Metaphyseal dysplasia, Spahr type

Mendelian MONDO:0009597 Pathograph 6 Show in embeddings browser hereditary disease

Metaphyseal dysplasia, Spahr type (MDST) is an autosomal recessive metaphyseal dysplasia caused by biallelic MMP13 variants. It was described in 1961 in four of five siblings with moderate short stature, metaphyseal irregularity and mild genu varum but entirely normal blood chemistry, and it kept that clinical-only definition for more than fifty years until exome sequencing identified MMP13 in 2014. MMP13 is the collagenase that remodels the cartilaginous matrix of the growing physis, and the reported disease alleles sit in the catalytic domain, disabling the enzyme rather than misregulating it. The clinical picture is dominated by how convincingly it imitates rickets: metaphyseal fraying, splaying and cupping with bowed legs, in a child whose calcium, phosphate, alkaline phosphatase and vitamin D are all normal. Distinguishing it matters because the treatments for rickets do nothing here, and because recurrence risk is recessive rather than dominant.

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1
Inheritance
3
Pathophys.
9
Phenotypes
1
Gaps
6
Pathograph
1
Genes
3
Medical Actions
4
Differentials
1
References
🏷

Classifications

ISDS Skeletal Nosology
metaphyseal dysplasias
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic MMP13 variants, reported both as homozygous variants in consanguineous families and as segregating homozygous variants in multiplex sibships.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:24648384 SUPPORT Human Clinical
"The MDST phenotype is associated with recessive MMP13 mutations, confirming the importance of this metalloproteinase in the metaphyseal growth plate."
Establishes the recessive mode and the causal gene in the family that originally defined the disease.
PMID:27576021 SUPPORT Human Clinical
"We report on two siblings of Iraqi descent with clinical and radiographic features of metaphyseal dysplasia, Spahr type (MDST), born to consanguineous unaffected parents. Molecular testing confirmed pathogenic mutations in MMP13."
Independent recessive sibship with unaffected consanguineous parents.
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Discussions and Knowledge Gaps

1
Is metaphyseal dysplasia, Spahr type regressive or persistent, and does the answer depend on which part of the phenotype is measured?
KNOWLEDGE GAP OPEN gap_mdst_regressive_or_persistent
Attached to
pathophysiology#Metaphyseal Irregularity with Lower-Limb Deformity phenotypes#Disproportionate short stature
The literature is not consistent. Long-term follow-up of the founding family reports moderate short stature and knee pain persisting in adults, while an independent sibship describes MDST as regressive. Both statements may be true of different components - radiographic metaphyseal change may resolve while stature and joint symptoms do not - but no series has separated them. Since regression is exactly the axis on which the nosology distinguishes this entity from dominant metaphyseal anadysplasia, resolving it would sharpen a classification boundary as well as prognostic counselling.
Show evidence (2 references)
PMID:24648384 SUPPORT Human Clinical
"The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed."
The persistence side of the disagreement, from adult follow-up of the founding family.
PMID:27576021 SUPPORT Human Clinical
"These cases confirm the phenotypic variability and regressive nature of MDST in addition to suggesting bone fragility as a feature."
The regression side of the same disagreement, from an independent sibship.
⚙

Pathophysiology

3
Biallelic MMP13 Catalytic-Domain Loss of Function
The variants reported in MDST fall in the catalytic domain of MMP13. The founding family's p.Trp207Gly substitution disrupts a hydrogen bond in the calcium-binding region of that domain, disabling the collagenase. This is the mechanistic contrast with dominant metaphyseal anadysplasia, where the variants sit in the prodomain and cause premature autoactivation rather than simple inactivation.
MMP13 hgnc:7159 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MMP13 (hgnc:7159). hgnc:7159 is a gene from the HUGO Gene Nomenclature Committee.
metalloendopeptidase activity GO:0004222 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves metalloendopeptidase activity (GO:0004222), qualified as loss of function. GO:0004222 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Failure of Physeal Collagen Remodelling Loss of MMP13 collagenase activity removes the enzyme that degrades collagen and other matrix proteins during physeal remodelling.
Show evidence (2 references)
PMID:24648384 SUPPORT Computational
"The predicted non-conservative amino acid substitution, p.Trp207Gly, disrupts a crucial hydrogen bond in the calcium-binding region of the catalytic domain of the matrix metalloproteinase, MMP13."
Structural modelling of the founding variant locating the lesion in the catalytic domain.
PMID:40514045 SUPPORT Human Clinical
"we reinforce the dyadic naming system for the two groups of MMP13-related metaphyseal dysplasia, differentiated solely by their inheritance patterns, which also exhibit consistency with the location of the variants"
Supports the claim that the recessive and dominant MMP13 entities differ by variant location as well as by inheritance.
Failure of Physeal Collagen Remodelling
Without MMP13, the cartilaginous matrix at the chondro-osseous junction is not degraded on schedule, so the orderly conversion of hypertrophic cartilage to metaphyseal bone is disrupted. In mice, ablation of Mmp13 alone or together with Mmp9 severely distorts the metaphyseal growth plate, which is the animal counterpart of the human lesion.
hypertrophic chondrocyte CL:0000743 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hypertrophic chondrocyte (CL:0000743). CL:0000743 is a cell type from the Cell Ontology.
collagen catabolic process GO:0030574 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen catabolic process (GO:0030574). GO:0030574 is a biological process from the Gene Ontology. ↓ DECREASED endochondral ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Metaphyseal Irregularity with Lower-Limb Deformity Disordered metaphyseal remodelling produces the fraying, splaying and cupping seen radiographically and the varus deformity that follows from asymmetric physeal growth.
Show evidence (1 reference)
PMID:19615667 SUPPORT Model Organism
"In mice, ablation of Mmp9, Mmp13, or both Mmp9 and Mmp13 causes severe distortion of the metaphyseal growth plate."
Mouse genetics establishing that loss of Mmp13 distorts the metaphyseal growth plate.
Metaphyseal Irregularity with Lower-Limb Deformity
The expressed disease: moderate short stature with disproportionate upper-to-lower segment ratio, genu varum, metaphyseal fraying, splaying and cupping, and coxa vara. Expressivity varies substantially even within a sibship, from a child with pain and deformity requiring surgery to a sibling with radiographic change alone. Extra-skeletal complications do not occur, but adults report persistent short stature and knee pain, so the disease is not regressive in the way metaphyseal anadysplasia is.
Show evidence (2 references)
PMID:24648384 SUPPORT Human Clinical
"The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed."
Long-term follow-up of the founding family establishing the persistent, skeletally confined adult phenotype.
PMID:36873332 SUPPORT Human Clinical
"The clinical consequences of these dysplastic changes are highly variable, but most uniformly include decreased stature, increased upper-to-lower segment proportions, genu varus, and knee pain."
Source for the segment disproportion and the variability recorded in this node.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Metaphyseal dysplasia, Spahr type Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Limbs 5
Metaphyseal irregularity HP:0003025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal irregularity (HP:0003025). HP:0003025 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"It is characterized by mild short stature, genu varum, and metaphyseal irregularities including fraying, splaying, and cupping of the long bones."
Primary description of the defining radiographic finding.
Metaphyseal cupping HP:0003021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal cupping (HP:0003021). HP:0003021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"It is characterized by mild short stature, genu varum, and metaphyseal irregularities including fraying, splaying, and cupping of the long bones."
Names cupping among the metaphyseal changes.
Metaphyseal widening HP:0003016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal widening (HP:0003016). HP:0003016 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"Radiographies revealed advanced bone age, mildly enlarged epiphyses, wide and irregular metaphyses of the long tubular bones, mildly thickened long tubular bones, and coxa vara."
Radiographic report documenting metaphyseal widening.
Genu varum HP:0002970 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu varum (HP:0002970). HP:0002970 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36873332 SUPPORT Human Clinical
"is a rare primary bone dysplasia that was first clinically described in 1961 in four of five siblings with moderate short stature, metaphyseal dysplasia, mild genu vara, and no biochemical signs of rickets."
The original 1961 clinical description records mild genu vara alongside the metaphyseal dysplasia and normal biochemistry.
Coxa vara HP:0002812 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coxa vara (HP:0002812). HP:0002812 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"Radiographies revealed advanced bone age, mildly enlarged epiphyses, wide and irregular metaphyses of the long tubular bones, mildly thickened long tubular bones, and coxa vara."
Radiographic report documenting coxa vara.
Musculoskeletal 1
Accelerated skeletal maturation HP:0005616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Accelerated skeletal maturation (HP:0005616). HP:0005616 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"Radiographies revealed advanced bone age, mildly enlarged epiphyses, wide and irregular metaphyses of the long tubular bones, mildly thickened long tubular bones, and coxa vara."
Radiographic report documenting advanced bone age in a confirmed patient.
Growth 1
Disproportionate short stature HP:0003498 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disproportionate short stature (HP:0003498), qualified as severity moderate. HP:0003498 is a phenotype from the Human Phenotype Ontology.
Severity: MODERATE
Show evidence (2 references)
PMID:36873332 SUPPORT Human Clinical
"The clinical consequences of these dysplastic changes are highly variable, but most uniformly include decreased stature, increased upper-to-lower segment proportions, genu varus, and knee pain."
Source for the disproportion recorded here.
PMID:24648384 SUPPORT Human Clinical
"The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed."
Establishes that short stature persists into adult life.
Other 2
Knee pain HP:0030839 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Knee pain (HP:0030839). HP:0030839 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24648384 SUPPORT Human Clinical
"The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed."
Documents adult knee pain as part of the phenotype.
Increased susceptibility to fractures HP:0002659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased susceptibility to fractures (HP:0002659). HP:0002659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27576021 SUPPORT Human Clinical
"These cases confirm the phenotypic variability and regressive nature of MDST in addition to suggesting bone fragility as a feature."
The source itself only suggests bone fragility, which is why this phenotype is marked as partially supported and occasional.
🧬

Genetic Associations

1
MMP13 (Causal biallelic variant)
Gene: MMP13 hgnc:7159 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MMP13 (hgnc:7159). hgnc:7159 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:24648384 SUPPORT Human Clinical
"The sequencing showed that MDST segregated with a c.619T>G single nucleotide transversion in MMP13."
The segregating variant that established MMP13 as the causal gene.
PMID:31413057 SUPPORT Human Clinical
"We present a case of a 7-year-old boy, finally diagnosed with metaphyseal dysplasia, Spahr type (MDST) (OMIM # 250400) after his exome sequencing revealed novel variations in the MMP13 gene (OMIM * 600108)."
Independent confirmation of MMP13 in a separately ascertained patient.
💊

Medical Actions

3
Guided growth surgery for lower-limb deformity
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Physeal tethering of the distal femur and proximal tibia has been used for symptomatic varus deformity, with reduced pain at follow-up although the deformity itself persisted. No standard of care exists, and the evidence base is a handful of case reports.
Mechanism Target:
MODULATES Metaphyseal Irregularity with Lower-Limb Deformity — Redirects growth mechanically at the physis; it does nothing to the underlying collagenase deficiency.
Show evidence (1 reference)
PMID:36873332 SUPPORT Human Clinical
"At 16 months post tethering, she reports reduced pain although varus deformity persists."
Reports symptomatic benefit without correction of the deformity, which is why the effect is recorded as partial.
Target Phenotypes: Genu varum HP:0002970 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Genu varum (HP:0002970). HP:0002970 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36873332 SUPPORT Human Clinical
"Patient 1 presented at age 8 for medial ankle pain and bilateral lower extremity bowing of several years. Radiographs showed bilateral metaphyseal irregularities, and the patient underwent bilateral lateral distal femoral and proximal tibial physeal tethering at 9 years 11 months."
The reported surgical intervention on which this treatment entry rests.
Avoidance of unnecessary rickets treatment
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Because the disorder mimics rickets, affected children are commonly given vitamin D or phosphate before the diagnosis is made. Establishing MDST stops ineffective treatment and redirects care to orthopaedic follow-up.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"Herein, we present a 39-month-old girl patient who was initially evaluated for rickets due to mild short stature, bowing of the lower extremities, and metaphyseal changes."
Documents the initial rickets workup that molecular diagnosis redirects.
Genetic counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Recessive recurrence risk of 25% for siblings. Distinguishing MDST from dominant metaphyseal anadysplasia, which involves the same gene, changes the counselling entirely.
Show evidence (1 reference)
PMID:24648384 SUPPORT Human Clinical
"Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis."
States that molecular confirmation is what enables accurate recurrence-risk counselling.
🔬

Biochemical Markers

1
Serum calcium, phosphate, alkaline phosphatase and vitamin D (Normal)
Context: All normal. This is the single most important laboratory observation in the disease, because it is what excludes the rickets that the radiographs otherwise suggest.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"Biochemical tests including calcium, phosphate, alkaline phosphatase, and vitamin D levels were all within normal ranges."
Direct report of normal bone biochemistry in a molecularly confirmed patient.
🔬

Diagnosis

2
Skeletal radiography with normal bone biochemistry
The diagnostic pattern is metaphyseal irregularity plus disproportionate short stature plus genu varum in a child whose bone biochemistry is normal. Advanced rather than delayed bone age further argues against rickets.
X-ray imaging NCIT:C38101 NCI Thesaurus (NCIT)
Results: Metaphyseal fraying, splaying and cupping with normal calcium, phosphate, alkaline phosphatase and vitamin D.
Show evidence (1 reference)
PMID:36873332 SUPPORT Human Clinical
"Suspicion for MDST should be elevated in the setting of short-stature, upper-to-lower segment disproportionality, focal metaphyseal irregularities, and normal biochemical presentation."
Explicit diagnostic-suspicion criteria from a clinical case series.
MMP13 sequencing
Exome or targeted sequencing confirms the diagnosis and, critically, assigns the mode of inheritance by showing whether the variants are biallelic and where in MMP13 they lie.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic MMP13 variants, typically in the catalytic domain.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"Clinical exome sequencing identified a homozygous variant in the MMP13 gene, confirming the diagnosis of metaphyseal dysplasia Spahr type."
Exome sequencing as the confirmatory diagnostic step.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
No population estimate exists; about a dozen molecularly confirmed patients have been reported in total.
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"MMP13-related metaphyseal dysplasia Spahr type, is an extremely rare skeletal disorder, and only a dozen patients with a confirmed molecular diagnosis have been reported."
Direct source for the count of molecularly confirmed cases.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Metaphyseal dysplasia, Spahr type:

Rickets
Overlapping Features The dominant differential and the usual initial diagnosis. Clinical and radiological features overlap almost completely; biochemistry does not.
Distinguishing Features
  • Calcium, phosphate, alkaline phosphatase and vitamin D are normal in MDST
  • Bone age may be advanced in MDST rather than delayed
  • No extra-skeletal complications
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"The disorder is in the differential diagnosis of rickets, a relatively common disorder in childhood that shares similar clinical and radiological features with metaphyseal dysplasia."
States the overlap that makes rickets the principal differential.
Metaphyseal anadysplasia MONDO:0015177
Overlapping Features The dominant MMP13 entity, and the closest genetic mimic. It regresses spontaneously in childhood, whereas MDST persists.
Distinguishing Features
  • Monoallelic prodomain MMP13 variants rather than biallelic catalytic-domain variants
  • Spontaneous regression of the metaphyseal changes in childhood
Show evidence (1 reference)
PMID:40514045 SUPPORT Human Clinical
"we reinforce the dyadic naming system for the two groups of MMP13-related metaphyseal dysplasia, differentiated solely by their inheritance patterns, which also exhibit consistency with the location of the variants"
States that the two MMP13 entities are separated by inheritance and variant location.
Metaphyseal chondrodysplasia, Schmid type MONDO:0007983
Overlapping Features The commonest metaphyseal dysplasia. Dominant, COL10A1-related, and typically with more prominent coxa vara and waddling gait.
Distinguishing Features
  • Autosomal dominant COL10A1 variants
  • Prominent coxa vara with waddling gait
Show evidence (1 reference)
PMID:24648384 SUPPORT Human Clinical
"Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis."
Names Schmid type as a condition MDST must be distinguished from.
Cartilage-hair hypoplasia MONDO:0009595
Overlapping Features A more severe, multisystem metaphyseal dysplasia with hypotrichosis and immunodeficiency; the presence of extra-skeletal features separates it from MDST.
Distinguishing Features
  • Hypotrichosis and immunodeficiency
  • Biallelic RMRP variants
Show evidence (1 reference)
PMID:24648384 SUPPORT Human Clinical
"Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis."
Names cartilage-hair hypoplasia as the multisystem condition MDST must be distinguished from.
{ }

Source YAML

click to show 
name: Metaphyseal dysplasia, Spahr type
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Metaphyseal dysplasia, Spahr type (MDST) is an autosomal recessive metaphyseal
  dysplasia caused by biallelic MMP13 variants. It was described in 1961 in four
  of five siblings with moderate short stature, metaphyseal irregularity and
  mild genu varum but entirely normal blood chemistry, and it kept that
  clinical-only definition for more than fifty years until exome sequencing
  identified MMP13 in 2014. MMP13 is the collagenase that remodels the
  cartilaginous matrix of the growing physis, and the reported disease alleles
  sit in the catalytic domain, disabling the enzyme rather than misregulating
  it. The clinical picture is dominated by how convincingly it imitates rickets:
  metaphyseal fraying, splaying and cupping with bowed legs, in a child whose
  calcium, phosphate, alkaline phosphatase and vitamin D are all normal.
  Distinguishing it matters because the treatments for rickets do nothing here,
  and because recurrence risk is recessive rather than dominant.
disease_term:
  preferred_term: metaphyseal chondrodysplasia, Spahr type
  term:
    id: MONDO:0009597
    label: metaphyseal chondrodysplasia, Spahr type
parents:
- hereditary disease
synonyms:
- MDST
- Spahr-type metaphyseal chondrodysplasia
- MMP13-related metaphyseal dysplasia, recessive type
classifications:
  isds_skeletal_category:
  - classification_value: metaphyseal_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger,
      Ferreira, Mortier et al., PMID:36779427), Table 1 group 11 "Metaphyseal
      dysplasias", row NOS 11-0090 "Metaphyseal dysplasia Spahr, MMP13-related"
      (MIM 250400, autosomal recessive). The group's other MMP13 row, NOS
      11-0100 "Metaphyseal anadysplasia, MMP13-related" (MIM 602111), is the
      dominant entity and is curated on the Metaphyseal anadysplasia entry; the
      two are separated by inheritance and by where in MMP13 the variants fall.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic MMP13 variants, reported both as homozygous variants in
    consanguineous families and as segregating homozygous variants in
    multiplex sibships.
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MDST phenotype is associated with recessive MMP13 mutations, confirming the importance of this metalloproteinase in the metaphyseal growth plate.
    explanation: >-
      Establishes the recessive mode and the causal gene in the family that
      originally defined the disease.
  - reference: PMID:27576021
    reference_title: >-
      Metaphyseal dysplasia, Spahr type; missense MMP13 mutations in two Iraqi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on two siblings of Iraqi descent with clinical and radiographic features of metaphyseal dysplasia, Spahr type (MDST), born to consanguineous unaffected parents. Molecular testing confirmed pathogenic mutations in MMP13.
    explanation: >-
      Independent recessive sibship with unaffected consanguineous parents.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    No population estimate exists; about a dozen molecularly confirmed patients
    have been reported in total.
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MMP13-related metaphyseal dysplasia Spahr type, is an extremely rare skeletal disorder, and only a dozen patients with a confirmed molecular diagnosis have been reported.
    explanation: >-
      Direct source for the count of molecularly confirmed cases.
pathophysiology:
- name: Biallelic MMP13 Catalytic-Domain Loss of Function
  biological_scale: MOLECULAR
  description: >-
    The variants reported in MDST fall in the catalytic domain of MMP13. The
    founding family's p.Trp207Gly substitution disrupts a hydrogen bond in the
    calcium-binding region of that domain, disabling the collagenase. This is
    the mechanistic contrast with dominant metaphyseal anadysplasia, where the
    variants sit in the prodomain and cause premature autoactivation rather than
    simple inactivation.
  genes:
  - preferred_term: MMP13
    term:
      id: hgnc:7159
      label: MMP13
  molecular_functions:
  - preferred_term: metalloendopeptidase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The predicted non-conservative amino acid substitution, p.Trp207Gly, disrupts a crucial hydrogen bond in the calcium-binding region of the catalytic domain of the matrix metalloproteinase, MMP13.
    explanation: >-
      Structural modelling of the founding variant locating the lesion in the
      catalytic domain.
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we reinforce the dyadic naming system for the two groups of MMP13-related metaphyseal dysplasia, differentiated solely by their inheritance patterns, which also exhibit consistency with the location of the variants
    explanation: >-
      Supports the claim that the recessive and dominant MMP13 entities differ
      by variant location as well as by inheritance.
  downstream:
  - target: Failure of Physeal Collagen Remodelling
    description: >-
      Loss of MMP13 collagenase activity removes the enzyme that degrades
      collagen and other matrix proteins during physeal remodelling.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36873332
      reference_title: >-
        Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This protein plays a role in the degradation of collagen and other proteins in the extracellular matrix with particular importance in the maturation and remodeling of the cartilaginous component of physes in growing children
      explanation: >-
        States the physeal remodelling function that the loss-of-function
        variants remove.
- name: Failure of Physeal Collagen Remodelling
  biological_scale: TISSUE
  description: >-
    Without MMP13, the cartilaginous matrix at the chondro-osseous junction is
    not degraded on schedule, so the orderly conversion of hypertrophic
    cartilage to metaphyseal bone is disrupted. In mice, ablation of Mmp13 alone
    or together with Mmp9 severely distorts the metaphyseal growth plate, which
    is the animal counterpart of the human lesion.
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: collagen catabolic process
    modifier: DECREASED
    term:
      id: GO:0030574
      label: collagen catabolic process
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:19615667
    reference_title: >-
      Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, ablation of Mmp9, Mmp13, or both Mmp9 and Mmp13 causes severe distortion of the metaphyseal growth plate.
    explanation: >-
      Mouse genetics establishing that loss of Mmp13 distorts the metaphyseal
      growth plate.
  downstream:
  - target: Metaphyseal Irregularity with Lower-Limb Deformity
    description: >-
      Disordered metaphyseal remodelling produces the fraying, splaying and
      cupping seen radiographically and the varus deformity that follows from
      asymmetric physeal growth.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40514045
      reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It is characterized by mild short stature, genu varum, and metaphyseal irregularities including fraying, splaying, and cupping of the long bones.
      explanation: >-
        Describes the radiographic and clinical lesion this edge produces.
- name: Metaphyseal Irregularity with Lower-Limb Deformity
  biological_scale: ORGANISM
  description: >-
    The expressed disease: moderate short stature with disproportionate
    upper-to-lower segment ratio, genu varum, metaphyseal fraying, splaying and
    cupping, and coxa vara. Expressivity varies substantially even within a
    sibship, from a child with pain and deformity requiring surgery to a sibling
    with radiographic change alone. Extra-skeletal complications do not occur,
    but adults report persistent short stature and knee pain, so the disease is
    not regressive in the way metaphyseal anadysplasia is.
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed.
    explanation: >-
      Long-term follow-up of the founding family establishing the persistent,
      skeletally confined adult phenotype.
  - reference: PMID:36873332
    reference_title: >-
      Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical consequences of these dysplastic changes are highly variable, but most uniformly include decreased stature, increased upper-to-lower segment proportions, genu varus, and knee pain.
    explanation: >-
      Source for the segment disproportion and the variability recorded in this
      node.
phenotypes:
- name: Metaphyseal irregularity
  category: Skeletal
  diagnostic: true
  description: >-
    Fraying, splaying and cupping of the long-bone metaphyses, focal rather than
    generalised, and radiographically indistinguishable from rickets.
  phenotype_term:
    preferred_term: Metaphyseal irregularity
    term:
      id: HP:0003025
      label: Metaphyseal irregularity
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by mild short stature, genu varum, and metaphyseal irregularities including fraying, splaying, and cupping of the long bones.
    explanation: >-
      Primary description of the defining radiographic finding.
- name: Metaphyseal cupping
  category: Skeletal
  description: >-
    Cupping of the metaphyses, one of the specific rickets-mimicking features.
  phenotype_term:
    preferred_term: Metaphyseal cupping
    term:
      id: HP:0003021
      label: Metaphyseal cupping
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by mild short stature, genu varum, and metaphyseal irregularities including fraying, splaying, and cupping of the long bones.
    explanation: >-
      Names cupping among the metaphyseal changes.
- name: Metaphyseal widening
  category: Skeletal
  description: >-
    Wide, irregular metaphyses of the long tubular bones on radiography.
  phenotype_term:
    preferred_term: Metaphyseal widening
    term:
      id: HP:0003016
      label: Metaphyseal widening
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographies revealed advanced bone age, mildly enlarged epiphyses, wide and irregular metaphyses of the long tubular bones, mildly thickened long tubular bones, and coxa vara.
    explanation: >-
      Radiographic report documenting metaphyseal widening.
- name: Genu varum
  category: Skeletal
  diagnostic: true
  description: >-
    Bowing of the lower limbs, usually the presenting complaint and the feature
    that prompts investigation for rickets.
  phenotype_term:
    preferred_term: Genu varum
    term:
      id: HP:0002970
      label: Genu varum
  evidence:
  - reference: PMID:36873332
    reference_title: >-
      Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is a rare primary bone dysplasia that was first clinically described in 1961 in four of five siblings with moderate short stature, metaphyseal dysplasia, mild genu vara, and no biochemical signs of rickets.
    explanation: >-
      The original 1961 clinical description records mild genu vara alongside
      the metaphyseal dysplasia and normal biochemistry.
- name: Coxa vara
  category: Skeletal
  description: >-
    Reduced femoral neck-shaft angle, reported on radiography alongside the
    metaphyseal changes.
  phenotype_term:
    preferred_term: Coxa vara
    term:
      id: HP:0002812
      label: Coxa vara
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographies revealed advanced bone age, mildly enlarged epiphyses, wide and irregular metaphyses of the long tubular bones, mildly thickened long tubular bones, and coxa vara.
    explanation: >-
      Radiographic report documenting coxa vara.
- name: Accelerated skeletal maturation
  category: Skeletal
  description: >-
    Advanced bone age was reported in a molecularly confirmed case. It is a
    useful negative discriminator against rickets, in which bone age is
    typically delayed rather than advanced.
  phenotype_term:
    preferred_term: Accelerated skeletal maturation
    term:
      id: HP:0005616
      label: Accelerated skeletal maturation
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographies revealed advanced bone age, mildly enlarged epiphyses, wide and irregular metaphyses of the long tubular bones, mildly thickened long tubular bones, and coxa vara.
    explanation: >-
      Radiographic report documenting advanced bone age in a confirmed patient.
- name: Disproportionate short stature
  category: Growth
  description: >-
    Moderate short stature with an increased upper-to-lower segment ratio,
    reflecting the predominantly lower-limb physeal involvement. It persists
    into adult life.
  phenotype_term:
    preferred_term: Disproportionate short stature
    term:
      id: HP:0003498
      label: Disproportionate short stature
    severity: MODERATE
  evidence:
  - reference: PMID:36873332
    reference_title: >-
      Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical consequences of these dysplastic changes are highly variable, but most uniformly include decreased stature, increased upper-to-lower segment proportions, genu varus, and knee pain.
    explanation: >-
      Source for the disproportion recorded here.
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed.
    explanation: >-
      Establishes that short stature persists into adult life.
- name: Knee pain
  category: Musculoskeletal
  description: >-
    Knee pain in adults is the main symptomatic burden of the disease, and
    lower-limb pain is what brings some affected children to orthopaedic
    attention.
  phenotype_term:
    preferred_term: Knee pain
    term:
      id: HP:0030839
      label: Knee pain
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed.
    explanation: >-
      Documents adult knee pain as part of the phenotype.
- name: Increased susceptibility to fractures
  category: Skeletal
  description: >-
    Bone fragility was proposed as a feature on the basis of a single sibship
    and has not been confirmed in the other reported families; it is recorded
    here as a suggested rather than established manifestation. No frequency is
    given because the source suggests the feature rather than quantifying it.
  phenotype_term:
    preferred_term: Increased susceptibility to fractures
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: PMID:27576021
    reference_title: >-
      Metaphyseal dysplasia, Spahr type; missense MMP13 mutations in two Iraqi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases confirm the phenotypic variability and regressive nature of MDST in addition to suggesting bone fragility as a feature.
    explanation: >-
      The source itself only suggests bone fragility, which is why this
      phenotype is marked as partially supported and occasional.
biochemical:
- name: Serum calcium, phosphate, alkaline phosphatase and vitamin D
  presence: Normal
  context: >-
    All normal. This is the single most important laboratory observation in the
    disease, because it is what excludes the rickets that the radiographs
    otherwise suggest.
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical tests including calcium, phosphate, alkaline phosphatase, and vitamin D levels were all within normal ranges.
    explanation: >-
      Direct report of normal bone biochemistry in a molecularly confirmed
      patient.
genetic:
- name: MMP13
  association: Causal biallelic variant
  gene_term:
    preferred_term: MMP13
    term:
      id: hgnc:7159
      label: MMP13
  notes: >-
    Biallelic catalytic-domain variants. The founding family carried
    c.619T>G p.Trp207Gly; other families carry different missense and nonsense
    changes. Monoallelic prodomain variants in the same gene cause dominant
    metaphyseal anadysplasia instead.
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sequencing showed that MDST segregated with a c.619T>G single nucleotide transversion in MMP13.
    explanation: >-
      The segregating variant that established MMP13 as the causal gene.
  - reference: PMID:31413057
    reference_title: "Metaphyseal dysplasia, Spahr type: a mimicker of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a case of a 7-year-old boy, finally diagnosed with metaphyseal dysplasia, Spahr type (MDST) (OMIM # 250400) after his exome sequencing revealed novel variations in the MMP13 gene (OMIM * 600108).
    explanation: >-
      Independent confirmation of MMP13 in a separately ascertained patient.
environmental: []
treatments:
- name: Guided growth surgery for lower-limb deformity
  description: >-
    Physeal tethering of the distal femur and proximal tibia has been used for
    symptomatic varus deformity, with reduced pain at follow-up although the
    deformity itself persisted. No standard of care exists, and the evidence
    base is a handful of case reports.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Genu varum
    term:
      id: HP:0002970
      label: Genu varum
  target_mechanisms:
  - target: Metaphyseal Irregularity with Lower-Limb Deformity
    treatment_effect: MODULATES
    description: >-
      Redirects growth mechanically at the physis; it does nothing to the
      underlying collagenase deficiency.
    evidence:
    - reference: PMID:36873332
      reference_title: >-
        Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At 16 months post tethering, she reports reduced pain although varus deformity persists.
      explanation: >-
        Reports symptomatic benefit without correction of the deformity, which
        is why the effect is recorded as partial.
  evidence:
  - reference: PMID:36873332
    reference_title: >-
      Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 presented at age 8 for medial ankle pain and bilateral lower extremity bowing of several years. Radiographs showed bilateral metaphyseal irregularities, and the patient underwent bilateral lateral distal femoral and proximal tibial physeal tethering at 9 years 11 months.
    explanation: >-
      The reported surgical intervention on which this treatment entry rests.
- name: Avoidance of unnecessary rickets treatment
  description: >-
    Because the disorder mimics rickets, affected children are commonly given
    vitamin D or phosphate before the diagnosis is made. Establishing MDST stops
    ineffective treatment and redirects care to orthopaedic follow-up.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we present a 39-month-old girl patient who was initially evaluated for rickets due to mild short stature, bowing of the lower extremities, and metaphyseal changes.
    explanation: >-
      Documents the initial rickets workup that molecular diagnosis redirects.
- name: Genetic counselling
  description: >-
    Recessive recurrence risk of 25% for siblings. Distinguishing MDST from
    dominant metaphyseal anadysplasia, which involves the same gene, changes the
    counselling entirely.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis.
    explanation: >-
      States that molecular confirmation is what enables accurate recurrence-risk
      counselling.
diagnosis:
- name: Skeletal radiography with normal bone biochemistry
  description: >-
    The diagnostic pattern is metaphyseal irregularity plus disproportionate
    short stature plus genu varum in a child whose bone biochemistry is normal.
    Advanced rather than delayed bone age further argues against rickets.
  results: >-
    Metaphyseal fraying, splaying and cupping with normal calcium, phosphate,
    alkaline phosphatase and vitamin D.
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:36873332
    reference_title: >-
      Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Suspicion for MDST should be elevated in the setting of short-stature, upper-to-lower segment disproportionality, focal metaphyseal irregularities, and normal biochemical presentation.
    explanation: >-
      Explicit diagnostic-suspicion criteria from a clinical case series.
- name: MMP13 sequencing
  description: >-
    Exome or targeted sequencing confirms the diagnosis and, critically,
    assigns the mode of inheritance by showing whether the variants are
    biallelic and where in MMP13 they lie.
  results: >-
    Biallelic MMP13 variants, typically in the catalytic domain.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exome sequencing identified a homozygous variant in the MMP13 gene, confirming the diagnosis of metaphyseal dysplasia Spahr type.
    explanation: >-
      Exome sequencing as the confirmatory diagnostic step.
differential_diagnoses:
- name: Rickets
  description: >-
    The dominant differential and the usual initial diagnosis. Clinical and
    radiological features overlap almost completely; biochemistry does not.
  distinguishing_features:
  - Calcium, phosphate, alkaline phosphatase and vitamin D are normal in MDST
  - Bone age may be advanced in MDST rather than delayed
  - No extra-skeletal complications
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disorder is in the differential diagnosis of rickets, a relatively common disorder in childhood that shares similar clinical and radiological features with metaphyseal dysplasia.
    explanation: >-
      States the overlap that makes rickets the principal differential.
- name: Metaphyseal anadysplasia
  description: >-
    The dominant MMP13 entity, and the closest genetic mimic. It regresses
    spontaneously in childhood, whereas MDST persists.
  disease_term:
    preferred_term: metaphyseal anadysplasia
    term:
      id: MONDO:0015177
      label: metaphyseal anadysplasia
  distinguishing_features:
  - Monoallelic prodomain MMP13 variants rather than biallelic catalytic-domain variants
  - Spontaneous regression of the metaphyseal changes in childhood
  evidence:
  - reference: PMID:40514045
    reference_title: "MMP13-related metaphyseal dysplasia: a differential diagnosis of rickets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we reinforce the dyadic naming system for the two groups of MMP13-related metaphyseal dysplasia, differentiated solely by their inheritance patterns, which also exhibit consistency with the location of the variants
    explanation: >-
      States that the two MMP13 entities are separated by inheritance and
      variant location.
- name: Metaphyseal chondrodysplasia, Schmid type
  description: >-
    The commonest metaphyseal dysplasia. Dominant, COL10A1-related, and
    typically with more prominent coxa vara and waddling gait.
  disease_term:
    preferred_term: Schmid metaphyseal chondrodysplasia
    term:
      id: MONDO:0007983
      label: Schmid metaphyseal chondrodysplasia
  distinguishing_features:
  - Autosomal dominant COL10A1 variants
  - Prominent coxa vara with waddling gait
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis.
    explanation: >-
      Names Schmid type as a condition MDST must be distinguished from.
- name: Cartilage-hair hypoplasia
  description: >-
    A more severe, multisystem metaphyseal dysplasia with hypotrichosis and
    immunodeficiency; the presence of extra-skeletal features separates it from
    MDST.
  disease_term:
    preferred_term: cartilage-hair hypoplasia
    term:
      id: MONDO:0009595
      label: cartilage-hair hypoplasia
  distinguishing_features:
  - Hypotrichosis and immunodeficiency
  - Biallelic RMRP variants
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis.
    explanation: >-
      Names cartilage-hair hypoplasia as the multisystem condition MDST must be
      distinguished from.
discussions:
- discussion_id: gap_mdst_regressive_or_persistent
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is metaphyseal dysplasia, Spahr type regressive or persistent, and does the
    answer depend on which part of the phenotype is measured?
  attaches_to:
  - pathophysiology#Metaphyseal Irregularity with Lower-Limb Deformity
  - phenotypes#Disproportionate short stature
  rationale: >-
    The literature is not consistent. Long-term follow-up of the founding family
    reports moderate short stature and knee pain persisting in adults, while an
    independent sibship describes MDST as regressive. Both statements may be
    true of different components - radiographic metaphyseal change may resolve
    while stature and joint symptoms do not - but no series has separated them.
    Since regression is exactly the axis on which the nosology distinguishes this
    entity from dominant metaphyseal anadysplasia, resolving it would sharpen a
    classification boundary as well as prognostic counselling.
  evidence:
  - reference: PMID:24648384
    reference_title: MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed.
    explanation: >-
      The persistence side of the disagreement, from adult follow-up of the
      founding family.
  - reference: PMID:27576021
    reference_title: >-
      Metaphyseal dysplasia, Spahr type; missense MMP13 mutations in two Iraqi siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases confirm the phenotypic variability and regressive nature of MDST in addition to suggesting bone fragility as a feature.
    explanation: >-
      The regression side of the same disagreement, from an independent sibship.
clinical_trials: []
datasets: []
notes: >-
  Curated to complete ISDS Nosology group 11 (Metaphyseal dysplasias), row
  NOS 11-0090. MONDO:0009597 carries the label "metaphyseal chondrodysplasia,
  Spahr type"; this entry uses "Metaphyseal dysplasia, Spahr type" as the
  human-facing name, matching both the 2023 nosology row and the abbreviation
  MDST used throughout the literature.
references:
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
  findings: []
📚

References & Deep Research

References

1
PMID:36779427
Nosology of genetic skeletal disorders: 2023 revision.
No top-level findings curated for this source.