Metaphyseal anadysplasia

Mendelian MONDO:0015177 Pathograph 9 Show in embeddings browser hereditary disease

Metaphyseal anadysplasia is a very rare metaphyseal dysplasia that is defined as much by its trajectory as by its radiology: severe metaphyseal irregularity, bowing of the legs and mild short stature appear in the first months or years of life and then regress spontaneously, so that radiographs normalise during childhood and adult stature is essentially unaffected. The "ana-" in the name records that regression. It is caused by deficiency of the two matrix metalloproteinases that remodel the metaphyseal extracellular matrix: type 1 arises from dominant MMP13 prodomain missense variants that autoactivate the enzyme and trigger intracellular degradation of both MMP13 and MMP9, producing a double enzymatic deficiency, while type 2 arises from biallelic MMP9 loss of function. Because the metaphyseal changes mimic rickets but blood chemistry is normal, the disorder is repeatedly misdiagnosed as nutritional or hypophosphataemic rickets.

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2
Inheritance
5
Pathophys.
6
Phenotypes
1
Gaps
9
Pathograph
2
Genes
2
Medical Actions
2
Subtypes
3
Differentials
1
References
🏷

Classifications

ISDS Skeletal Nosology
metaphyseal dysplasias
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Type 1 is dominant. The causal MMP13 changes are prodomain missense variants that act by autoactivating the enzyme rather than by simple haploinsufficiency.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:19615667 SUPPORT Human Clinical
"We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13, whereas dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double..."
Establishes the dominant mode and the specific prodomain-missense mechanism behind it.
PMID:30439533 SUPPORT Human Clinical
"Metaphyseal anadysplasia 1 (MIM# 602111) belongs to a heterogeneous group of skeletal diseases characterized by an autosomal dominant form of growth defects due to metaphyseal changes with epiphyseal involvement similar to other metaphyseal disorders."
Confirms the dominant mode for type 1 and notes the epiphyseal involvement that can accompany it.
Autosomal recessive inheritance HP:0000007
Type 2 is recessive, caused by biallelic MMP9 loss-of-function variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:28342220 SUPPORT Human Clinical
"Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs."
States the recessive mode and the transitory character of the MMP9-related form.
◆

Subtypes

2
Metaphyseal anadysplasia type 1 (MMP13-related)
MMP13 hgnc:7159 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MMP13 (hgnc:7159). hgnc:7159 is a gene from the HUGO Gene Nomenclature Committee.
The dominant, more severe form. Prodomain missense variants cause MMP13 to autoactivate intracellularly, and the activated enzyme degrades both itself and MMP9 before secretion, so a single mutant allele produces a combined MMP13 and MMP9 deficiency. Epiphyseal changes and rickets-like metaphyseal findings may accompany the metaphyseal disease.
Show evidence (2 references)
PMID:19615667 SUPPORT Human Clinical
"dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency"
Defines the molecular mechanism specific to this subtype. Graded HUMAN_CLINICAL because the quoted sentence is the paper's genotype-phenotype result across its patient cohort; the double-deficiency clause within it rests on the authors' transfection work, which the cached abstract does not report as a separate sentence.
PMID:34407464 SUPPORT Human Clinical
"Two types exist, the more severe form, type 1, with both autosomal dominant and recessive inheritance due to pathogenic variants in MMP13, whilst type 2, an even rarer form is due to biallelic MMP9 variants."
Places type 1 as the more severe, MMP13-related form of the two.
Metaphyseal anadysplasia type 2 (MMP9-related) MONDO:0013113
MMP9 hgnc:7176 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MMP9 (hgnc:7176). hgnc:7176 is a gene from the HUGO Gene Nomenclature Committee.
The recessive, even rarer form, caused by biallelic MMP9 loss of function. Fewer than a handful of families have been reported. Long-bone shortening may be detectable on prenatal ultrasound before any metaphyseal change is visible postnatally.
Show evidence (2 references)
PMID:34407464 SUPPORT Human Clinical
"This case confirms that biallelic MMP9 variants cause this very rare skeletal dysplasia, metaphyseal anadysplasia type 2 but also shows that the skeletal manifestations can improve within a short period time and at an early age."
Confirms causality for the MMP9 subtype and its early regression.
PMID:34407464 SUPPORT Human Clinical
"To date, only two metaphyseal anadysplasia type 2 families have been reported."
Documents how few families define this subtype.
?

Discussions and Knowledge Gaps

1
Why does a constitutive, lifelong deficiency of MMP9 and MMP13 produce a growth-plate lesion that resolves during childhood while the genetic defect persists unchanged?
KNOWLEDGE GAP OPEN gap_mad_mechanism_of_regression
Attached to
pathophysiology#Distorted Metaphyseal Growth Plate pathophysiology#Regressive Metaphyseal Irregularity and Limb Bowing progression#Spontaneous regression
Spontaneous regression is the defining feature of this disease and the reason it was named, yet no mechanism has been offered for it. The germline lesion does not change, so regression must reflect either a developmental shift in how much metaphyseal remodelling depends on these two proteases, or compensation by other matrix metalloproteinases as the growth rate falls. Neither has been tested. The question also matters practically: the same proteases are drug targets in osteoarthritis, and an endogenous compensatory route would be worth identifying.
Show evidence (1 reference)
PMID:34407464 SUPPORT Human Clinical
"Metaphyseal anadysplasia is a very rare hereditary skeletal dysplasia with onset occurring normally during the second and third years of life, but unlike many other dysplasias, symptoms appear to resolve by adolescence."
States the regression that this gap asks about, and marks it as unusual among skeletal dysplasias.
⚙

Pathophysiology

5
Dominant MMP13 Prodomain Autoactivation
Missense variants in the MMP13 prodomain destabilise the cysteine switch that holds the zymogen inactive, so the enzyme autoactivates before secretion. The prematurely active protease degrades itself and, because MMP9 traffics with it, degrades MMP9 as well. A single mutant allele therefore removes both enzymes rather than half of one, which is why the dominant form is more severe than the recessive single-gene forms.
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 gain of function. GO:0004222 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Combined MMP13 and MMP9 Deficiency at the Metaphyseal Front Autoactivation consumes both proteases intracellularly, so neither reaches the metaphyseal matrix.
Show evidence (1 reference)
PMID:19615667 SUPPORT Human Clinical
"dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency"
Establishes premature intracellular autoactivation as the proximal molecular lesion. The claim is carried by the authors' transfection experiments, but the quoted sentence is the cohort genotype-phenotype result that reports them, and the cached record is abstract-only, so the item is graded by what the sentence reports rather than by the assay behind one of its clauses.
Biallelic MMP9 Loss of Function
Homozygous or compound heterozygous MMP9 null variants remove gelatinase B from the metaphysis. Because MMP13 remains intact, the resulting matrix defect is milder than in the dominant form.
MMP9 hgnc:7176 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MMP9 (hgnc:7176). hgnc:7176 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Combined MMP13 and MMP9 Deficiency at the Metaphyseal Front Loss of MMP9 alone produces the same class of proteolytic deficit at the metaphyseal front, at lower severity.
Show evidence (1 reference)
PMID:19615667 SUPPORT Human Clinical
"We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13"
Establishes homozygous MMP9 loss of function as a cause of the recessive form.
Combined MMP13 and MMP9 Deficiency at the Metaphyseal Front
The converging molecular state of both subtypes: insufficient collagenase and gelatinase activity at the chondro-osseous junction. These two enzymes do double duty there, degrading extracellular matrix components and liberating matrix-sequestered signalling molecules such as VEGFA that couple cartilage resorption to vascular invasion.
extracellular matrix disassembly GO:0022617 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased extracellular matrix disassembly (GO:0022617). GO:0022617 is a biological process from the Gene Ontology. ↓ DECREASED 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
Downstream
Distorted Metaphyseal Growth Plate Loss of either or both enzymes distorts the growth plate; mouse ablation of Mmp9, Mmp13 or both reproduces this directly.
Show evidence (1 reference)
PMID:19615667 SUPPORT In Vitro
"The matrix metalloproteinases MMP9 and MMP13 catalyze the degradation of extracellular matrix (ECM) components in the growth plate and at the same time cleave and release biologically active molecules stored in the ECM, such as VEGFA."
Establishes the dual proteolytic and signal-releasing role that is lost in this node.
Distorted Metaphyseal Growth Plate
Histology of the upper tibial growth cartilage in an index case showed wide proliferative and hypertrophic zones, abnormal terminal hypertrophic chondrocytes, and a disordered zone of cartilage calcification and resorption. That last observation is the histological signature of the lesion: the failure is in the resorption and remodelling step at the chondro-osseous junction, not in chondrocyte proliferation or hypertrophy upstream of it.
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.
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
Regressive Metaphyseal Irregularity and Limb Bowing Disordered metaphyseal remodelling produces the radiographic irregularity and the varus bowing of the lower limbs.
Show evidence (1 reference)
PMID:1867263 SUPPORT Human Clinical
"The upper tibial growth cartilage, studied in one case, showed wide proliferative and hypertrophic zones with an unusual appearance of the last hypertrophic cells and an abnormal zone of cartilage calcification and resorption."
The only human growth-plate histology reported for this disease, and the basis for locating the lesion at the calcification and resorption zone.
Regressive Metaphyseal Irregularity and Limb Bowing
The clinically expressed disease: metaphyseal irregularity, mild varus bowing and slight shortness apparent within the first months to years of life, which then regress spontaneously. In the original series the radiographic anomalies disappeared after age two; in the type 2 series they resolved over roughly the same interval, and in the type II regressive series described separately they persisted to about age ten. Adult stature is essentially unaffected, and the natural history is benign.
Show evidence (2 references)
PMID:1867263 SUPPORT Human Clinical
"Those anomalies disappear after 2 years."
The regression that gives the disease its name, in the founding series.
PMID:1867263 SUPPORT Human Clinical
"The main manifestations are slight shortness and a light varus deformity of the lower limbs. Stature is not affected."
Establishes the mildness of the expressed phenotype and the preserved adult stature.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Metaphyseal anadysplasia 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

6
Limbs 2
Metaphyseal irregularity HP:0003025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal irregularity (HP:0003025), qualified as temporality transient. HP:0003025 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (2 references)
PMID:1867263 SUPPORT Human Clinical
"Distal metaphyses of long bones are very irregular. Femoral necks seem hypoplastic and the edges of the metaphyses are almost vertical; femoral shaft is bowed."
Primary radiographic description of the defining finding.
PMID:9799299 SUPPORT Human Clinical
"On radiographs the metaphyseal changes of the knees are specific with fine irregularities. The femoral necks are blurred but not hypoplastic."
Documents the same finding, with the femoral-neck difference that distinguished the second described form.
Genu varum HP:0002970 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu varum (HP:0002970), qualified as temporality transient. HP:0002970 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (2 references)
PMID:28342220 SUPPORT Human Clinical
"Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs."
States both the bowing and its transitory character.
PMID:34407464 SUPPORT Human Clinical
"Clinical and radiological examination revealed scoliosis, genu varum and metaphyseal abnormalities."
Documents genu varum in the molecularly confirmed MMP9 case.
Musculoskeletal 1
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650), qualified as temporality transient. HP:0002650 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:34407464 SUPPORT Human Clinical
"By the age of 39 months, lower limb alignment and metaphyseal features had already significantly improved and scoliosis had disappeared."
Records both the scoliosis and its spontaneous resolution.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322), qualified as severity mild. HP:0004322 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:1867263 SUPPORT Human Clinical
"The main manifestations are slight shortness and a light varus deformity of the lower limbs. Stature is not affected."
Source for both the mild shortness and the preserved final stature.
Other 2
Rickets-like metaphyseal changes with normal blood chemistry
Show evidence (2 references)
PMID:30439533 SUPPORT Human Clinical
"Here we reported the identification of a previously unreported pathogenic heterozygous de novo variant NM_002427.3:c.212T > C/p.Met71Thr in MMP13 in a Chinese male pediatric patient with metaphyseal anadysplasia 1 and additional phenotypes, including mild rickets-like changes observed on upper..."
Documents rickets-like metaphyseal change, and its resolution, in a molecularly confirmed type 1 patient.
PMID:9799299 SUPPORT Human Clinical
"The stature is not affected and there are no metabolic abnormalities."
Establishes the normal biochemistry that separates this from true rickets.
Enlargement of costochondral junctions Enlargement of the costochondral junction HP:0000920 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlargement of the costochondral junction (HP:0000920). HP:0000920 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9799299 SUPPORT Human Clinical
"During the first months of life the children present with enlargement of costochondral junctions and knobby wrists."
Describes the presenting physical findings recorded in this phenotype.
🧬

Genetic Associations

2
MMP13 (Causal monoallelic 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 (1 reference)
PMID:19615667 SUPPORT Human Clinical
"We report that mutations in either MMP9 or MMP13 are responsible for the human disease metaphyseal anadysplasia (MAD), a heterogeneous group of disorders for which a milder recessive variant and a more severe dominant variant are known."
Establishes MMP13 as one of the two causal genes.
MMP9 (Causal biallelic variant)
Gene: MMP9 hgnc:7176 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MMP9 (hgnc:7176). hgnc:7176 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:19615667 SUPPORT Human Clinical
"We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13"
Establishes homozygous MMP9 loss of function as causal.
PMID:28342220 SUPPORT Human Clinical
"the finding of homozygous mutation in non-consanguineous parents of Jewish-Caucasus ancestry may suggest unawareness of such relation or the occurrence of a founder mutation in this gene"
Source for the possible founder allele noted here.
💊

Medical Actions

2
Observation without intervention
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
No disease-modifying treatment exists and none is needed. Because the metaphyseal changes, bowing and even scoliosis resolve spontaneously, recognising the diagnosis is chiefly a way of avoiding unnecessary vitamin D or phosphate treatment for presumed rickets and unnecessary corrective osteotomy for the bowing.
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:34407464 SUPPORT Human Clinical
"By the age of 39 months, lower limb alignment and metaphyseal features had already significantly improved and scoliosis had disappeared."
Demonstrates spontaneous resolution without intervention, which is what makes observation the appropriate management.
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
Recurrence risk depends entirely on which gene is involved, and the two genes carry opposite modes of inheritance. Molecular diagnosis is therefore required before counselling.
Show evidence (1 reference)
PMID:19615667 SUPPORT Human Clinical
"We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13, whereas dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double..."
Establishes that the mode of inheritance, and so the recurrence risk, follows from the gene and variant class.
🔬

Diagnosis

2
Skeletal radiography with normal bone biochemistry
Radiographs show metaphyseal irregularity and bowing; calcium, phosphate and alkaline phosphatase are normal. Together these separate the disorder from nutritional and hypophosphataemic rickets, which is the differential it is most often confused with.
X-ray imaging NCIT:C38101 NCI Thesaurus (NCIT)
Results: Metaphyseal irregularity with normal calcium, phosphate and alkaline phosphatase.
Show evidence (1 reference)
PMID:9799299 SUPPORT Human Clinical
"The stature is not affected and there are no metabolic abnormalities."
Establishes the normal biochemistry that anchors this diagnostic step.
MMP13 and MMP9 sequencing
Molecular testing assigns the subtype and the mode of inheritance. Exome sequencing has been the route to diagnosis in most reported cases, including prenatally.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A heterozygous MMP13 prodomain missense variant (type 1) or biallelic MMP9 loss-of-function variants (type 2).
Show evidence (2 references)
PMID:34407464 SUPPORT Human Clinical
"A homozygous MMP9 nonsense variant, NM_004994.2:c.1764G>A; p.(Trp588*) was identified."
Example of molecular confirmation establishing the subtype.
PMID:28342220 SUPPORT Human Clinical
"Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP."
Documents exome sequencing as the diagnostic route, here applied prenatally.
📈

Progression

2
Infantile onset
Age: First months to third year of life
Metaphyseal changes and limb bowing appear within the first months to the third year of life. Long-bone shortening may be visible on prenatal ultrasound in the MMP9-related form before any postnatal metaphyseal change is seen.
Show evidence (1 reference)
PMID:28342220 SUPPORT Human Clinical
"Here, we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes."
Documents the prenatal detectability and the dissociation from postnatal radiographic change.
Spontaneous regression
Age: Early childhood to adolescence
Radiographic and clinical findings regress without treatment. Reported timing ranges from before age two in the founding series to adolescence, and the type II regressive form resolved by about age ten.
Show evidence (2 references)
PMID:34407464 SUPPORT Human Clinical
"Metaphyseal anadysplasia is a very rare hereditary skeletal dysplasia with onset occurring normally during the second and third years of life, but unlike many other dysplasias, symptoms appear to resolve by adolescence."
States the onset window and the resolution that defines this phase.
PMID:9799299 SUPPORT Human Clinical
"The radiographic findings regress during growth and the abnormalities disappear after the age of ten years."
The longer regression timescale reported for the type II regressive form.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
No population estimate exists. Type 2 in particular is defined by a handful of families; the case report used here was the third reported worldwide.
Show evidence (1 reference)
PMID:34407464 SUPPORT Human Clinical
"To date, only two metaphyseal anadysplasia type 2 families have been reported."
Establishes that reported cases, not a population rate, are all that is available.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Metaphyseal anadysplasia:

Rickets
Overlapping Features Nutritional and hypophosphataemic rickets produce very similar metaphyseal changes and bowing. The discriminator is biochemical, not radiographic.
Distinguishing Features
  • Calcium, phosphate and alkaline phosphatase are normal in anadysplasia
  • Radiographic changes regress spontaneously without vitamin D or phosphate
Show evidence (1 reference)
PMID:9799299 SUPPORT Human Clinical
"The stature is not affected and there are no metabolic abnormalities."
Normal biochemistry is what excludes rickets.
Metaphyseal dysplasia, Spahr type MONDO:0009597
Overlapping Features The recessive MMP13 entity. It shares the rickets-mimicking metaphyseal changes and normal blood chemistry but is not regressive: short stature persists into adult life and adults report knee pain.
Distinguishing Features
  • Biallelic rather than monoallelic MMP13 variants
  • Moderate short stature persists into adult life rather than regressing
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."
Establishes the persistent adult phenotype that distinguishes Spahr type from the regressive course here.
Metaphyseal chondrodysplasia, Schmid type MONDO:0007983
Overlapping Features The commonest metaphyseal dysplasia and the main dominant alternative. Unlike anadysplasia it does not regress, and it produces persistent coxa vara, waddling gait and short stature.
Distinguishing Features
  • COL10A1 rather than MMP13 or MMP9
  • Persistent coxa vara and short stature rather than spontaneous regression
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 the dominant condition this family of disorders must be distinguished from.
{ }

Source YAML

click to show 
name: Metaphyseal anadysplasia
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Metaphyseal anadysplasia is a very rare metaphyseal dysplasia that is defined
  as much by its trajectory as by its radiology: severe metaphyseal
  irregularity, bowing of the legs and mild short stature appear in the first
  months or years of life and then regress spontaneously, so that radiographs
  normalise during childhood and adult stature is essentially unaffected. The
  "ana-" in the name records that regression. It is caused by deficiency of the
  two matrix metalloproteinases that remodel the metaphyseal extracellular
  matrix: type 1 arises from dominant MMP13 prodomain missense variants that
  autoactivate the enzyme and trigger intracellular degradation of both MMP13
  and MMP9, producing a double enzymatic deficiency, while type 2 arises from
  biallelic MMP9 loss of function. Because the metaphyseal changes mimic
  rickets but blood chemistry is normal, the disorder is repeatedly misdiagnosed
  as nutritional or hypophosphataemic rickets.
disease_term:
  preferred_term: metaphyseal anadysplasia
  term:
    id: MONDO:0015177
    label: metaphyseal anadysplasia
parents:
- hereditary disease
synonyms:
- MAD
- MANDP
- regressive metaphyseal dysplasia
- Maroteaux-Verloes-Stanescu syndrome
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". This entry covers the two anadysplasia rows of that group:
      NOS 11-0100 "Metaphyseal anadysplasia, MMP13-related" (MIM 602111,
      autosomal dominant) and NOS 11-0110 "Metaphyseal anadysplasia,
      MMP9-related" (MIM 613073, autosomal recessive). The third MMP13 row of
      the group, NOS 11-0090 "Metaphyseal dysplasia Spahr, MMP13-related"
      (MIM 250400), is the recessive MMP13 entity and is curated separately as
      Metaphyseal dysplasia, Spahr type.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Type 1 is dominant. The causal MMP13 changes are prodomain missense variants
    that act by autoactivating the enzyme rather than by simple haploinsufficiency.
  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: HUMAN_CLINICAL
    snippet: >-
      We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13, whereas dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency.
    explanation: >-
      Establishes the dominant mode and the specific prodomain-missense
      mechanism behind it.
  - reference: PMID:30439533
    reference_title: >-
      A de novo variant in MMP13 identified in a patient with dominant metaphyseal anadysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal anadysplasia 1 (MIM# 602111) belongs to a heterogeneous group of skeletal diseases characterized by an autosomal dominant form of growth defects due to metaphyseal changes with epiphyseal involvement similar to other metaphyseal disorders.
    explanation: >-
      Confirms the dominant mode for type 1 and notes the epiphyseal involvement
      that can accompany it.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Type 2 is recessive, caused by biallelic MMP9 loss-of-function variants.
  evidence:
  - reference: PMID:28342220
    reference_title: >-
      Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs.
    explanation: >-
      States the recessive mode and the transitory character of the MMP9-related
      form.
has_subtypes:
- name: Type 1
  display_name: Metaphyseal anadysplasia type 1 (MMP13-related)
  description: >-
    The dominant, more severe form. Prodomain missense variants cause MMP13 to
    autoactivate intracellularly, and the activated enzyme degrades both itself
    and MMP9 before secretion, so a single mutant allele produces a combined
    MMP13 and MMP9 deficiency. Epiphyseal changes and rickets-like metaphyseal
    findings may accompany the metaphyseal disease.
  genes:
  - preferred_term: MMP13
    term:
      id: hgnc:7159
      label: MMP13
  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: HUMAN_CLINICAL
    snippet: >-
      dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency
    explanation: >-
      Defines the molecular mechanism specific to this subtype. Graded
      HUMAN_CLINICAL because the quoted sentence is the paper's
      genotype-phenotype result across its patient cohort; the
      double-deficiency clause within it rests on the authors' transfection
      work, which the cached abstract does not report as a separate sentence.
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two types exist, the more severe form, type 1, with both autosomal dominant and recessive inheritance due to pathogenic variants in MMP13, whilst type 2, an even rarer form is due to biallelic MMP9 variants.
    explanation: >-
      Places type 1 as the more severe, MMP13-related form of the two.
- name: Type 2
  display_name: Metaphyseal anadysplasia type 2 (MMP9-related)
  subtype_term:
    preferred_term: metaphyseal anadysplasia 2
    term:
      id: MONDO:0013113
      label: metaphyseal anadysplasia 2
  description: >-
    The recessive, even rarer form, caused by biallelic MMP9 loss of function.
    Fewer than a handful of families have been reported. Long-bone shortening may
    be detectable on prenatal ultrasound before any metaphyseal change is
    visible postnatally.
  genes:
  - preferred_term: MMP9
    term:
      id: hgnc:7176
      label: MMP9
  evidence:
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case confirms that biallelic MMP9 variants cause this very rare skeletal dysplasia, metaphyseal anadysplasia type 2 but also shows that the skeletal manifestations can improve within a short period time and at an early age.
    explanation: >-
      Confirms causality for the MMP9 subtype and its early regression.
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only two metaphyseal anadysplasia type 2 families have been reported.
    explanation: >-
      Documents how few families define this subtype.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    No population estimate exists. Type 2 in particular is defined by a handful
    of families; the case report used here was the third reported worldwide.
  evidence:
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only two metaphyseal anadysplasia type 2 families have been reported.
    explanation: >-
      Establishes that reported cases, not a population rate, are all that is
      available.
pathophysiology:
- name: Dominant MMP13 Prodomain Autoactivation
  biological_scale: MOLECULAR
  description: >-
    Missense variants in the MMP13 prodomain destabilise the cysteine switch
    that holds the zymogen inactive, so the enzyme autoactivates before
    secretion. The prematurely active protease degrades itself and, because
    MMP9 traffics with it, degrades MMP9 as well. A single mutant allele
    therefore removes both enzymes rather than half of one, which is why the
    dominant form is more severe than the recessive single-gene forms.
  genes:
  - preferred_term: MMP13
    term:
      id: hgnc:7159
      label: MMP13
  molecular_functions:
  - preferred_term: metalloendopeptidase activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
  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: HUMAN_CLINICAL
    snippet: >-
      dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency
    explanation: >-
      Establishes premature intracellular autoactivation as the proximal
      molecular lesion. The claim is carried by the authors' transfection
      experiments, but the quoted sentence is the cohort genotype-phenotype
      result that reports them, and the cached record is abstract-only, so the
      item is graded by what the sentence reports rather than by the assay
      behind one of its clauses.
  downstream:
  - target: Combined MMP13 and MMP9 Deficiency at the Metaphyseal Front
    description: >-
      Autoactivation consumes both proteases intracellularly, so neither reaches
      the metaphyseal matrix.
    causal_link_type: DIRECT
    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: HUMAN_CLINICAL
      snippet: >-
        intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency
      explanation: >-
        States the double deficiency that this edge asserts. The mechanism was
        shown by transfection; the sentence quoted here is the paper's
        genotype-phenotype conclusion, which is what fixes its grading.
- name: Biallelic MMP9 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous MMP9 null variants remove gelatinase B
    from the metaphysis. Because MMP13 remains intact, the resulting matrix
    defect is milder than in the dominant form.
  genes:
  - preferred_term: MMP9
    term:
      id: hgnc:7176
      label: MMP9
  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: HUMAN_CLINICAL
    snippet: >-
      We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13
    explanation: >-
      Establishes homozygous MMP9 loss of function as a cause of the recessive
      form.
  downstream:
  - target: Combined MMP13 and MMP9 Deficiency at the Metaphyseal Front
    description: >-
      Loss of MMP9 alone produces the same class of proteolytic deficit at the
      metaphyseal front, at lower severity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34407464
      reference_title: >-
        Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This case confirms that biallelic MMP9 variants cause this very rare skeletal dysplasia, metaphyseal anadysplasia type 2 but also shows that the skeletal manifestations can improve within a short period time and at an early age.
      explanation: >-
        Confirms that MMP9 loss alone produces the anadysplasia phenotype.
- name: Combined MMP13 and MMP9 Deficiency at the Metaphyseal Front
  biological_scale: MOLECULAR
  description: >-
    The converging molecular state of both subtypes: insufficient collagenase
    and gelatinase activity at the chondro-osseous junction. These two enzymes
    do double duty there, degrading extracellular matrix components and
    liberating matrix-sequestered signalling molecules such as VEGFA that
    couple cartilage resorption to vascular invasion.
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    modifier: DECREASED
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
  - preferred_term: collagen catabolic process
    modifier: DECREASED
    term:
      id: GO:0030574
      label: collagen catabolic process
  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: IN_VITRO
    snippet: >-
      The matrix metalloproteinases MMP9 and MMP13 catalyze the degradation of extracellular matrix (ECM) components in the growth plate and at the same time cleave and release biologically active molecules stored in the ECM, such as VEGFA.
    explanation: >-
      Establishes the dual proteolytic and signal-releasing role that is lost in
      this node.
  downstream:
  - target: Distorted Metaphyseal Growth Plate
    description: >-
      Loss of either or both enzymes distorts the growth plate; mouse ablation of
      Mmp9, Mmp13 or both reproduces this directly.
    causal_link_type: DIRECT
    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 establish the causal link from the enzyme deficiency to
        growth-plate distortion.
- name: Distorted Metaphyseal Growth Plate
  biological_scale: TISSUE
  description: >-
    Histology of the upper tibial growth cartilage in an index case showed wide
    proliferative and hypertrophic zones, abnormal terminal hypertrophic
    chondrocytes, and a disordered zone of cartilage calcification and
    resorption. That last observation is the histological signature of the
    lesion: the failure is in the resorption and remodelling step at the
    chondro-osseous junction, not in chondrocyte proliferation or hypertrophy
    upstream of it.
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:1867263
    reference_title: >-
      Metaphyseal anadysplasia: a metaphyseal dysplasia of early onset with radiological regression and benign course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The upper tibial growth cartilage, studied in one case, showed wide proliferative and hypertrophic zones with an unusual appearance of the last hypertrophic cells and an abnormal zone of cartilage calcification and resorption.
    explanation: >-
      The only human growth-plate histology reported for this disease, and the
      basis for locating the lesion at the calcification and resorption zone.
  downstream:
  - target: Regressive Metaphyseal Irregularity and Limb Bowing
    description: >-
      Disordered metaphyseal remodelling produces the radiographic irregularity
      and the varus bowing of the lower limbs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:1867263
      reference_title: >-
        Metaphyseal anadysplasia: a metaphyseal dysplasia of early onset with radiological regression and benign course.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Distal metaphyses of long bones are very irregular. Femoral necks seem hypoplastic and the edges of the metaphyses are almost vertical; femoral shaft is bowed.
      explanation: >-
        The radiographic description of the metaphyseal lesion and the resulting
        bowing.
- name: Regressive Metaphyseal Irregularity and Limb Bowing
  biological_scale: ORGANISM
  description: >-
    The clinically expressed disease: metaphyseal irregularity, mild varus
    bowing and slight shortness apparent within the first months to years of
    life, which then regress spontaneously. In the original series the
    radiographic anomalies disappeared after age two; in the type 2 series they
    resolved over roughly the same interval, and in the type II regressive
    series described separately they persisted to about age ten. Adult stature
    is essentially unaffected, and the natural history is benign.
  evidence:
  - reference: PMID:1867263
    reference_title: >-
      Metaphyseal anadysplasia: a metaphyseal dysplasia of early onset with radiological regression and benign course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Those anomalies disappear after 2 years.
    explanation: >-
      The regression that gives the disease its name, in the founding series.
  - reference: PMID:1867263
    reference_title: >-
      Metaphyseal anadysplasia: a metaphyseal dysplasia of early onset with radiological regression and benign course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main manifestations are slight shortness and a light varus deformity of the lower limbs. Stature is not affected.
    explanation: >-
      Establishes the mildness of the expressed phenotype and the preserved
      adult stature.
phenotypes:
- name: Metaphyseal irregularity
  category: Skeletal
  diagnostic: true
  description: >-
    Marked irregularity of the long-bone metaphyses, most obvious distally and
    at the knees, appearing in infancy and resolving during childhood.
  phenotype_term:
    preferred_term: Metaphyseal irregularity
    term:
      id: HP:0003025
      label: Metaphyseal irregularity
    temporality: TRANSIENT
  evidence:
  - reference: PMID:1867263
    reference_title: >-
      Metaphyseal anadysplasia: a metaphyseal dysplasia of early onset with radiological regression and benign course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal metaphyses of long bones are very irregular. Femoral necks seem hypoplastic and the edges of the metaphyses are almost vertical; femoral shaft is bowed.
    explanation: >-
      Primary radiographic description of the defining finding.
  - reference: PMID:9799299
    reference_title: >-
      Metaphyseal anadysplasia type II: a new regressive metaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On radiographs the metaphyseal changes of the knees are specific with fine irregularities. The femoral necks are blurred but not hypoplastic.
    explanation: >-
      Documents the same finding, with the femoral-neck difference that
      distinguished the second described form.
- name: Genu varum
  category: Skeletal
  description: >-
    Bowing of the legs, usually the presenting complaint, and transitory.
  phenotype_term:
    preferred_term: Genu varum
    term:
      id: HP:0002970
      label: Genu varum
    temporality: TRANSIENT
  evidence:
  - reference: PMID:28342220
    reference_title: >-
      Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs.
    explanation: >-
      States both the bowing and its transitory character.
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical and radiological examination revealed scoliosis, genu varum and metaphyseal abnormalities.
    explanation: >-
      Documents genu varum in the molecularly confirmed MMP9 case.
- name: Scoliosis
  category: Skeletal
  description: >-
    Reported in the MMP9-related case, and notable because it resolved along
    with the metaphyseal changes rather than progressing.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    temporality: TRANSIENT
  evidence:
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By the age of 39 months, lower limb alignment and metaphyseal features had already significantly improved and scoliosis had disappeared.
    explanation: >-
      Records both the scoliosis and its spontaneous resolution.
- name: Short stature
  category: Growth
  description: >-
    Mild short stature in early childhood. In the founding series adult stature
    was not affected, so this is better described as transient shortness than as
    a growth defect.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
    severity: MILD
  evidence:
  - reference: PMID:1867263
    reference_title: >-
      Metaphyseal anadysplasia: a metaphyseal dysplasia of early onset with radiological regression and benign course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main manifestations are slight shortness and a light varus deformity of the lower limbs. Stature is not affected.
    explanation: >-
      Source for both the mild shortness and the preserved final stature.
- name: Rickets-like metaphyseal changes with normal blood chemistry
  category: Skeletal
  diagnostic: true
  description: >-
    The metaphyseal changes closely mimic rickets, but calcium, phosphate and
    alkaline phosphatase are normal. This combination is the single most useful
    diagnostic discriminator and the commonest source of misdiagnosis.
    Deliberately left unbound: HP:0002748 Rickets is etiologically defined by
    defective growth-plate mineralization, which is precisely what the normal
    biochemistry here rules out, so binding it would assert the claim this
    entry exists to refute. No HPO term captures "radiographically
    rickets-like with normal biochemistry".
  phenotype_term:
    preferred_term: Rickets-like metaphyseal change with normal bone biochemistry
  evidence:
  - reference: PMID:30439533
    reference_title: >-
      A de novo variant in MMP13 identified in a patient with dominant metaphyseal anadysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we reported the identification of a previously unreported pathogenic heterozygous de novo variant NM_002427.3:c.212T > C/p.Met71Thr in MMP13 in a Chinese male pediatric patient with metaphyseal anadysplasia 1 and additional phenotypes, including mild rickets-like changes observed on upper long bone metaphyses and patchy bone defects on the spine vertebrae particularly resolved by childhood.
    explanation: >-
      Documents rickets-like metaphyseal change, and its resolution, in a
      molecularly confirmed type 1 patient.
  - reference: PMID:9799299
    reference_title: >-
      Metaphyseal anadysplasia type II: a new regressive metaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The stature is not affected and there are no metabolic abnormalities.
    explanation: >-
      Establishes the normal biochemistry that separates this from true rickets.
- name: Enlargement of costochondral junctions
  category: Skeletal
  description: >-
    Rachitic-rosary-like enlargement of the costochondral junctions with knobby
    wrists in the first months of life, another feature that drives the
    misdiagnosis as rickets.
  phenotype_term:
    preferred_term: Enlargement of the costochondral junction
    term:
      id: HP:0000920
      label: Enlargement of the costochondral junction
  evidence:
  - reference: PMID:9799299
    reference_title: >-
      Metaphyseal anadysplasia type II: a new regressive metaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the first months of life the children present with enlargement of costochondral junctions and knobby wrists.
    explanation: >-
      Describes the presenting physical findings recorded in this phenotype.
progression:
- phase: Infantile onset
  age_range: First months to third year of life
  notes: >-
    Metaphyseal changes and limb bowing appear within the first months to the
    third year of life. Long-bone shortening may be visible on prenatal
    ultrasound in the MMP9-related form before any postnatal metaphyseal change
    is seen.
  evidence:
  - reference: PMID:28342220
    reference_title: >-
      Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes.
    explanation: >-
      Documents the prenatal detectability and the dissociation from postnatal
      radiographic change.
- phase: Spontaneous regression
  age_range: Early childhood to adolescence
  notes: >-
    Radiographic and clinical findings regress without treatment. Reported
    timing ranges from before age two in the founding series to adolescence, and
    the type II regressive form resolved by about age ten.
  evidence:
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal anadysplasia is a very rare hereditary skeletal dysplasia with onset occurring normally during the second and third years of life, but unlike many other dysplasias, symptoms appear to resolve by adolescence.
    explanation: >-
      States the onset window and the resolution that defines this phase.
  - reference: PMID:9799299
    reference_title: >-
      Metaphyseal anadysplasia type II: a new regressive metaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiographic findings regress during growth and the abnormalities disappear after the age of ten years.
    explanation: >-
      The longer regression timescale reported for the type II regressive form.
biochemical: []
genetic:
- name: MMP13
  association: Causal monoallelic variant
  gene_term:
    preferred_term: MMP13
    term:
      id: hgnc:7159
      label: MMP13
  notes: >-
    Heterozygous prodomain missense variants cause type 1. Biallelic MMP13 loss
    of function causes the recessive MMP13 entity that the 2023 nosology lists
    separately as metaphyseal dysplasia, Spahr type.
  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: HUMAN_CLINICAL
    snippet: >-
      We report that mutations in either MMP9 or MMP13 are responsible for the human disease metaphyseal anadysplasia (MAD), a heterogeneous group of disorders for which a milder recessive variant and a more severe dominant variant are known.
    explanation: >-
      Establishes MMP13 as one of the two causal genes.
- name: MMP9
  association: Causal biallelic variant
  gene_term:
    preferred_term: MMP9
    term:
      id: hgnc:7176
      label: MMP9
  notes: >-
    Biallelic loss of function causes type 2. A reported homozygous nonsense
    variant in non-consanguineous parents of Jewish-Caucasus ancestry raises the
    possibility of a founder allele.
  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: HUMAN_CLINICAL
    snippet: >-
      We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13
    explanation: >-
      Establishes homozygous MMP9 loss of function as causal.
  - reference: PMID:28342220
    reference_title: >-
      Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the finding of homozygous mutation in non-consanguineous parents of Jewish-Caucasus ancestry may suggest unawareness of such relation or the occurrence of a founder mutation in this gene
    explanation: >-
      Source for the possible founder allele noted here.
environmental: []
treatments:
- name: Observation without intervention
  description: >-
    No disease-modifying treatment exists and none is needed. Because the
    metaphyseal changes, bowing and even scoliosis resolve spontaneously,
    recognising the diagnosis is chiefly a way of avoiding unnecessary vitamin D
    or phosphate treatment for presumed rickets and unnecessary corrective
    osteotomy for the bowing.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Genu varum
    term:
      id: HP:0002970
      label: Genu varum
  evidence:
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By the age of 39 months, lower limb alignment and metaphyseal features had already significantly improved and scoliosis had disappeared.
    explanation: >-
      Demonstrates spontaneous resolution without intervention, which is what
      makes observation the appropriate management.
- name: Genetic counselling
  description: >-
    Recurrence risk depends entirely on which gene is involved, and the two
    genes carry opposite modes of inheritance. Molecular diagnosis is therefore
    required before counselling.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  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: HUMAN_CLINICAL
    snippet: >-
      We found that recessive MAD is caused by homozygous loss of function of either MMP9 or MMP13, whereas dominant MAD is associated with missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency.
    explanation: >-
      Establishes that the mode of inheritance, and so the recurrence risk,
      follows from the gene and variant class.
diagnosis:
- name: Skeletal radiography with normal bone biochemistry
  description: >-
    Radiographs show metaphyseal irregularity and bowing; calcium, phosphate and
    alkaline phosphatase are normal. Together these separate the disorder from
    nutritional and hypophosphataemic rickets, which is the differential it is
    most often confused with.
  results: >-
    Metaphyseal irregularity with normal calcium, phosphate and alkaline
    phosphatase.
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:9799299
    reference_title: >-
      Metaphyseal anadysplasia type II: a new regressive metaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The stature is not affected and there are no metabolic abnormalities.
    explanation: >-
      Establishes the normal biochemistry that anchors this diagnostic step.
- name: MMP13 and MMP9 sequencing
  description: >-
    Molecular testing assigns the subtype and the mode of inheritance. Exome
    sequencing has been the route to diagnosis in most reported cases, including
    prenatally.
  results: >-
    A heterozygous MMP13 prodomain missense variant (type 1) or biallelic MMP9
    loss-of-function variants (type 2).
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous MMP9 nonsense variant, NM_004994.2:c.1764G>A; p.(Trp588*) was identified.
    explanation: >-
      Example of molecular confirmation establishing the subtype.
  - reference: PMID:28342220
    reference_title: >-
      Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP.
    explanation: >-
      Documents exome sequencing as the diagnostic route, here applied
      prenatally.
differential_diagnoses:
- name: Rickets
  description: >-
    Nutritional and hypophosphataemic rickets produce very similar metaphyseal
    changes and bowing. The discriminator is biochemical, not radiographic.
  distinguishing_features:
  - Calcium, phosphate and alkaline phosphatase are normal in anadysplasia
  - Radiographic changes regress spontaneously without vitamin D or phosphate
  evidence:
  - reference: PMID:9799299
    reference_title: >-
      Metaphyseal anadysplasia type II: a new regressive metaphyseal dysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The stature is not affected and there are no metabolic abnormalities.
    explanation: >-
      Normal biochemistry is what excludes rickets.
- name: Metaphyseal dysplasia, Spahr type
  description: >-
    The recessive MMP13 entity. It shares the rickets-mimicking metaphyseal
    changes and normal blood chemistry but is not regressive: short stature
    persists into adult life and adults report knee pain.
  disease_term:
    preferred_term: metaphyseal chondrodysplasia, Spahr type
    term:
      id: MONDO:0009597
      label: metaphyseal chondrodysplasia, Spahr type
  distinguishing_features:
  - Biallelic rather than monoallelic MMP13 variants
  - Moderate short stature persists into adult life rather than regressing
  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: >-
      Establishes the persistent adult phenotype that distinguishes Spahr type
      from the regressive course here.
- name: Metaphyseal chondrodysplasia, Schmid type
  description: >-
    The commonest metaphyseal dysplasia and the main dominant alternative.
    Unlike anadysplasia it does not regress, and it produces persistent coxa
    vara, waddling gait and short stature.
  disease_term:
    preferred_term: Schmid metaphyseal chondrodysplasia
    term:
      id: MONDO:0007983
      label: Schmid metaphyseal chondrodysplasia
  distinguishing_features:
  - COL10A1 rather than MMP13 or MMP9
  - Persistent coxa vara and short stature rather than spontaneous regression
  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 the dominant condition this family of disorders must
      be distinguished from.
discussions:
- discussion_id: gap_mad_mechanism_of_regression
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does a constitutive, lifelong deficiency of MMP9 and MMP13 produce a
    growth-plate lesion that resolves during childhood while the genetic defect
    persists unchanged?
  attaches_to:
  - pathophysiology#Distorted Metaphyseal Growth Plate
  - pathophysiology#Regressive Metaphyseal Irregularity and Limb Bowing
  - progression#Spontaneous regression
  rationale: >-
    Spontaneous regression is the defining feature of this disease and the
    reason it was named, yet no mechanism has been offered for it. The germline
    lesion does not change, so regression must reflect either a developmental
    shift in how much metaphyseal remodelling depends on these two proteases, or
    compensation by other matrix metalloproteinases as the growth rate falls.
    Neither has been tested. The question also matters practically: the same
    proteases are drug targets in osteoarthritis, and an endogenous compensatory
    route would be worth identifying.
  evidence:
  - reference: PMID:34407464
    reference_title: >-
      Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal anadysplasia is a very rare hereditary skeletal dysplasia with onset occurring normally during the second and third years of life, but unlike many other dysplasias, symptoms appear to resolve by adolescence.
    explanation: >-
      States the regression that this gap asks about, and marks it as unusual
      among skeletal dysplasias.
clinical_trials: []
datasets: []
notes: >-
  Curated to complete ISDS Nosology group 11 (Metaphyseal dysplasias). The entry
  is keyed on MONDO:0015177, which MONDO treats as the anadysplasia parent
  class; MONDO has a distinct class only for type 2 (MMP9), so type 1 carries no
  subtype_term. Note a nosological disagreement in the literature that this
  entry follows the ISDS on: PMID:34407464 describes type 1 as having both
  dominant and recessive MMP13 inheritance, whereas PMID:24648384 argues the
  recessive MMP13 cases are the same entity as metaphyseal dysplasia, Spahr
  type. The 2023 nosology lists them as separate rows (11-0090 and 11-0100), and
  they are curated as separate entries here.
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.