Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly

Mendelian MONDO:0007984 Pathograph 9 Show in embeddings browser hereditary disease

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an ultra-rare autosomal dominant bone dysplasia combining metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, dystrophic teeth, variable brachydactyly and mild osteoporosis. It was described in a French Canadian family in 1982 and stayed a clinical entity until 2013, when the cause was found to be an intragenic tandem duplication of RUNX2 spanning the exons that encode the Q/A domain and the DNA-binding runt domain. That finding is what makes the disorder mechanistically interesting: every other RUNX2 disease allele known at the time was loss of function causing cleidocranial dysplasia, whereas the MDMHB duplication raises cellular RUNX2 protein levels and behaves as a gain of function. Dental problems are often the presenting complaint, and because the radiographic picture overlaps Pyle disease the disorder is a standing argument that RUNX2 and sFRP4 signalling intersect in metaphyseal modelling.

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

Classifications

ISDS Skeletal Nosology
metaphyseal dysplasias
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Dominant, with the duplication segregating through multi-generation pedigrees; at least one reported case arose de novo.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:23290074 SUPPORT Human Clinical
"Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth."
States the dominant mode alongside the defining clinical features.
PMID:38108099 SUPPORT Human Clinical
"Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7."
Documents a de novo occurrence, showing the disease is not confined to inherited pedigrees.
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Discussions and Knowledge Gaps

1
By what route does an intragenic RUNX2 duplication raise cellular RUNX2 protein levels, and is the resulting phenotype driven by more RUNX2 activity or by an altered RUNX2 protein?
KNOWLEDGE GAP OPEN gap_mdmhb_gain_of_function_mechanism
Attached to
pathophysiology#Intragenic RUNX2 Tandem Duplication pathophysiology#Elevated Cellular RUNX2 Protein and Gain of Transcription Factor Function
The transfection experiment shows raised levels of the duplication-bearing protein and the authors themselves phrase the conclusion as an apparent gain of function. Two quite different models fit that observation: a stabilised or degradation-resistant protein present at higher steady-state level, or a structurally altered factor with a duplicated runt domain and changed DNA-binding or partner behaviour. The distinction matters because only the first predicts that a whole-gene RUNX2 duplication should produce the same skeletal disease, and the reported whole-gene duplication family has a predominantly oro-dental phenotype rather than the full MDMHB picture. No study has separated the two models.
Show evidence (2 references)
PMID:23290074 SUPPORT In Vitro
"Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function."
The observation the gap is built on, and the hedged wording that leaves the mechanism open.
PMID:29852250 SUPPORT Human Clinical
"We describe here the oro-dental phenotype of four patients of a unique family with a 285 kb duplication including the entire sequence of RUNX2, likely responsible for three functional copies of the gene, leading to an increased RUNX2 dosage."
The whole-gene duplication comparator referred to in the rationale; it raises RUNX2 dosage without the intragenic rearrangement, so its phenotype bears on which model is right.
⚙

Pathophysiology

6
Intragenic RUNX2 Tandem Duplication
A heterozygous tandem duplication inside RUNX2, spanning exons 3 to 5, 3 to 6, or 3 to 7 in the reported families. The duplicated interval encodes the Q/A domain and the DNA-binding runt domain, so the mutant transcript carries a second copy of the functionally essential part of the protein. Breakpoints differ between families while the consequence on the transcript is the same, which argues that the duplicated exon content rather than any particular breakpoint is what matters.
RUNX2 hgnc:10472 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RUNX2 (hgnc:10472). hgnc:10472 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context RUNX2 hgnc:10472 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns RUNX2 (hgnc:10472). hgnc:10472 is a gene from the HUGO Gene Nomenclature Committee. allele_type: DUPLICATION variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
A heterozygous intragenic tandem duplication of RUNX2 exons 3-5, 3-6 or 3-7, spanning the Q/A and DNA-binding runt domains. Transfection of the duplication-bearing construct yields markedly higher cellular RUNX2 than wild type, which the discovery paper reads as a gain of function - the first such RUNX2 allele, against the loss-of-function variants that cause cleidocranial dysplasia.
Downstream
Elevated Cellular RUNX2 Protein and Gain of Transcription Factor Function The duplication-bearing transcript yields markedly higher cellular protein levels than wild-type RUNX2 in transfection assays.
Show evidence (3 references)
PMID:23290074 SUPPORT Human Clinical
"confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2"
Identifies the causal structural variant in the founding pedigree.
PMID:23290074 SUPPORT Human Clinical
"These three exons code for the Q/A domain and the functionally essential DNA-binding runt domain of RUNX2."
Establishes which functional domains the duplicated interval encodes.
PMID:25311905 SUPPORT Human Clinical
"The results demonstrated that the intronic breakpoints of the duplication differed from those previously found in the French Canadian family, but that the consequences on RUNX2 transcript were identical."
Supports the claim that the transcript consequence, not the breakpoint, is the shared lesion.
Elevated Cellular RUNX2 Protein and Gain of Transcription Factor Function
RUNX2 is the master transcription factor of osteoblast differentiation and of the chondrocyte hypertrophy that precedes endochondral bone formation. In MDMHB it is present at raised cellular levels and acts as a gain of function. This is the mirror image of cleidocranial dysplasia, where RUNX2 haploinsufficiency causes clavicular hypoplasia and delayed cranial ossification, and it is why the skeletal phenotypes of the two RUNX2 diseases barely overlap: the clavicles are enlarged here and hypoplastic or absent there.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ⚠ ABNORMAL
DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves DNA-binding transcription factor activity (GO:0003700), qualified as gain of function. GO:0003700 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Disordered Metaphyseal Modelling Raised RUNX2 activity in the growth plate and metaphyseal osteoblast compartment disturbs the modelling that normally narrows the metaphysis as the bone lengthens.
Impaired Intramembranous Craniofacial and Dental Development The same transcription factor governs maxillary intramembranous ossification and tooth morphogenesis, which is why the craniofacial and dental features travel with the metaphyseal ones.
Show evidence (1 reference)
PMID:23290074 SUPPORT Other
"Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease."
States explicitly that this is a gain-of-function RUNX2 disease, in contrast with every previously known RUNX2 allele.
Disordered Metaphyseal Modelling
Failure of the normal funnelling of the metaphysis produces flaring of the long-bone metaphyses with thin cortices and an osteoporotic radiographic appearance, together with enlargement of the medial halves of the clavicles. Metaphyseal funnelling is osteoclastic resorption of the periosteal surface as the bone lengthens, which is why the node is bound to bone resorption and the osteoclast alongside the chondrocyte-side endochondral terms - the same resorption step whose failure produces the Erlenmeyer-flask metaphysis of Pyle disease. This radiographic combination is close enough to Pyle disease to have been proposed as evidence that RUNX2 and sFRP4 act on intersecting pathways in metaphyseal modelling.
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. osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 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 bone resorption GO:0045453 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bone resorption (GO:0045453). GO:0045453 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Metaphyseal Flaring with Skeletal Fragility Flared metaphyses with thin cortices translate clinically into an osteoporotic skeleton and genu valgum.
Show evidence (1 reference)
PMID:38108099 SUPPORT Human Clinical
"We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4."
Source for the Pyle-disease resemblance and the proposed pathway intersection described in this node.
Impaired Intramembranous Craniofacial and Dental Development
Maxillary hypoplasia with a beaked nose, short philtrum and thin lips, plus dystrophic yellowish teeth. The dental component is often what brings affected people to medical attention, ahead of any skeletal complaint.
Downstream
Dental Disease as Presenting Complaint The dental anomalies are severe enough to dominate presentation.
Show evidence (1 reference)
PMID:7137223 SUPPORT Human Clinical
"Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth."
The original clinical description of the craniofacial and dental phenotype.
Metaphyseal Flaring with Skeletal Fragility
The expressed skeletal disease: flared metaphyses, enlarged medial clavicles, thin cortices, mild osteoporosis, genu valgum, and disproportionate short stature with variable brachydactyly.
Show evidence (1 reference)
PMID:23290074 SUPPORT Human Clinical
"Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth."
Defines the expressed skeletal phenotype recorded in this node.
Dental Disease as Presenting Complaint
Significant dental problems, usually in childhood or adolescence, are the route by which most affected people enter the diagnostic pathway. Recognising the skeletal dysplasia behind them is the clinical lesson of the disorder.
Show evidence (1 reference)
PMID:29891876 SUPPORT Human Clinical
"highlight the importance of considering an underlying skeletal dysplasia in patients presenting with significant dental problems and other suggestive features, including disproportionate short stature and/or digital anomalies"
States the diagnostic implication that defines 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 with maxillary hypoplasia and brachydactyly Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Head and Neck 1
Abnormal dental morphology HP:0006482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal dental morphology (HP:0006482). HP:0006482 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:7137223 SUPPORT Human Clinical
"Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth."
Original description of the dystrophic dentition.
PMID:29891876 SUPPORT Human Clinical
"Dental problems were the primary presenting feature in all four affected individuals."
Establishes the dental phenotype as the leading clinical problem.
Limbs 3
Flared metaphysis HP:0003015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flared metaphysis (HP:0003015). HP:0003015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23290074 SUPPORT Human Clinical
"Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth."
Names metaphyseal flaring first among the defining features.
Brachydactyly FREQUENT HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:7137223 SUPPORT Human Clinical
"Acral changes include bilateral shortness of metacarpal 5 and/or 2nd middle phalanx of fingers 2 and 5."
Original description of the digital shortening.
PMID:38108099 SUPPORT Human Clinical
"In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly."
Documents an affected patient without brachydactyly, which is why the frequency here is recorded as frequent rather than obligate.
Genu valgum HP:0002857 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu valgum (HP:0002857). HP:0002857 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38108099 SUPPORT Human Clinical
"Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance."
Radiographic report documenting genua valga.
Musculoskeletal 1
Osteoporosis HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939), qualified as severity mild. HP:0000939 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:29891876 SUPPORT Human Clinical
"Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis."
Records mild osteoporosis among the defining features.
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). HP:0003498 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:7137223 SUPPORT Human Clinical
"We report the familial occurrence in a French Canadian family of metaphyseal dysplasia associated to short stature and previously undescribed facial and acral anomalies."
Original report pairing short stature with the metaphyseal dysplasia.
Other 3
Hypoplasia of the maxilla HP:0000327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the maxilla (HP:0000327). HP:0000327 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:7137223 SUPPORT Human Clinical
"Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth."
Original description of maxillary hypoplasia in the founding family.
Abnormal clavicle morphology HP:0000889 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal clavicle morphology (HP:0000889). HP:0000889 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23290074 SUPPORT Human Clinical
"Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth."
Records the clavicular enlargement among the defining features.
Thin bony cortex HP:0002753 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin bony cortex (HP:0002753). HP:0002753 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38108099 SUPPORT Human Clinical
"Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance."
Radiographic report documenting thin cortices.
🧬

Genetic Associations

1
RUNX2 (Causal monoallelic intragenic duplication)
Gene: RUNX2 hgnc:10472 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RUNX2 (hgnc:10472). hgnc:10472 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:38108099 SUPPORT Human Clinical
"Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2."
States the causal variant class and the duplicated exon intervals.
PMID:23290074 SUPPORT Human Clinical
"Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage."
Segregation evidence establishing RUNX2 as the causal locus.
💊

Medical Actions

2
Dental and orthodontic management
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
Management is symptomatic and led by dentistry, since the dental anomalies are the dominant clinical burden and the usual presenting problem.
Target Phenotypes: Abnormal dental morphology HP:0006482 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Abnormal dental morphology (HP:0006482). HP:0006482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29891876 SUPPORT Human Clinical
"Dental problems were the primary presenting feature in all four affected individuals."
Establishes the dental burden that this management addresses. No disease-modifying therapy exists.
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
Dominant inheritance with a 50% recurrence risk for offspring, though de novo cases occur. Counselling depends on recognising that the RUNX2 lesion here is a duplication rather than a loss-of-function variant.
Show evidence (1 reference)
PMID:23290074 SUPPORT Human Clinical
"Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth."
Establishes the dominant inheritance on which the recurrence risk rests.
🔬

Diagnosis

2
Skeletal survey
Radiographs show metaphyseal flaring, enlarged medial clavicles, thin cortices and an osteoporotic appearance. The clavicular finding is the most discriminating, because it points away from cleidocranial dysplasia rather than towards it.
X-ray imaging NCIT:C38101 NCI Thesaurus (NCIT)
Results: Metaphyseal flaring with enlarged medial clavicles, thin cortices and osteopenic appearance.
Show evidence (1 reference)
PMID:38108099 SUPPORT Human Clinical
"Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance."
The radiographic pattern on which the diagnosis is raised.
RUNX2 copy-number analysis
Diagnosis requires detecting an intragenic duplication, by copy-number analysis of genomic DNA or by sequencing fibroblast RUNX2 cDNA. A standard sequence-variant report will be normal.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Heterozygous intragenic tandem duplication of RUNX2 exons 3-5, 3-6 or 3-7.
Show evidence (1 reference)
PMID:25311905 SUPPORT Human Clinical
"Copy number variant assays based on quantitative PCR of genomic DNA showed the presence of three copies within a part of RUNX2. Sequencing RUNX2 cDNA from the skin fibroblasts revealed a duplication of exons 3 to 5."
Documents both diagnostic routes used to detect the intragenic duplication.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. As of the 2018 report the literature held one large French Canadian family and a single Finnish woman; a three-generation family and a Belgian de novo case have been added since.
Show evidence (1 reference)
PMID:29891876 SUPPORT Human Clinical
"To date, only one large French Canadian family and a Finnish woman have been reported with the condition."
Direct statement of how few cases define the disease.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly:

Pyle disease Not Yet Curated MONDO:0009943
Overlapping Features The closest radiographic mimic. Pyle disease is recessive and SFRP4-related, with more extreme metaphyseal flaring, but the resemblance is close enough that it has been used to argue for an intersection between the RUNX2 and sFRP4 pathways.
Distinguishing Features
  • Autosomal recessive SFRP4 variants rather than dominant RUNX2 duplication
  • Maxillary hypoplasia and dystrophic teeth are not features
Show evidence (1 reference)
PMID:38108099 SUPPORT Human Clinical
"We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4."
States the resemblance that makes Pyle disease the leading differential.
Cleidocranial dysplasia MONDO:0007340
Overlapping Features The other RUNX2 disease, and the one a clinician is likely to think of on seeing a RUNX2 finding. It is caused by loss of function and its clavicular phenotype is the opposite: hypoplastic or absent clavicles rather than enlarged medial halves.
Distinguishing Features
  • RUNX2 loss of function rather than intragenic duplication
  • Hypoplastic or absent clavicles rather than enlarged medial clavicles
  • Delayed cranial ossification with wide fontanelles
Show evidence (1 reference)
PMID:23290074 SUPPORT Other
"Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease."
States the mechanistic opposition between MDMHB and the RUNX2 loss-of-function disease.
{ }

Source YAML

click to show 
name: Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is
  an ultra-rare autosomal dominant bone dysplasia combining metaphyseal flaring
  of the long bones, enlargement of the medial halves of the clavicles,
  maxillary hypoplasia, dystrophic teeth, variable brachydactyly and mild
  osteoporosis. It was described in a French Canadian family in 1982 and stayed
  a clinical entity until 2013, when the cause was found to be an intragenic
  tandem duplication of RUNX2 spanning the exons that encode the Q/A domain and
  the DNA-binding runt domain. That finding is what makes the disorder
  mechanistically interesting: every other RUNX2 disease allele known at the
  time was loss of function causing cleidocranial dysplasia, whereas the MDMHB
  duplication raises cellular RUNX2 protein levels and behaves as a gain of
  function. Dental problems are often the presenting complaint, and because the
  radiographic picture overlaps Pyle disease the disorder is a standing argument
  that RUNX2 and sFRP4 signalling intersect in metaphyseal modelling.
disease_term:
  preferred_term: metaphyseal dysplasia with maxillary hypoplasia and brachydactyly
  term:
    id: MONDO:0007984
    label: metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome
parents:
- hereditary disease
synonyms:
- MDMHB
- metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly
- RUNX2-related metaphyseal dysplasia with maxillary hypoplasia
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 11-0120 "Metaphyseal dysplasia with maxillary
      hypoplasia, RUNX2-related" (MIM 156510, autosomal dominant). RUNX2's other
      diseases are placed elsewhere in the nosology: cleidocranial dysplasia,
      caused by RUNX2 loss of function, is in the cleidocranial dysplasia and
      isolated cranial ossification defects group, so the two RUNX2 entities sit
      in different groups because they differ in mechanism and in phenotype, not
      in gene.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Dominant, with the duplication segregating through multi-generation
    pedigrees; at least one reported case arose de novo.
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth.
    explanation: >-
      States the dominant mode alongside the defining clinical features.
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7.
    explanation: >-
      Documents a de novo occurrence, showing the disease is not confined to
      inherited pedigrees.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. As of the 2018 report the literature held one large French
    Canadian family and a single Finnish woman; a three-generation family and a
    Belgian de novo case have been added since.
  evidence:
  - reference: PMID:29891876
    reference_title: >-
      A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only one large French Canadian family and a Finnish woman have been reported with the condition.
    explanation: >-
      Direct statement of how few cases define the disease.
pathophysiology:
- name: Intragenic RUNX2 Tandem Duplication
  biological_scale: MOLECULAR
  description: >-
    A heterozygous tandem duplication inside RUNX2, spanning exons 3 to 5, 3 to
    6, or 3 to 7 in the reported families. The duplicated interval encodes the
    Q/A domain and the DNA-binding runt domain, so the mutant transcript carries
    a second copy of the functionally essential part of the protein. Breakpoints
    differ between families while the consequence on the transcript is the same,
    which argues that the duplicated exon content rather than any particular
    breakpoint is what matters.
  genes:
  - preferred_term: RUNX2
    term:
      id: hgnc:10472
      label: RUNX2
  genetic_context:
    gene:
      preferred_term: RUNX2
      term:
        id: hgnc:10472
        label: RUNX2
    allele_type: DUPLICATION
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      A heterozygous intragenic tandem duplication of RUNX2 exons 3-5, 3-6 or
      3-7, spanning the Q/A and DNA-binding runt domains. Transfection of the
      duplication-bearing construct yields markedly higher cellular RUNX2 than
      wild type, which the discovery paper reads as a gain of function - the
      first such RUNX2 allele, against the loss-of-function variants that cause
      cleidocranial dysplasia.
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2
    explanation: >-
      Identifies the causal structural variant in the founding pedigree.
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These three exons code for the Q/A domain and the functionally essential DNA-binding runt domain of RUNX2.
    explanation: >-
      Establishes which functional domains the duplicated interval encodes.
  - reference: PMID:25311905
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly in a Finnish woman: first confirmation of a duplication in RUNX2 as pathogenic variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results demonstrated that the intronic breakpoints of the duplication differed from those previously found in the French Canadian family, but that the consequences on RUNX2 transcript were identical.
    explanation: >-
      Supports the claim that the transcript consequence, not the breakpoint, is
      the shared lesion.
  downstream:
  - target: Elevated Cellular RUNX2 Protein and Gain of Transcription Factor Function
    description: >-
      The duplication-bearing transcript yields markedly higher cellular protein
      levels than wild-type RUNX2 in transfection assays.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23290074
      reference_title: >-
        Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function.
      explanation: >-
        The functional experiment that establishes this edge.
- name: Elevated Cellular RUNX2 Protein and Gain of Transcription Factor Function
  biological_scale: MOLECULAR
  description: >-
    RUNX2 is the master transcription factor of osteoblast differentiation and
    of the chondrocyte hypertrophy that precedes endochondral bone formation.
    In MDMHB it is present at raised cellular levels and acts as a gain of
    function. This is the mirror image of cleidocranial dysplasia, where RUNX2
    haploinsufficiency causes clavicular hypoplasia and delayed cranial
    ossification, and it is why the skeletal phenotypes of the two RUNX2
    diseases barely overlap: the clavicles are enlarged here and hypoplastic
    or absent there.
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  biological_processes:
  - preferred_term: osteoblast differentiation
    modifier: ABNORMAL
    term:
      id: GO:0001649
      label: osteoblast differentiation
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease.
    explanation: >-
      States explicitly that this is a gain-of-function RUNX2 disease, in
      contrast with every previously known RUNX2 allele.
  downstream:
  - target: Disordered Metaphyseal Modelling
    description: >-
      Raised RUNX2 activity in the growth plate and metaphyseal osteoblast
      compartment disturbs the modelling that normally narrows the metaphysis
      as the bone lengthens.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38108099
      reference_title: >-
        RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance.
      explanation: >-
        Documents the metaphyseal flaring with thin cortices that this node
        produces.
  - target: Impaired Intramembranous Craniofacial and Dental Development
    description: >-
      The same transcription factor governs maxillary intramembranous
      ossification and tooth morphogenesis, which is why the craniofacial and
      dental features travel with the metaphyseal ones.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29852250
      reference_title: Oro-dental phenotype in patients with RUNX2 duplication.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Runt-related transcription factor 2 (RUNX2) is well-known for its role in bone development and tooth morphogenesis.
      explanation: >-
        Establishes RUNX2's role in tooth morphogenesis, the basis for linking
        the dental phenotype to the same transcription factor. Note the cohort
        in that paper carries a whole-gene rather than an intragenic RUNX2
        duplication, so it is cited here for the gene's role, not as an MDMHB
        case series.
- name: Disordered Metaphyseal Modelling
  biological_scale: TISSUE
  description: >-
    Failure of the normal funnelling of the metaphysis produces flaring of the
    long-bone metaphyses with thin cortices and an osteoporotic radiographic
    appearance, together with enlargement of the medial halves of the clavicles.
    Metaphyseal funnelling is osteoclastic resorption of the periosteal surface
    as the bone lengthens, which is why the node is bound to bone resorption and
    the osteoclast alongside the chondrocyte-side endochondral terms - the same
    resorption step whose failure produces the Erlenmeyer-flask metaphysis of
    Pyle disease.
    This radiographic combination is close enough to Pyle disease to have been
    proposed as evidence that RUNX2 and sFRP4 act on intersecting pathways in
    metaphyseal modelling.
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  - preferred_term: bone resorption
    modifier: DECREASED
    term:
      id: GO:0045453
      label: bone resorption
  evidence:
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4.
    explanation: >-
      Source for the Pyle-disease resemblance and the proposed pathway
      intersection described in this node.
  downstream:
  - target: Metaphyseal Flaring with Skeletal Fragility
    description: >-
      Flared metaphyses with thin cortices translate clinically into an
      osteoporotic skeleton and genu valgum.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29891876
      reference_title: >-
        A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis.
      explanation: >-
        Lists mild osteoporosis alongside the metaphyseal flaring, which is the
        link this edge asserts.
- name: Impaired Intramembranous Craniofacial and Dental Development
  biological_scale: TISSUE
  description: >-
    Maxillary hypoplasia with a beaked nose, short philtrum and thin lips, plus
    dystrophic yellowish teeth. The dental component is often what brings
    affected people to medical attention, ahead of any skeletal complaint.
  evidence:
  - reference: PMID:7137223
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth.
    explanation: >-
      The original clinical description of the craniofacial and dental
      phenotype.
  downstream:
  - target: Dental Disease as Presenting Complaint
    description: >-
      The dental anomalies are severe enough to dominate presentation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29891876
      reference_title: >-
        A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dental problems were the primary presenting feature in all four affected individuals.
      explanation: >-
        Direct evidence that the dental phenotype leads the presentation.
- name: Metaphyseal Flaring with Skeletal Fragility
  biological_scale: ORGANISM
  description: >-
    The expressed skeletal disease: flared metaphyses, enlarged medial clavicles,
    thin cortices, mild osteoporosis, genu valgum, and disproportionate short
    stature with variable brachydactyly.
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth.
    explanation: >-
      Defines the expressed skeletal phenotype recorded in this node.
- name: Dental Disease as Presenting Complaint
  biological_scale: ORGANISM
  description: >-
    Significant dental problems, usually in childhood or adolescence, are the
    route by which most affected people enter the diagnostic pathway. Recognising
    the skeletal dysplasia behind them is the clinical lesson of the disorder.
  evidence:
  - reference: PMID:29891876
    reference_title: >-
      A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      highlight the importance of considering an underlying skeletal dysplasia in patients presenting with significant dental problems and other suggestive features, including disproportionate short stature and/or digital anomalies
    explanation: >-
      States the diagnostic implication that defines this node.
phenotypes:
- name: Flared metaphysis
  category: Skeletal
  diagnostic: true
  description: >-
    Metaphyseal flaring of the long bones, the cardinal radiographic finding.
  phenotype_term:
    preferred_term: Flared metaphysis
    term:
      id: HP:0003015
      label: Flared metaphysis
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth.
    explanation: >-
      Names metaphyseal flaring first among the defining features.
- name: Hypoplasia of the maxilla
  category: Craniofacial
  diagnostic: true
  description: >-
    Maxillary hypoplasia with a characteristic facial appearance of beaked nose,
    short philtrum and thin lips.
  phenotype_term:
    preferred_term: Hypoplasia of the maxilla
    term:
      id: HP:0000327
      label: Hypoplasia of the maxilla
  evidence:
  - reference: PMID:7137223
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth.
    explanation: >-
      Original description of maxillary hypoplasia in the founding family.
- name: Abnormal clavicle morphology
  category: Skeletal
  diagnostic: true
  description: >-
    Enlargement of the medial halves of the clavicles. This is the sharpest
    contrast with cleidocranial dysplasia, the RUNX2 loss-of-function disease,
    in which the clavicles are hypoplastic or absent.
  phenotype_term:
    preferred_term: Abnormal clavicle morphology
    term:
      id: HP:0000889
      label: Abnormal clavicle morphology
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth.
    explanation: >-
      Records the clavicular enlargement among the defining features.
- name: Brachydactyly
  category: Skeletal
  frequency: FREQUENT
  description: >-
    Variable, and explicitly absent in at least one molecularly confirmed
    patient, which is why the disorder is now often written as metaphyseal
    dysplasia with maxillary hypoplasia with or without brachydactyly. The
    original family showed shortening of the fifth metacarpal and of the middle
    phalanges of the second and fifth fingers.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:7137223
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acral changes include bilateral shortness of metacarpal 5 and/or 2nd middle phalanx of fingers 2 and 5.
    explanation: >-
      Original description of the digital shortening.
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly.
    explanation: >-
      Documents an affected patient without brachydactyly, which is why the
      frequency here is recorded as frequent rather than obligate.
- name: Abnormal dental morphology
  category: Dental
  diagnostic: true
  description: >-
    Dystrophic yellowish teeth with a range of anomalies of number, morphology
    and position. Dental problems are the usual presenting complaint.
  phenotype_term:
    preferred_term: Abnormal dental morphology
    term:
      id: HP:0006482
      label: Abnormal dental morphology
  evidence:
  - reference: PMID:7137223
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth.
    explanation: >-
      Original description of the dystrophic dentition.
  - reference: PMID:29891876
    reference_title: >-
      A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental problems were the primary presenting feature in all four affected individuals.
    explanation: >-
      Establishes the dental phenotype as the leading clinical problem.
- name: Osteoporosis
  category: Skeletal
  description: >-
    Mild osteoporosis with thin cortices, giving the skeleton an osteoporotic
    radiographic appearance.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
    severity: MILD
  evidence:
  - reference: PMID:29891876
    reference_title: >-
      A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant skeletal dysplasia characterised by metaphyseal flaring of the long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, brachydactyly, dental anomalies and mild osteoporosis.
    explanation: >-
      Records mild osteoporosis among the defining features.
- name: Thin bony cortex
  category: Skeletal
  description: >-
    Thin cortices accompany the metaphyseal flaring, the same combination seen
    in Pyle disease.
  phenotype_term:
    preferred_term: Thin bony cortex
    term:
      id: HP:0002753
      label: Thin bony cortex
  evidence:
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance.
    explanation: >-
      Radiographic report documenting thin cortices.
- name: Genu valgum
  category: Skeletal
  description: >-
    Knock-knee deformity, reported alongside the metaphyseal flaring.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance.
    explanation: >-
      Radiographic report documenting genua valga.
- name: Disproportionate short stature
  category: Growth
  description: >-
    Short stature was part of the original clinical description and remains a
    feature that should prompt consideration of the diagnosis in someone
    presenting with dental disease.
  phenotype_term:
    preferred_term: Disproportionate short stature
    term:
      id: HP:0003498
      label: Disproportionate short stature
  evidence:
  - reference: PMID:7137223
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the familial occurrence in a French Canadian family of metaphyseal dysplasia associated to short stature and previously undescribed facial and acral anomalies.
    explanation: >-
      Original report pairing short stature with the metaphyseal dysplasia.
biochemical: []
genetic:
- name: RUNX2
  association: Causal monoallelic intragenic duplication
  gene_term:
    preferred_term: RUNX2
    term:
      id: hgnc:10472
      label: RUNX2
  notes: >-
    Heterozygous intragenic tandem duplication spanning RUNX2 exons 3-5, 3-6 or
    3-7. Because this is a copy-number change inside a gene, exome or targeted
    sequencing must be analysed for intragenic CNVs; plain variant calling will
    miss it. The same gene causes cleidocranial dysplasia by loss of function,
    so the direction of the RUNX2 lesion, not merely its presence, determines
    which disease results.
  evidence:
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2.
    explanation: >-
      States the causal variant class and the duplicated exon intervals.
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage.
    explanation: >-
      Segregation evidence establishing RUNX2 as the causal locus.
environmental: []
treatments:
- name: Dental and orthodontic management
  description: >-
    Management is symptomatic and led by dentistry, since the dental anomalies
    are the dominant clinical burden and the usual presenting problem.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Abnormal dental morphology
    term:
      id: HP:0006482
      label: Abnormal dental morphology
  evidence:
  - reference: PMID:29891876
    reference_title: >-
      A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental problems were the primary presenting feature in all four affected individuals.
    explanation: >-
      Establishes the dental burden that this management addresses. No
      disease-modifying therapy exists.
- name: Genetic counselling
  description: >-
    Dominant inheritance with a 50% recurrence risk for offspring, though de
    novo cases occur. Counselling depends on recognising that the RUNX2 lesion
    here is a duplication rather than a loss-of-function variant.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth.
    explanation: >-
      Establishes the dominant inheritance on which the recurrence risk rests.
diagnosis:
- name: Skeletal survey
  description: >-
    Radiographs show metaphyseal flaring, enlarged medial clavicles, thin
    cortices and an osteoporotic appearance. The clavicular finding is the most
    discriminating, because it points away from cleidocranial dysplasia rather
    than towards it.
  results: >-
    Metaphyseal flaring with enlarged medial clavicles, thin cortices and
    osteopenic appearance.
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance.
    explanation: >-
      The radiographic pattern on which the diagnosis is raised.
- name: RUNX2 copy-number analysis
  description: >-
    Diagnosis requires detecting an intragenic duplication, by copy-number
    analysis of genomic DNA or by sequencing fibroblast RUNX2 cDNA. A standard
    sequence-variant report will be normal.
  results: >-
    Heterozygous intragenic tandem duplication of RUNX2 exons 3-5, 3-6 or 3-7.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:25311905
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly in a Finnish woman: first confirmation of a duplication in RUNX2 as pathogenic variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Copy number variant assays based on quantitative PCR of genomic DNA showed the presence of three copies within a part of RUNX2. Sequencing RUNX2 cDNA from the skin fibroblasts revealed a duplication of exons 3 to 5.
    explanation: >-
      Documents both diagnostic routes used to detect the intragenic
      duplication.
differential_diagnoses:
- name: Pyle disease
  description: >-
    The closest radiographic mimic. Pyle disease is recessive and SFRP4-related,
    with more extreme metaphyseal flaring, but the resemblance is close enough
    that it has been used to argue for an intersection between the RUNX2 and
    sFRP4 pathways.
  disease_term:
    preferred_term: Pyle disease
    term:
      id: MONDO:0009943
      label: Pyle disease
  distinguishing_features:
  - Autosomal recessive SFRP4 variants rather than dominant RUNX2 duplication
  - Maxillary hypoplasia and dystrophic teeth are not features
  evidence:
  - reference: PMID:38108099
    reference_title: >-
      RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4.
    explanation: >-
      States the resemblance that makes Pyle disease the leading differential.
- name: Cleidocranial dysplasia
  description: >-
    The other RUNX2 disease, and the one a clinician is likely to think of on
    seeing a RUNX2 finding. It is caused by loss of function and its clavicular
    phenotype is the opposite: hypoplastic or absent clavicles rather than
    enlarged medial halves.
  disease_term:
    preferred_term: cleidocranial dysplasia 1
    term:
      id: MONDO:0007340
      label: cleidocranial dysplasia 1
  distinguishing_features:
  - RUNX2 loss of function rather than intragenic duplication
  - Hypoplastic or absent clavicles rather than enlarged medial clavicles
  - Delayed cranial ossification with wide fontanelles
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease.
    explanation: >-
      States the mechanistic opposition between MDMHB and the RUNX2
      loss-of-function disease.
discussions:
- discussion_id: gap_mdmhb_gain_of_function_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what route does an intragenic RUNX2 duplication raise cellular RUNX2
    protein levels, and is the resulting phenotype driven by more RUNX2 activity
    or by an altered RUNX2 protein?
  attaches_to:
  - pathophysiology#Intragenic RUNX2 Tandem Duplication
  - pathophysiology#Elevated Cellular RUNX2 Protein and Gain of Transcription Factor Function
  rationale: >-
    The transfection experiment shows raised levels of the duplication-bearing
    protein and the authors themselves phrase the conclusion as an apparent gain
    of function. Two quite different models fit that observation: a
    stabilised or degradation-resistant protein present at higher steady-state
    level, or a structurally altered factor with a duplicated runt domain and
    changed DNA-binding or partner behaviour. The distinction matters because
    only the first predicts that a whole-gene RUNX2 duplication should produce
    the same skeletal disease, and the reported whole-gene duplication family
    has a predominantly oro-dental phenotype rather than the full MDMHB
    picture. No study has separated the two models.
  evidence:
  - reference: PMID:23290074
    reference_title: >-
      Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function.
    explanation: >-
      The observation the gap is built on, and the hedged wording that leaves
      the mechanism open.
  - reference: PMID:29852250
    reference_title: Oro-dental phenotype in patients with RUNX2 duplication.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe here the oro-dental phenotype of four patients of a unique family with a 285 kb duplication including the entire sequence of RUNX2, likely responsible for three functional copies of the gene, leading to an increased RUNX2 dosage.
    explanation: >-
      The whole-gene duplication comparator referred to in the rationale; it
      raises RUNX2 dosage without the intragenic rearrangement, so its phenotype
      bears on which model is right.
clinical_trials: []
datasets: []
notes: >-
  Curated to complete ISDS Nosology group 11 (Metaphyseal dysplasias), row
  NOS 11-0120. MONDO:0007984's canonical label contains a typo
  ("brachydacty"); the label is reproduced exactly as MONDO carries it, as term
  validation requires, while the entry name uses the correct spelling.
  PMID:29852250 is cited twice, and in both places the citation is explicit that
  its family carries a whole-gene rather than an intragenic RUNX2 duplication -
  it is used for RUNX2 biology and as a comparator, not as an MDMHB case series.
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.