP/ATF4 allowing stressed cells to survive (wang2018inhibitingtheintegrated pages 1-2) | 10.7554/eLife.37673 | https://doi.org/10.7554/eLife.37673 | 2018 |
| Gene | SOX9, CEBPB, RUNX2 | HGNC:11204, 1834, 10472 | Master differentiation regulators dysregulated by UPR/ISR | Cameron 2015, Wang 2018: CEBPB/RUNX2 suppressed, SOX9 aberrantly induced (cameron2015xbp1independentuprpathways pages 1-2, wang2018inhibitingtheintegrated pages 1-2) | 10.1371/journal.pgen.1005505 | https://doi.org/10.1371/journal.pgen.1005505 | 2015 |
| GO Biological Process | Angiogenesis (VEGFA) / Osteoclast differentiation | GO:0001525 / GO:0030316 | Impaired vascular invasion delays endochondral ossification | Rajpar 2009: Targeted ER stress reduces VEGFA-mediated invasion and osteoclast recruitment (rajpar2009targetedinductionof pages 1-2) | 10.1371/journal.pgen.1000691 | https://doi.org/10.1371/journal.pgen.1000691 | 2009 |
| CL cell type | Hypertrophic chondrocyte | CL:0000138 | Primary affected cell type retaining mutant collagen | Kung 2012: HZ expansion depends on gene dosage and latent ER capacity (kung2012hypertrophicchondrocyteshave pages 1-2) | 10.1369/0022155412458436 | https://doi.org/10.1369/0022155412458436 | 2012 |
| UBERON anatomy | Epiphyseal plate / Metaphysis | UBERON:0001645 / UBERON:0001460 | Anatomical sites of radiographic flaring and dysplasia | Richmond 2024: Clinical features including metaphyseal widening and coxa vara (richmond2024schmidmetaphysealchondrodysplasia pages 6-8, richmond2024schmidmetaphysealchondrodysplasia pages 3-6) | 10.1007/978-1-60327-161-5_164 | https://doi.org/10.1007/978-1-60327-161-5_164 | 2024 |
| GO Cellular Component | Rough endoplasmic reticulum / ER lumen | GO:0005791 / GO:0005788 | Site of mutant COL10A1 aggregation and swelling | Tan 2024: TEM reveals swollen and fragmented RER cisternae in mutants (tan2024acollagen10a1mutation media 7b4c3afa) | 10.1016/j.isci.2024.109405 | https://doi.org/10.1016/j.isci.2024.109405 | 2024 |
| GO Biological Process | ERAD (ER-associated ubiquitin-dependent catabolism) | GO:0030433 | Induced pathway to clear misfolded collagen X | Patterson 2014: UPR branches mediate ERAD induction in chondrodysplasia (patterson2014mechanismsandmodels pages 3-4, cameron2011transcriptionalprofilingof pages 1-2) | 10.1002/dvdy.24131 | https://doi.org/10.1002/dvdy.24131 | 2014 |
| CHEBI chemical | Carbamazepine / ISRIB | CHEBI:3423 / CHEBI:90656 | CBZ reduces ER stress; ISRIB inhibits PERK/ISR | Forouhan 2018, Wang 2018: CBZ enhances proteolysis; ISRIB prevents dedifferentiation (wang2018inhibitingtheintegrated pages 19-21, forouhan2018carbamazepinereducesdisease pages 7-9) | 10.1093/hmg/ddy253 | https://doi.org/10.1093/hmg/ddy253 | 2018 |
| GO Biological Process | Establishment of cell polarity / MTOC | GO:0030010 / GO:0005815 | Disrupted spatial organization of gamma-tubulin in cartilage | Tan 2024: Mutants show disorganized stacking; rescued by CBZ (tan2024acollagen10a1mutation pages 1-2, tan2024acollagen10a1mutation media 7b4c3afa) | 10.1016/j.isci.2024.109405 | https://doi.org/10.1016/j.isci.2024.109405 | 2024 |
Table: A structured mapping of key molecular, cellular, and anatomical components in Schmid metaphyseal chondrodysplasia to standardized ontology terms, highlighting the central role of ER stress and the unfolded protein response.
| Mechanistic layer | Key molecules/processes | Evidence (study type/model) | Key quantitative data/statistics if available | PMID/DOI | Publication year | URL |
|---|---|---|---|---|---|---|
| Genetic lesion | Heterozygous pathogenic variants in COL10A1 encoding type X collagen; variants include missense, nonsense, frameshift, small deletions, with strong enrichment in the NC1 trimerization domain; autosomal dominant inheritance with occasional de novo and rare biallelic cases (richmond2024schmidmetaphysealchondrodysplasia pages 12-15, meng2026clinicalmolecularcharacteristics pages 8-9, richmond2024schmidmetaphysealchondrodysplasia pages 3-6) | Clinical review and aggregated case summaries; literature-based genotype spectrum (richmond2024schmidmetaphysealchondrodysplasia pages 12-15, meng2026clinicalmolecularcharacteristics pages 8-9, richmond2024schmidmetaphysealchondrodysplasia pages 3-6) | Estimated prevalence 3–6 per million; >150 unrelated individuals with confirmed COL10A1 variants reported; among 114 genetically characterized cases, 53.5% missense, 44.7% truncating, 90.4% NC1-domain, 17.6% de novo, 92.3% heterozygous, 7.7% homozygous (richmond2024schmidmetaphysealchondrodysplasia pages 6-8, richmond2024schmidmetaphysealchondrodysplasia pages 3-6, meng2026clinicalmolecularcharacteristics pages 8-9) | DOI:10.1007/978-1-60327-161-5_164; DOI:10.1007/s00223-025-01457-8 | 2024; 2026 | https://doi.org/10.1007/978-1-60327-161-5_164 ; https://doi.org/10.1007/s00223-025-01457-8 |
| Protein consequence | Mutant collagen X chains are misfolded, fail to trimerize normally, and are retained intracellularly in hypertrophic chondrocytes; some truncating alleles may act via gain-of-function when mutant mRNA/protein persists rather than being fully removed by NMD (ho2007col10a1nonsenseand pages 1-2, rajpar2009targetedinductionof pages 1-2, forouhan2018carbamazepinereducesdisease pages 4-7) | Human genetic/pathology study and knock-in/transgenic mouse models (FCdel, N617K, Y632X) (ho2007col10a1nonsenseand pages 1-2, rajpar2009targetedinductionof pages 1-2, forouhan2018carbamazepinereducesdisease pages 4-7) | In one human case with a truncating mutation, cartilage contained 64% wild-type and 36% mutant COL10A1 mRNA; in Y632X knock-in mice, mutant mRNA had stability similar to wild type and produced retained truncated protein (ho2007col10a1nonsenseand pages 1-2, forouhan2018carbamazepinereducesdisease pages 4-7) | DOI:10.1093/hmg/ddm067; DOI:10.1371/journal.pgen.1000691; DOI:10.1093/hmg/ddy253 | 2007; 2009; 2018 | https://doi.org/10.1093/hmg/ddm067 ; https://doi.org/10.1371/journal.pgen.1000691 ; https://doi.org/10.1093/hmg/ddy253 |
| Cellular stress response | Intracellular retention of mutant collagen X triggers ER stress and a canonical UPR/ISR involving BiP/GRP78, PERK–eIF2α–ATF4–CHOP, IRE1–XBP1, ATF6, with induction of chaperones, foldases, and ERAD machinery including CRELD2, SYVN1, WFS1, ARMET, Fgf21 (rajpar2009targetedinductionof pages 1-2, cameron2011transcriptionalprofilingof pages 1-2, cameron2015xbp1independentuprpathways pages 1-2, patterson2014mechanismsandmodels pages 3-4) | Knock-in and transgenic mouse growth-plate studies; transcriptomics of microdissected hypertrophic zones (rajpar2009targetedinductionof pages 1-2, cameron2011transcriptionalprofilingof pages 1-2, cameron2015xbp1independentuprpathways pages 1-2) | In Y632X mice, Xbp1s increased ~2-fold; Bip, Creld2, Chop mRNAs and Atf4 plus cleaved Atf6a(N) proteins increased; in embryonic N617K mice, homozygotes showed UPR at E14.5, delayed primary ossification at E15.5, and hypertrophic-zone expansion by E17.5 (forouhan2018carbamazepinereducesdisease pages 4-7, kung2012hypertrophicchondrocyteshave pages 1-2) | DOI:10.1371/journal.pgen.1000691; DOI:10.1371/journal.pone.0024600; DOI:10.1371/journal.pgen.1005505; DOI:10.1002/dvdy.24131; DOI:10.1369/0022155412458436 | 2009; 2011; 2015; 2014; 2012 | https://doi.org/10.1371/journal.pgen.1000691 ; https://doi.org/10.1371/journal.pone.0024600 ; https://doi.org/10.1371/journal.pgen.1005505 ; https://doi.org/10.1002/dvdy.24131 ; https://doi.org/10.1369/0022155412458436 |
| Differentiation defect | ER-stressed hypertrophic chondrocytes survive but undergo impaired maturation: persistence of proliferative-like programs, suppression of hypertrophic differentiation, and dysregulation of C/EBPβ, RUNX2, GADD45β, SOX9; pathology is largely XBP1-independent and strongly linked to PERK/ATF4/CHOP signaling (cameron2011transcriptionalprofilingof pages 1-2, cameron2015xbp1independentuprpathways pages 1-2, wang2018inhibitingtheintegrated pages 1-2) | Transcriptomics and genetic epistasis in MCDS mice; PERK/ISR intervention studies (cameron2011transcriptionalprofilingof pages 1-2, cameron2015xbp1independentuprpathways pages 1-2, wang2018inhibitingtheintegrated pages 1-2) | Transcriptomic analysis identified 886 XBP1-dependent vs 688 XBP1-independent probes; genotype-phenotype severity was unchanged by cartilage-specific Xbp1 deletion, supporting redundancy of IRE1/XBP1 in MCDS; PERK inhibition prevented differentiation defects in vivo (cameron2015xbp1independentuprpathways pages 13-15, cameron2015xbp1independentuprpathways pages 1-2, wang2018inhibitingtheintegrated pages 1-2) | DOI:10.1371/journal.pone.0024600; DOI:10.1371/journal.pgen.1005505; DOI:10.7554/eLife.37673 | 2011; 2015; 2018 | https://doi.org/10.1371/journal.pone.0024600 ; https://doi.org/10.1371/journal.pgen.1005505 ; https://doi.org/10.7554/eLife.37673 |
| Tissue-level consequence | Defective hypertrophic maturation reduces VEGF-mediated vascular invasion of the growth plate and lowers osteoclast recruitment at the vascular invasion front, expanding the hypertrophic zone and delaying endochondral ossification (rajpar2009targetedinductionof pages 1-2, rellmann2018differentformsof pages 6-7) | Knock-in mouse and ER-stress transgenic mouse models; review synthesis of model findings (rajpar2009targetedinductionof pages 1-2, rellmann2018differentformsof pages 6-7) | In Y632X mice at 3 weeks, hypertrophic zone expanded 3.5-fold in wt/m and 5-fold in m/m animals; hip angle increased approximately 2-fold in wt/m mice; CBZ later reduced HZ width by half (forouhan2018carbamazepinereducesdisease pages 4-7, forouhan2018carbamazepinereducesdisease pages 7-9) | DOI:10.1371/journal.pgen.1000691; DOI:10.1155/2018/8421394; DOI:10.1093/hmg/ddy253 | 2009; 2018; 2018 | https://doi.org/10.1371/journal.pgen.1000691 ; https://doi.org/10.1155/2018/8421394 ; https://doi.org/10.1093/hmg/ddy253 |
| Clinical phenotype | Core phenotypes reflect growth-plate dysfunction: short-limbed short stature, waddling gait, genu varum, lumbar lordosis, coxa vara, bowed femora/tibiae, enlarged capital femoral epiphyses, metaphyseal flaring/widening, usually normal intelligence and craniofacial appearance (richmond2024schmidmetaphysealchondrodysplasia pages 6-8, richmond2024schmidmetaphysealchondrodysplasia pages 3-6, meng2026clinicalmolecularcharacteristics pages 8-9) | 2024 clinical review and 2026 literature-plus-cohort genotype-phenotype analysis (richmond2024schmidmetaphysealchondrodysplasia pages 6-8, richmond2024schmidmetaphysealchondrodysplasia pages 3-6, meng2026clinicalmolecularcharacteristics pages 8-9) | Frequencies in aggregated clinical datasets: waddling gait >80% or 88.5%, genu varum >80% or 83.6%, short stature >60%, lumbar lordosis >60% or 51.6%, coxa vara 50–80% or 80.0%, short femoral neck 81.7%, bowed femurs/tibiae 81.5%, enlarged capital femoral epiphysis 77.4%; median age at first diagnosis 3.5 years (richmond2024schmidmetaphysealchondrodysplasia pages 3-6, meng2026clinicalmolecularcharacteristics pages 8-9) | DOI:10.1007/978-1-60327-161-5_164; DOI:10.1007/s00223-025-01457-8 | 2024; 2026 | https://doi.org/10.1007/978-1-60327-161-5_164 ; https://doi.org/10.1007/s00223-025-01457-8 |
| Genotype–phenotype signal | Domain and mutation-class effects suggest earlier onset and greater severity for NC1 and missense variants versus non-NC1/truncating variants, though older reviews note that firm genotype-phenotype rules remain incomplete (richmond2024schmidmetaphysealchondrodysplasia pages 6-8, meng2026clinicalmolecularcharacteristics pages 8-9, wu2021characterizationofa pages 1-2) | Literature review and pooled case analysis (richmond2024schmidmetaphysealchondrodysplasia pages 6-8, meng2026clinicalmolecularcharacteristics pages 8-9, wu2021characterizationofa pages 1-2) | NC1 mutations associated with earlier onset: 12 vs 72 months (P=0.0014); missense variants associated with lower height Z-score at presentation: −3.62 ± 1.95 vs −1.99 ± 1.28 (P=0.013); distal radius/ulna metaphyseal irregularities more frequent with missense variants (P=0.019); last-evaluation height differed by NC1 status: −5.58 ± 1.95 vs −2.61 ± 1.46 (P=0.0001) (meng2026clinicalmolecularcharacteristics pages 1-2, meng2026clinicalmolecularcharacteristics pages 8-9) | DOI:10.1007/978-1-60327-161-5_164; DOI:10.1007/s00223-025-01457-8; DOI:10.1002/mgg3.1668 | 2024; 2026; 2021 | https://doi.org/10.1007/978-1-60327-161-5_164 ; https://doi.org/10.1007/s00223-025-01457-8 ; https://doi.org/10.1002/mgg3.1668 |
| Recent 2024 development | A medaka col10a1 model extends the disease mechanism beyond ER stress to include loss of cell polarity in chondrocytes and osteoblasts, with disorganized stacking and abnormal matrix secretion; ER stress reduction rescues polarity and skeletal shape (tan2024acollagen10a1mutation pages 1-2, tan2024acollagen10a1mutation media 7b4c3afa) | 2024 animal model (medaka) with imaging, transcriptomics, TEM, and pharmacologic rescue (tan2024acollagen10a1mutation pages 1-2, tan2024acollagen10a1mutation media 7b4c3afa) | Heterozygous fish recapitulated MCDS-like defects; 10 mg/L carbamazepine rescued ceratobranchial tortuosity and improved polarity-associated abnormalities; TEM showed swollen/fragmented RER in mutant chondrocytes and osteoblasts (tan2024acollagen10a1mutation media 7b4c3afa) | DOI:10.1016/j.isci.2024.109405 | 2024 | https://doi.org/10.1016/j.isci.2024.109405 |
| Therapeutic leverage point | Targeting proteostasis and ISR signaling can ameliorate disease in vivo: carbamazepine (CBZ) enhances mutant collagen X degradation and lowers UPR signaling; ISR/PERK inhibition lowers ATF4/CHOP-driven dedifferentiation and improves chondrodysplasia (briggs2020newdevelopmentsin pages 3-5, wang2018inhibitingtheintegrated pages 19-21, forouhan2018carbamazepinereducesdisease pages 7-9, wang2018inhibitingtheintegrated pages 1-2) | Mouse preclinical treatment studies; review noting clinical translation efforts (briggs2020newdevelopmentsin pages 3-5, forouhan2018carbamazepinereducesdisease pages 7-9, wang2018inhibitingtheintegrated pages 1-2) | In Y632X mice, oral CBZ 250 mg/kg/day increased femur/tibia growth, normalized hip geometry after 2 weeks, reduced hypertrophic-zone width by ~50%, lowered Bip/Creld2/Chop, suppressed Xbp1 splicing, and reduced Atf4 and cleaved Atf6α; ISRIB/chemical PERK inhibition improved phenotype in 13del mice, though rescue was incomplete (forouhan2018carbamazepinereducesdisease pages 7-9, wang2018inhibitingtheintegrated pages 21-22, wang2018inhibitingtheintegrated pages 1-2) | DOI:10.1093/hmg/ddy253; DOI:10.7554/eLife.37673; DOI:10.12688/f1000research.22275.1 | 2018; 2018; 2020 | https://doi.org/10.1093/hmg/ddy253 ; https://doi.org/10.7554/eLife.37673 ; https://doi.org/10.12688/f1000research.22275.1 |
Table: This table summarizes the main mechanistic layers of Metaphyseal Chondrodysplasia, Schmid type, linking COL10A1 mutations to ER stress, disrupted hypertrophic differentiation, growth-plate pathology, clinical manifestations, and therapeutic intervention points. It integrates landmark mechanistic studies with recent clinical and 2024 animal-model updates.
Note: In the retrieved full texts above, PMIDs were not included in the tool outputs; therefore DOI-based identifiers are provided for unambiguous traceability. - Rajpar et al., PLoS Genetics, Oct 2009, DOI:10.1371/journal.pgen.1000691 (rajpar2009targetedinductionof pages 1-2) - Cameron et al., PLoS ONE, Sep 2011, DOI:10.1371/journal.pone.0024600 (cameron2011transcriptionalprofilingof pages 1-2) - Kung et al., J Histochem Cytochem, Oct 2012, DOI:10.1369/0022155412458436 (kung2012hypertrophicchondrocyteshave pages 1-2) - Cameron et al., PLOS Genetics, Sep 2015, DOI:10.1371/journal.pgen.1005505 (cameron2015xbp1independentuprpathways pages 1-2) - Wang et al., eLife, Jul 2018, DOI:10.7554/eLife.37673 (wang2018inhibitingtheintegrated pages 1-2) - Forouhan et al., Hum Mol Genet, Jul 2018, DOI:10.1093/hmg/ddy253 (forouhan2018carbamazepinereducesdisease pages 7-9) - Tan et al., iScience, Apr 2024, DOI:10.1016/j.isci.2024.109405 (tan2024acollagen10a1mutation media 7b4c3afa) - Richmond & Savarirayan, (GeneReviews chapter as represented), 2024 update, DOI:10.1007/978-1-60327-161-5_164 (richmond2024schmidmetaphysealchondrodysplasia pages 10-12)
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MCDS is caused by heterozygous pathogenic variants in COL10A1 and is inherited in an autosomal dominant pattern. Foundational segregation data demonstrated a COL10A1 deletion segregating with autosomal dominant MCDS in a large kindred (PMID:8220429). Subsequent series confirmed COL10A1 mutations across affected patients and reinforced autosomal dominant inheritance (PMID:16088909; PMID:15880705).
COL10A1 encodes type X collagen, which is specifically expressed in hypertrophic chondrocytes in growth plates during endochondral ossification (PMID:8220429; PMID:15695517). Disease mechanisms include:
Key features repeatedly reported include:
These are directly supported in a 10-patient clinical/radiographic cohort (PMID:16088909).
MCDS severity varies substantially among affected individuals even within the same molecular diagnosis. Orthopedic burden is common, and clinical management is driven by deformity severity and growth trajectory (PMID:16088909).