Osteogenesis Imperfecta Type XX

Mendelian MONDO:0032846 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XX (OI type XX; MESD-related OI) is an autosomal recessive, progressively deforming brittle-bone disease caused by biallelic loss-of-function (hypomorphic) variants in MESD (Mesoderm Development LRP Chaperone; prior symbol MESDC2). MESD encodes an endoplasmic-reticulum (ER) chaperone required for the proper folding and surface trafficking of the canonical WNT co-receptors LRP5 and LRP6. Like WNT1-related OI type XV, OI type XX is therefore a WNT-signaling OI rather than a primary collagen-defect OI: the proximal lesion lies in the LRP5/LRP6-mediated WNT/beta-catenin osteoanabolic axis rather than in type I collagen. The OI-associated MESD alleles are truncating/frameshift mutations located downstream of the chaperone activity domain but upstream of the ER-retention domain; the resulting protein fails to be retained in the ER and significantly reduces (but does not completely eliminate) LRP5/LRP6 trafficking. Because complete MESD loss is embryonic-lethal in mice, viable human disease reflects these hypomorphic alleles. The consequence is diminished canonical WNT signaling in bone, reduced osteoblast-mediated bone formation, low bone mass, and severe skeletal fragility. Affected individuals have recurrent fractures with a progressively deforming phenotype; oligodontia (a reduced-LRP6 feature) is part of the spectrum, and complete loss-of-function alleles in the chaperone domain (e.g., exon 2 frameshifts) produce a neonatal-lethal form with multiple intrauterine fractures and severe deformity. Because the defect is in WNT co-receptor trafficking, biologic agents that increase LRP5/LRP6-mediated WNT signaling are a proposed therapeutic strategy.

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1
Inheritance
3
Pathophys.
7
Phenotypes
3
Pathograph
1
Genes
3
Medical Actions
4
References
🏷

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from biallelic (homozygous or compound heterozygous) hypomorphic loss-of-function MESD variants; heterozygous carriers are clinically unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31564437 SUPPORT Human Clinical
"Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD."
Establishes the autosomal recessive inheritance of OI type XX from biallelic (homozygous) loss-of-function MESD variants across five families.
⚙

Pathophysiology

3
MESD Loss Impairs ER Chaperoning and Trafficking of LRP5/LRP6
MESD encodes an endoplasmic-reticulum chaperone protein for the canonical WNT signaling co-receptors LRP5 and LRP6, folding them and chaperoning their transit to the cell surface. The OI-associated MESD mutations are truncating/frameshift alleles located downstream of the chaperone activity domain but upstream of the ER-retention domain, so mutant MESD fails to be retained within the ER; this significantly reduces (but does not completely eliminate) LRP5/LRP6 trafficking. The proximal lesion is thus failure of WNT co-receptor maturation rather than a defect in type I collagen, placing OI type XX mechanistically alongside WNT1-related OI type XV.
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. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
protein folding (ER chaperoning of LRP5/LRP6 by MESD) GO:0006457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein folding (ER chaperoning of LRP5/LRP6 by MESD), annotated with protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Canonical WNT/Beta-Catenin Signaling and Osteoblast Bone Formation Reduced LRP5/LRP6 co-receptor availability at the cell surface diminishes canonical WNT/beta-catenin signaling, impairing the osteoanabolic osteoblast bone-formation program.
Show evidence (3 references)
PMID:31564437 SUPPORT Human Clinical
"MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6."
Defines MESD as the ER chaperone for the WNT co-receptors LRP5/LRP6, the function lost in OI type XX.
PMID:31564437 SUPPORT In Vitro
"Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking."
Documents that the OI-associated MESD alleles are hypomorphic and reduce ER-dependent LRP5/LRP6 trafficking, the proximal molecular defect.
PMID:35047842 SUPPORT In Vitro
"MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface."
Independent confirmation that MESD folds and chaperons LRP5/LRP6 to the cell surface within the WNT signaling pathway.
Reduced Canonical WNT/Beta-Catenin Signaling and Osteoblast Bone Formation
With LRP5/LRP6 trafficking reduced, canonical WNT/beta-catenin signaling — the osteoanabolic axis essential for osteoblast differentiation and bone formation — is diminished. The phenotype mirrors the consequences of reduced LRP5 and LRP6 function: bone-mass accrual and dental patterning are inferred to be more sensitive to reduced canonical WNT signaling than other developmental processes, so the disease manifests predominantly as skeletal fragility (reduced LRP5) and oligodontia (reduced LRP6) without the eye, limb, or brain patterning defects of complete LRP5/LRP6 loss.
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.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↓ DECREASED Wnt signaling pathway GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology. ↓ DECREASED osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Bone Mass and Skeletal Fragility Deficient WNT-driven osteoblast bone formation yields low bone mass and a mechanically weak, fracture-prone, progressively deforming skeleton.
Show evidence (2 references)
PMID:31564437 SUPPORT Human Clinical
"we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes."
Links reduced canonical WNT signaling to the impaired bone-mass accrual (and dental patterning) that defines the OI type XX phenotype.
PMID:35047842 SUPPORT Human Clinical
"underscores the necessity of MESD for normal WNT signaling in bone formation."
Confirms that MESD is required for normal WNT signaling in bone formation, the osteoanabolic step impaired in OI type XX.
Reduced Bone Mass and Skeletal Fragility
The deficit in WNT-driven osteoblast bone formation produces low bone mineral density, impaired and heterogeneous matrix mineralization, and impaired osseous development, manifesting clinically as recurrent fractures, growth deficiency, and progressive long-bone deformity. In the neonatal-lethal end of the spectrum, histology shows impaired osseous development with altered osteocyte morphology, reduced canalicular connectivity, and more heterogeneous matrix mineralization, alongside multiple intrauterine fractures and severe skeletal deformity.
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.
bone mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bone mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↓ DECREASED ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:33596325 SUPPORT Human Clinical
"Histological evaluation of MESD specimens revealed an impaired osseous development with an altered osteocyte morphology and reduced canalicular connectivity."
Documents impaired osseous development and altered bone cell morphology resulting from MESD loss, the cellular basis of the skeletal fragility.
PMID:33596325 SUPPORT Human Clinical
"analysis of bone mineral density distribution by qBEI indicated an impaired and more heterogeneous matrix mineralization in individuals with MESD mutations than in controls."
Documents impaired, heterogeneous bone matrix mineralization in MESD-deficient bone, the mineralization defect underlying OI type XX.
⬡

Pathograph

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

7
Head and Neck 1
Oligodontia HP:0000677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligodontia (HP:0000677). HP:0000677 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31564437 SUPPORT Human Clinical
"Affected individuals had recurrent fractures and at least one had oligodontia."
Documents oligodontia in MESD-related OI; as a variable (reduced-LRP6) feature it is present in a subset of affected individuals.
Limbs 1
Progressive Bone Deformity Bowing of the long bones HP:0006487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone deformity (progressive long-bone deformity), annotated with Bowing of the long bones (HP:0006487). HP:0006487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33596325 SUPPORT Human Clinical
"the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals."
Documents severe skeletal deformity as part of the OI type XX phenotype.
Musculoskeletal 2
Recurrent Fractures HP:0002757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fractures (HP:0002757). HP:0002757 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31564437 SUPPORT Human Clinical
"Affected individuals had recurrent fractures and at least one had oligodontia."
Documents recurrent fractures as a defining feature of MESD-related OI type XX.
Reduced Bone Mineral Density HP:0004349 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced bone mineral density (HP:0004349). HP:0004349 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33596325 SUPPORT Human Clinical
"a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures."
Documents low bone mineral density as a predominant feature of the OI phenotype caused by MESD mutations.
Growth 1
Growth Deficiency Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31564437 SUPPORT Human Clinical
"Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD."
Documents the progressively deforming OI phenotype within which growth deficiency develops as a consequence of recurrent fractures and deformity.
Other 2
Multiple Prenatal Fractures (Lethal End of the Spectrum) HP:0005855 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple intrauterine fractures, annotated with Multiple prenatal fractures (HP:0005855). HP:0005855 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33596325 SUPPORT Human Clinical
"the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals."
Documents multiple intrauterine (prenatal) fractures in the neonatal-lethal end of the OI type XX spectrum caused by complete-loss-of-function MESD alleles.
Absent Eye Abnormalities (Distinguishing Hypomorphic MESD from Complete LRP5 Loss) Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Eye abnormalities, annotated with Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (1 reference)
PMID:31564437 SUPPORT Human Clinical
"Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5)"
Documents that MESD-related OI type XX individuals have no eye abnormalities, unlike those with complete LRP5 loss — an explicitly absent, distinguishing feature of the hypomorphic MESD phenotype.
🧬

Genetic Associations

1
MESD Loss-of-Function (Hypomorphic) Mutations (Causative)
Gene: MESD (Mesoderm Development LRP Chaperone; prior symbol MESDC2) hgnc:13520 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MESD (Mesoderm Development LRP Chaperone; prior symbol MESDC2), annotated with MESD (hgnc:13520). hgnc:13520 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:31564437 SUPPORT Human Clinical
"we identified four homozygous truncation or frameshift mutations in MESD."
Identifies MESD as the causative gene of OI type XX through biallelic truncation/frameshift mutations.
PMID:35047842 SUPPORT Human Clinical
"To date, two reports have linked Mesoderm Development LRP Chaperone (MESD) to autosomal recessive OI type XX."
Confirms MESD (Mesoderm Development LRP Chaperone) as the OI type XX gene and spells out the gene name underlying the MESDC2 prior symbol.
PMID:33596325 SUPPORT Human Clinical
"In each of the affected individuals, compound heterozygous mutations in MESD exon 2 and exon 3 were detected."
Documents biallelic (compound heterozygous) MESD mutations, including a complete-loss-of-function exon 2 allele in the lethal form.
💊

Medical Actions

3
Bisphosphonate Therapy
Action: Bisphosphonate TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Bisphosphonate Therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. NCIT:C198585
Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the pharmacological mainstay of severe OI, increasing bone mineral density and reducing fracture frequency. They are antiresorptive and do not correct the underlying WNT-signaling/MESD chaperone defect.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"Bisphosphonates continue to be used most extensively in those with vertebral fractures, frequent long bone fractures, or more severe OI."
GeneReviews documents bisphosphonates as the mainstay pharmacotherapy for severe OI, the management category that applies to OI type XX.
Orthopedic Surgery and Intramedullary Rodding
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize fracture-prone, deformed long bones; spinal surgery addresses progressive scoliosis.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"intramedullary rodding when indicated to provide anatomic positioning of limbs"
GeneReviews documents intramedullary rodding as standard orthopedic management for OI long-bone fractures and deformity.
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical and occupational therapy increase bone stability, improve mobility and muscle strength, and prevent contractures and deformity; early physical therapy follows brief post-fracture immobilization.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"Fractures are treated with as short a period of immobility as is practical, small and lightweight casts, and physical therapy as soon as casts are removed"
GeneReviews documents early physical therapy and brief immobilization as part of standard OI fracture rehabilitation.
🔬

Diagnosis

1
Molecular Genetic Diagnosis
OI type XX is suspected in an infant or child with severe, progressively deforming recessive OI (recurrent fractures, low bone mineral density, deformity), particularly when oligodontia is present and COL1A1/COL1A2 and other recessive OI genes are negative. Diagnosis is confirmed by identifying biallelic MESD (MESDC2) variants by gene-panel or exome sequencing; whole-exome sequencing identified the gene in the original kindreds.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33596325 SUPPORT Human Clinical
"whole-exome sequencing of three stillbirths in one family was performed to evaluate the presence of a hereditary disorder."
Illustrates the molecular diagnostic pathway (exome sequencing) used to identify biallelic MESD variants establishing the OI type XX diagnosis.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XX
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 20
  term:
    id: MONDO:0032846
    label: osteogenesis imperfecta, type 20
description: >-
  Osteogenesis imperfecta type XX (OI type XX; MESD-related OI) is an autosomal
  recessive, progressively deforming brittle-bone disease caused by biallelic
  loss-of-function (hypomorphic) variants in MESD (Mesoderm Development LRP
  Chaperone; prior symbol MESDC2). MESD encodes an endoplasmic-reticulum (ER)
  chaperone required for the proper folding and surface trafficking of the
  canonical WNT co-receptors LRP5 and LRP6. Like WNT1-related OI type XV, OI type
  XX is therefore a WNT-signaling OI rather than a primary collagen-defect OI:
  the proximal lesion lies in the LRP5/LRP6-mediated WNT/beta-catenin
  osteoanabolic axis rather than in type I collagen. The OI-associated MESD
  alleles are truncating/frameshift mutations located downstream of the chaperone
  activity domain but upstream of the ER-retention domain; the resulting protein
  fails to be retained in the ER and significantly reduces (but does not
  completely eliminate) LRP5/LRP6 trafficking. Because complete MESD loss is
  embryonic-lethal in mice, viable human disease reflects these hypomorphic
  alleles. The consequence is diminished canonical WNT signaling in bone, reduced
  osteoblast-mediated bone formation, low bone mass, and severe skeletal
  fragility. Affected individuals have recurrent fractures with a progressively
  deforming phenotype; oligodontia (a reduced-LRP6 feature) is part of the
  spectrum, and complete loss-of-function alleles in the chaperone domain (e.g.,
  exon 2 frameshifts) produce a neonatal-lethal form with multiple intrauterine
  fractures and severe deformity. Because the defect is in WNT co-receptor
  trafficking, biologic agents that increase LRP5/LRP6-mediated WNT signaling are
  a proposed therapeutic strategy.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic (homozygous or compound
    heterozygous) hypomorphic loss-of-function MESD variants; heterozygous
    carriers are clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report on five independent families with a progressively
      deforming type of OI, in whom we identified four homozygous truncation or
      frameshift mutations in MESD.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type XX from
      biallelic (homozygous) loss-of-function MESD variants across five families.
classifications:
  isds_skeletal_category:
  - classification_value: osteogenesis_imperfecta_and_decreased_bone_density
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 25 "Osteogenesis
      Imperfecta and decreased bone density group"; this entry corresponds to the
      phenotypic osteogenesis imperfecta entries (OI types 1-5), which the
      nosology lists by clinical severity rather than by the gene-numbered OI type
      used for this entry.
pathophysiology:
- name: MESD Loss Impairs ER Chaperoning and Trafficking of LRP5/LRP6
  description: >-
    MESD encodes an endoplasmic-reticulum chaperone protein for the canonical WNT
    signaling co-receptors LRP5 and LRP6, folding them and chaperoning their
    transit to the cell surface. The OI-associated MESD mutations are
    truncating/frameshift alleles located downstream of the chaperone activity
    domain but upstream of the ER-retention domain, so mutant MESD fails to be
    retained within the ER; this significantly reduces (but does not completely
    eliminate) LRP5/LRP6 trafficking. The proximal lesion is thus failure of WNT
    co-receptor maturation rather than a defect in type I collagen, placing OI
    type XX mechanistically alongside WNT1-related OI type XV.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: protein folding (ER chaperoning of LRP5/LRP6 by MESD)
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MESD encodes an endoplasmic reticulum (ER) chaperone protein for the
      canonical Wingless-related integration site (WNT) signaling receptors LRP5
      and LRP6.
    explanation: >-
      Defines MESD as the ER chaperone for the WNT co-receptors LRP5/LRP6, the
      function lost in OI type XX.
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, OI-associated MESD mutations produce hypomorphic alleles whose
      failure to remain within the ER significantly reduces but does not
      completely eliminate LRP5 and LRP6 trafficking.
    explanation: >-
      Documents that the OI-associated MESD alleles are hypomorphic and reduce
      ER-dependent LRP5/LRP6 trafficking, the proximal molecular defect.
  - reference: PMID:35047842
    reference_title: "Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MESD acts in the WNT signaling pathway, where it is thought to play a role
      in the folding of the WNT co-receptors low-density lipoprotein
      receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their
      transit to the cell surface.
    explanation: >-
      Independent confirmation that MESD folds and chaperons LRP5/LRP6 to the
      cell surface within the WNT signaling pathway.
  downstream:
  - target: Reduced Canonical WNT/Beta-Catenin Signaling and Osteoblast Bone Formation
    description: >-
      Reduced LRP5/LRP6 co-receptor availability at the cell surface diminishes
      canonical WNT/beta-catenin signaling, impairing the osteoanabolic
      osteoblast bone-formation program.
- name: Reduced Canonical WNT/Beta-Catenin Signaling and Osteoblast Bone Formation
  description: >-
    With LRP5/LRP6 trafficking reduced, canonical WNT/beta-catenin signaling — the
    osteoanabolic axis essential for osteoblast differentiation and bone
    formation — is diminished. The phenotype mirrors the consequences of reduced
    LRP5 and LRP6 function: bone-mass accrual and dental patterning are inferred
    to be more sensitive to reduced canonical WNT signaling than other
    developmental processes, so the disease manifests predominantly as skeletal
    fragility (reduced LRP5) and oligodontia (reduced LRP6) without the eye, limb,
    or brain patterning defects of complete LRP5/LRP6 loss.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we infer that bone mass accrual and dental patterning are more sensitive to
      reduced canonical WNT signaling than are other developmental processes.
    explanation: >-
      Links reduced canonical WNT signaling to the impaired bone-mass accrual
      (and dental patterning) that defines the OI type XX phenotype.
  - reference: PMID:35047842
    reference_title: "Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      underscores the necessity of MESD for normal WNT signaling in bone
      formation.
    explanation: >-
      Confirms that MESD is required for normal WNT signaling in bone formation,
      the osteoanabolic step impaired in OI type XX.
  downstream:
  - target: Reduced Bone Mass and Skeletal Fragility
    description: >-
      Deficient WNT-driven osteoblast bone formation yields low bone mass and a
      mechanically weak, fracture-prone, progressively deforming skeleton.
- name: Reduced Bone Mass and Skeletal Fragility
  description: >-
    The deficit in WNT-driven osteoblast bone formation produces low bone mineral
    density, impaired and heterogeneous matrix mineralization, and impaired
    osseous development, manifesting clinically as recurrent fractures, growth
    deficiency, and progressive long-bone deformity. In the neonatal-lethal end
    of the spectrum, histology shows impaired osseous development with altered
    osteocyte morphology, reduced canalicular connectivity, and more heterogeneous
    matrix mineralization, alongside multiple intrauterine fractures and severe
    skeletal deformity.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: DECREASED
  evidence:
  - reference: PMID:33596325
    reference_title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological evaluation of MESD specimens revealed an impaired osseous
      development with an altered osteocyte morphology and reduced canalicular
      connectivity.
    explanation: >-
      Documents impaired osseous development and altered bone cell morphology
      resulting from MESD loss, the cellular basis of the skeletal fragility.
  - reference: PMID:33596325
    reference_title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      analysis of bone mineral density distribution by qBEI indicated an impaired
      and more heterogeneous matrix mineralization in individuals with MESD
      mutations than in controls.
    explanation: >-
      Documents impaired, heterogeneous bone matrix mineralization in
      MESD-deficient bone, the mineralization defect underlying OI type XX.
genetic:
- name: MESD Loss-of-Function (Hypomorphic) Mutations
  association: Causative
  gene_term:
    preferred_term: MESD (Mesoderm Development LRP Chaperone; prior symbol MESDC2)
    term:
      id: hgnc:13520
      label: MESD
  notes: >-
    OI type XX is caused by biallelic loss-of-function variants in MESD (prior
    gene symbol MESDC2), the gene encoding the ER chaperone for the WNT
    co-receptors LRP5/LRP6. Reported OI-associated alleles are truncating or
    frameshift variants (e.g., c.632dupA p.Lys212Glufs, c.676C>T p.Arg226*)
    located downstream of the chaperone activity domain but upstream of the
    ER-retention domain, behaving as hypomorphic alleles. More proximal,
    complete-loss-of-function alleles in the chaperone domain (e.g., exon 2
    frameshifts) cause a neonatal-lethal form.
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified four homozygous truncation or frameshift mutations in MESD.
    explanation: >-
      Identifies MESD as the causative gene of OI type XX through biallelic
      truncation/frameshift mutations.
  - reference: PMID:35047842
    reference_title: "Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, two reports have linked Mesoderm Development LRP Chaperone (MESD)
      to autosomal recessive OI type XX.
    explanation: >-
      Confirms MESD (Mesoderm Development LRP Chaperone) as the OI type XX gene
      and spells out the gene name underlying the MESDC2 prior symbol.
  - reference: PMID:33596325
    reference_title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In each of the affected individuals, compound heterozygous mutations in
      MESD exon 2 and exon 3 were detected.
    explanation: >-
      Documents biallelic (compound heterozygous) MESD mutations, including a
      complete-loss-of-function exon 2 allele in the lethal form.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Recurrent low-trauma fractures with a progressively deforming course are the
    cardinal feature of OI type XX.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals had recurrent fractures and at least one had
      oligodontia.
    explanation: >-
      Documents recurrent fractures as a defining feature of MESD-related OI type
      XX.
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mineral density with impaired, heterogeneous matrix mineralization,
    reflecting deficient WNT-driven osteoblastic bone formation.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:33596325
    reference_title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a phenotypically and genetically heterogenous bone disorder, marked
      predominantly by low bone mineral density and increased risk of fractures.
    explanation: >-
      Documents low bone mineral density as a predominant feature of the OI
      phenotype caused by MESD mutations.
- name: Progressive Bone Deformity
  description: >-
    A progressively deforming skeletal phenotype, including long-bone deformity,
    accompanies the recurrent fractures and low bone mass in OI type XX.
  phenotype_term:
    preferred_term: Bone deformity (progressive long-bone deformity)
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:33596325
    reference_title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the skeletal phenotype, which was characterized by multiple intrauterine
      fractures and severe skeletal deformity, OI XX was diagnosed in these
      individuals.
    explanation: >-
      Documents severe skeletal deformity as part of the OI type XX phenotype.
- name: Oligodontia
  description: >-
    Oligodontia (congenital absence of multiple teeth) occurs in OI type XX,
    reflecting reduced LRP6-mediated WNT signaling in dental patterning — a
    feature that helps distinguish MESD-related OI from collagen-defect OI.
  phenotype_term:
    preferred_term: Oligodontia
    term:
      id: HP:0000677
      label: Oligodontia
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals had recurrent fractures and at least one had
      oligodontia.
    explanation: >-
      Documents oligodontia in MESD-related OI; as a variable (reduced-LRP6)
      feature it is present in a subset of affected individuals.
- name: Multiple Prenatal Fractures (Lethal End of the Spectrum)
  description: >-
    In the neonatal-lethal end of the OI type XX spectrum (complete-loss-of-function
    exon 2 MESD alleles), affected fetuses present with multiple intrauterine
    fractures detectable at birth, alongside severe skeletal deformity.
  phenotype_term:
    preferred_term: Multiple intrauterine fractures
    term:
      id: HP:0005855
      label: Multiple prenatal fractures
  evidence:
  - reference: PMID:33596325
    reference_title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the skeletal phenotype, which was characterized by multiple intrauterine
      fractures and severe skeletal deformity, OI XX was diagnosed in these
      individuals.
    explanation: >-
      Documents multiple intrauterine (prenatal) fractures in the neonatal-lethal
      end of the OI type XX spectrum caused by complete-loss-of-function MESD
      alleles.
- name: Absent Eye Abnormalities (Distinguishing Hypomorphic MESD from Complete LRP5 Loss)
  description: >-
    Unlike individuals who completely lack LRP5 — in whom ocular abnormalities
    occur (as in osteoporosis-pseudoglioma syndrome) — persons with hypomorphic
    MESD alleles causing OI type XX have no eye abnormalities. Recorded here as an
    explicitly absent phenotype: the residual LRP5/LRP6 trafficking preserved by
    the hypomorphic alleles is sufficient for ocular development, so the disease is
    largely restricted to skeletal fragility (reduced LRP5) and oligodontia
    (reduced LRP6). This distinguishes OI type XX from complete LRP5 loss and is
    consistent with its WNT-signaling (rather than collagen-defect) mechanism.
  phenotype_term:
    preferred_term: Eye abnormalities
    modifier: ABSENT
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since these individuals have no eye abnormalities (which occur in
      individuals completely lacking LRP5)
    explanation: >-
      Documents that MESD-related OI type XX individuals have no eye abnormalities,
      unlike those with complete LRP5 loss — an explicitly absent, distinguishing
      feature of the hypomorphic MESD phenotype.
- name: Growth Deficiency
  description: >-
    Growth deficiency accompanies the severe, progressively deforming skeletal
    phenotype of OI type XX, consistent with the broader OI disease spectrum.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:31564437
    reference_title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report on five independent families with a progressively
      deforming type of OI, in whom we identified four homozygous truncation or
      frameshift mutations in MESD.
    explanation: >-
      Documents the progressively deforming OI phenotype within which growth
      deficiency develops as a consequence of recurrent fractures and deformity.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XX is suspected in an infant or child with severe, progressively
    deforming recessive OI (recurrent fractures, low bone mineral density,
    deformity), particularly when oligodontia is present and COL1A1/COL1A2 and
    other recessive OI genes are negative. Diagnosis is confirmed by identifying
    biallelic MESD (MESDC2) variants by gene-panel or exome sequencing;
    whole-exome sequencing identified the gene in the original kindreds.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:33596325
    reference_title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whole-exome sequencing of three stillbirths in one family was performed to
      evaluate the presence of a hereditary disorder.
    explanation: >-
      Illustrates the molecular diagnostic pathway (exome sequencing) used to
      identify biallelic MESD variants establishing the OI type XX diagnosis.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the
    pharmacological mainstay of severe OI, increasing bone mineral density and
    reducing fracture frequency. They are antiresorptive and do not correct the
    underlying WNT-signaling/MESD chaperone defect.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bisphosphonates continue to be used most extensively in those with
      vertebral fractures, frequent long bone fractures, or more severe OI.
    explanation: >-
      GeneReviews documents bisphosphonates as the mainstay pharmacotherapy for
      severe OI, the management category that applies to OI type XX.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, deformed long bones; spinal surgery addresses progressive
    scoliosis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intramedullary rodding when
      indicated to provide anatomic positioning of limbs
    explanation: >-
      GeneReviews documents intramedullary rodding as standard orthopedic
      management for OI long-bone fractures and deformity.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy increase bone stability, improve mobility
    and muscle strength, and prevent contractures and deformity; early physical
    therapy follows brief post-fracture immobilization.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fractures are treated with as
      short a period of immobility as is practical, small and lightweight casts, and
      physical therapy as soon as casts are removed
    explanation: >-
      GeneReviews documents early physical therapy and brief immobilization as
      part of standard OI fracture rehabilitation.
datasets: []
references:
- reference: PMID:31564437
  title: "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."
- reference: PMID:35047842
  title: "Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta."
- reference: PMID:33596325
  title: "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

4
PMID:31564437
Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.
No top-level findings curated for this source.
PMID:35047842
Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:33596325
Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.