Osteogenesis Imperfecta Type XII

Mendelian MONDO:0013460 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XII (OI type XII) is a rare autosomal recessive brittle bone disease caused by biallelic loss-of-function variants in SP7, the gene encoding the osteoblast-specific zinc-finger transcription factor Osterix (OSX). Unlike the collagen-structural (COL1A1/COL1A2) and collagen-modification (CRTAP, P3H1, PPIB, SERPINH1) forms of OI, OI type XII is a transcription-factor / osteoblast-differentiation disorder: Osterix acts downstream of RUNX2 and is essential for the differentiation of preosteoblasts into mature, matrix-secreting osteoblasts and for bone formation. The defining human allele is a homozygous single-base-pair frameshift deletion (c.1052delA) that removes the last 81 amino acids of the protein, including the third Cys2-His2 zinc-finger DNA-binding motif, abolishing the transcription factor's function. A second consanguineous sibship carrying a homozygous missense variant (c.946C>T, p.Arg316Cys) confirmed the gene-disease relationship and added significant hearing loss to the recognized spectrum. Loss of Osterix impairs osteoblast differentiation and bone matrix deposition, producing a bone-formation deficit with low bone mineral density, recurrent low-trauma fractures, mild bone deformity, short stature, and delayed tooth eruption. The disorder was first defined in an Egyptian child (Lapunzina et al., 2010) and is recapitulated by the bone-free phenotype of Osx-null mice (Nakashima et al., 2002).

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1
Inheritance
3
Pathophys.
6
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 a biallelic (homozygous) loss-of-function SP7/Osterix variant in a consanguineous kindred; heterozygous carriers are clinically unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20579626 SUPPORT Human Clinical
"we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta."
Establishes the autosomal recessive inheritance of OI type XII from a biallelic (homozygous) SP7/Osterix variant.
PMID:29382611 SUPPORT Human Clinical
"A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in all affected relatives; c.946C>T (p.Arg316Cys)."
A second consanguineous sibship with a homozygous SP7/Osx variant confirms the recessive inheritance of the disorder.
⚙

Pathophysiology

3
SP7/Osterix Loss-of-Function Eliminates the Osteoblast Master Transcription Factor
SP7 encodes Osterix (OSX), an osteoblast-specific zinc-finger transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus. Osterix is specifically expressed in all developing bones and acts downstream of RUNX2/Cbfa1 in the osteoblast differentiation cascade. The OI type XII frameshift deletion (c.1052delA) removes the last 81 amino acids, including the third zinc-finger motif, abolishing DNA-binding and transcriptional function. The missense variant (p.Arg316Cys) similarly impairs the factor. This is a transcription-factor lesion, distinct from the collagen-structural and collagen-modification mechanisms of other OI types.
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. mesenchymal stem cell (osteoblast precursor) CL:0000134 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mesenchymal stem cell (osteoblast precursor), annotated with mesenchymal stem cell (CL:0000134). CL:0000134 is a cell type from the Cell Ontology.
regulation of transcription by RNA polymerase II (Osterix transcriptional activity) GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of transcription by RNA polymerase II (Osterix transcriptional activity), annotated with regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Osteoblast Differentiation and Bone Matrix Deposition Without functional Osterix, RUNX2-expressing preosteoblasts cannot mature into bone-matrix-secreting osteoblasts, blocking osteogenesis.
Show evidence (2 references)
PMID:20579626 SUPPORT Human Clinical
"OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation."
Defines Osterix as a zinc-finger transcription factor essential for bone formation, the master regulator lost in OI type XII.
PMID:20579626 SUPPORT Human Clinical
"The frameshift caused by the c.1052delA deletion removes the last 81 amino acids of the protein, including the third zinc-finger motif."
Documents that the defining OI type XII frameshift truncates the Osterix DNA-binding zinc-finger domain, abolishing transcription-factor function.
Impaired Osteoblast Differentiation and Bone Matrix Deposition
Osterix is required for the terminal differentiation of preosteoblasts into mature osteoblasts that deposit bone matrix. In Osx-null mice no bone formation occurs: mesenchymal cells invade the cartilage but fail to deposit bone matrix and cannot differentiate into osteoblasts, even though they still express RUNX2/Cbfa1, placing Osterix downstream of RUNX2. In humans, Osterix is expressed primarily by osteoblasts and is vital for bone formation by promoting osteoblast differentiation and maturation; its loss impairs the bone-formation program rather than collagen structure.
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. mesenchymal stem cell (preosteoblast) CL:0000134 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mesenchymal stem cell (preosteoblast), annotated with mesenchymal stem cell (CL:0000134). CL:0000134 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 decreased osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ↓ DECREASED ossification (bone formation) GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ossification (bone formation), annotated with ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced Bone Matrix, Low Bone Density, and Skeletal Fragility Deficient osteoblast-mediated bone formation yields a hypomineralized, mechanically weak skeleton prone to fracture.
Show evidence (3 references)
PMID:11792318 SUPPORT Model Organism
"In Osx null mice, no bone formation occurs."
Demonstrates that loss of Osterix abolishes bone formation, the proximal bone-formation deficit underlying OI type XII.
PMID:11792318 SUPPORT Model Organism
"However, the mesenchymal cells do not deposit bone matrix. Similarly, cells in the periosteum and in the condensed mesenchyme of membranous skeletal elements cannot differentiate into osteoblasts."
Documents the osteoblast-differentiation block and failed bone-matrix deposition that define the Osterix-deficient mechanism.
PMID:29382611 SUPPORT Human Clinical
"Osterix is expressed primarily by osteoblasts and has been shown to be vital for bone formation and bone homeostasis by promoting osteoblast differentiation and maturation."
Establishes in the human disease context that Osterix drives osteoblast differentiation and maturation, the function lost in OI type XII.
Reduced Bone Matrix, Low Bone Density, and Skeletal Fragility
The osteoblast-differentiation deficit produces a quantitatively reduced and poorly organized bone matrix with low bone mineral density and high trabecular bone turnover. Bone biopsies from affected children show significant cortical porosity and high trabecular bone turnover. Clinically this manifests as recurrent low-trauma fractures, mild bone deformity, short stature, and, in some families, progressive hearing loss from poor mineralization of the ossicles and petrous temporal bone.
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
Show evidence (2 references)
PMID:29382611 SUPPORT Human Clinical
"Bone biopsies in the proband and his male sibling revealed significant cortical porosity and high trabecular bone turnover."
Documents the abnormal bone microarchitecture (cortical porosity, high turnover) reflecting deficient Osterix-driven bone formation.
PMID:29382611 SUPPORT Human Clinical
"We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature."
Documents the low bone density, low-trauma fractures, and short stature that are the clinical manifestation of the bone-formation deficit.
⬡

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 XII Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Ear 1
Progressive Hearing Impairment HP:0001730 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive hearing impairment (HP:0001730), qualified as course progressive. HP:0001730 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:29382611 SUPPORT Human Clinical
"Progressive moderate-to-severe and severe-to-profound hearing loss secondary to otospongiosis and poor mineralization of ossicles and petrous temporal bone was also noted in two of the siblings."
Documents progressive hearing loss (from ossicle/petrous mineralization defects) as a distinguishing feature of OI type XII in the second sibship.
PMID:29382611 SUPPORT Human Clinical
"it is the first to describe the bone histomorphometry associated with this disorder and identifies a significant hearing loss as a potential feature in this OI subtype."
Confirms hearing loss as a newly recognized potential feature of the SP7/Osx OI subtype, warranting early audiology screening.
Head and Neck 1
Delayed Tooth Eruption Delayed eruption of teeth HP:0000684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed eruption of teeth (HP:0000684). HP:0000684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20579626 SUPPORT Human Clinical
"The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera."
Documents delayed tooth eruption in the index OI type XII patient.
Limbs 1
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 (bowing of the long bones), annotated with Bowing of the long bones (HP:0006487). HP:0006487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20579626 SUPPORT Human Clinical
"The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera."
Documents mild bone deformities (manifesting as long-bone bowing) as part of the OI type XII 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:20579626 SUPPORT Human Clinical
"The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera."
Documents recurrent fractures as the cardinal clinical feature of OI type XII in the index patient.
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:29382611 SUPPORT Human Clinical
"We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature."
Documents osteoporosis (reduced bone mineral density) as a feature of OI type XII.
Growth 1
Short Stature 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:29382611 SUPPORT Human Clinical
"We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature."
Documents short stature (growth deficiency) as part of the OI type XII phenotype.
🧬

Genetic Associations

1
SP7 (Osterix) Loss-of-Function Mutation (Causative)
Gene: SP7 (OSX, Osterix; osteoblast transcription factor) hgnc:17321 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SP7 (OSX, Osterix; osteoblast transcription factor), annotated with SP7 (hgnc:17321). hgnc:17321 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:20579626 SUPPORT Human Clinical
"This finding adds another locus to the spectrum of genes associated with osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in human bone development."
Identifies SP7/OSX as the causative locus for this recessive OI, defining OI type XII in humans.
PMID:29382611 SUPPORT Human Clinical
"A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in all affected relatives; c.946C>T (p.Arg316Cys)."
A second independent biallelic SP7 variant confirms SP7 as the OI type XII disease gene.
💊

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 more severe OI, increasing bone mineral density and reducing fracture frequency. They are antiresorptive and do not correct the underlying osteoblast-differentiation 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 XII.
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 XII is suspected in a child with recessive OI (recurrent low-trauma fractures, low bone mineral density, mild deformity, short stature, with or without hearing loss) when COL1A1/COL1A2 and the other recessive OI genes are negative. Diagnosis is confirmed by identifying a biallelic SP7 (Osterix) loss-of-function variant by gene-panel or exome sequencing.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20579626 SUPPORT Human Clinical
"Using a combination of homozygosity mapping and candidate gene approach, we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX)"
Molecular identification of a biallelic SP7 variant establishes the diagnosis of OI type XII.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XII
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 12
  term:
    id: MONDO:0013460
    label: osteogenesis imperfecta type 12
description: >-
  Osteogenesis imperfecta type XII (OI type XII) is a rare autosomal recessive
  brittle bone disease caused by biallelic loss-of-function variants in SP7,
  the gene encoding the osteoblast-specific zinc-finger transcription factor
  Osterix (OSX). Unlike the collagen-structural (COL1A1/COL1A2) and
  collagen-modification (CRTAP, P3H1, PPIB, SERPINH1) forms of OI, OI type XII
  is a transcription-factor / osteoblast-differentiation disorder: Osterix acts
  downstream of RUNX2 and is essential for the differentiation of preosteoblasts
  into mature, matrix-secreting osteoblasts and for bone formation. The defining
  human allele is a homozygous single-base-pair frameshift deletion (c.1052delA)
  that removes the last 81 amino acids of the protein, including the third
  Cys2-His2 zinc-finger DNA-binding motif, abolishing the transcription factor's
  function. A second consanguineous sibship carrying a homozygous missense
  variant (c.946C>T, p.Arg316Cys) confirmed the gene-disease relationship and
  added significant hearing loss to the recognized spectrum. Loss of Osterix
  impairs osteoblast differentiation and bone matrix deposition, producing a
  bone-formation deficit with low bone mineral density, recurrent low-trauma
  fractures, mild bone deformity, short stature, and delayed tooth eruption.
  The disorder was first defined in an Egyptian child (Lapunzina et al., 2010)
  and is recapitulated by the bone-free phenotype of Osx-null mice (Nakashima
  et al., 2002).
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from a biallelic (homozygous) loss-of-function
    SP7/Osterix variant in a consanguineous kindred; heterozygous carriers are
    clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we have identified a homozygous single base pair deletion (c.1052delA) in
      SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis
      imperfecta.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type XII from a
      biallelic (homozygous) SP7/Osterix variant.
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in
      all affected relatives; c.946C>T (p.Arg316Cys).
    explanation: >-
      A second consanguineous sibship with a homozygous SP7/Osx variant confirms
      the recessive inheritance of the disorder.
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: SP7/Osterix Loss-of-Function Eliminates the Osteoblast Master Transcription Factor
  description: >-
    SP7 encodes Osterix (OSX), an osteoblast-specific zinc-finger transcription
    factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C
    terminus. Osterix is specifically expressed in all developing bones and acts
    downstream of RUNX2/Cbfa1 in the osteoblast differentiation cascade. The OI
    type XII frameshift deletion (c.1052delA) removes the last 81 amino acids,
    including the third zinc-finger motif, abolishing DNA-binding and
    transcriptional function. The missense variant (p.Arg316Cys) similarly
    impairs the factor. This is a transcription-factor lesion, distinct from the
    collagen-structural and collagen-modification mechanisms of other OI types.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: mesenchymal stem cell (osteoblast precursor)
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II (Osterix transcriptional activity)
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OSX encodes a transcription factor containing three Cys2-His2 zinc-finger
      DNA-binding domains at its C terminus, which, in mice, has been shown to be
      essential for bone formation.
    explanation: >-
      Defines Osterix as a zinc-finger transcription factor essential for bone
      formation, the master regulator lost in OI type XII.
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frameshift caused by the c.1052delA deletion removes the last 81 amino
      acids of the protein, including the third zinc-finger motif.
    explanation: >-
      Documents that the defining OI type XII frameshift truncates the Osterix
      DNA-binding zinc-finger domain, abolishing transcription-factor function.
  downstream:
  - target: Impaired Osteoblast Differentiation and Bone Matrix Deposition
    description: >-
      Without functional Osterix, RUNX2-expressing preosteoblasts cannot mature
      into bone-matrix-secreting osteoblasts, blocking osteogenesis.
- name: Impaired Osteoblast Differentiation and Bone Matrix Deposition
  description: >-
    Osterix is required for the terminal differentiation of preosteoblasts into
    mature osteoblasts that deposit bone matrix. In Osx-null mice no bone
    formation occurs: mesenchymal cells invade the cartilage but fail to deposit
    bone matrix and cannot differentiate into osteoblasts, even though they still
    express RUNX2/Cbfa1, placing Osterix downstream of RUNX2. In humans, Osterix
    is expressed primarily by osteoblasts and is vital for bone formation by
    promoting osteoblast differentiation and maturation; its loss impairs the
    bone-formation program rather than collagen structure.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: mesenchymal stem cell (preosteoblast)
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  - preferred_term: ossification (bone formation)
    term:
      id: GO:0001503
      label: ossification
    modifier: DECREASED
  evidence:
  - reference: PMID:11792318
    reference_title: "The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Osx null mice, no bone formation occurs.
    explanation: >-
      Demonstrates that loss of Osterix abolishes bone formation, the proximal
      bone-formation deficit underlying OI type XII.
  - reference: PMID:11792318
    reference_title: "The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, the mesenchymal cells do not deposit bone matrix. Similarly, cells
      in the periosteum and in the condensed mesenchyme of membranous skeletal
      elements cannot differentiate into osteoblasts.
    explanation: >-
      Documents the osteoblast-differentiation block and failed bone-matrix
      deposition that define the Osterix-deficient mechanism.
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osterix is expressed primarily by osteoblasts and has been shown to be
      vital for bone formation and bone homeostasis by promoting osteoblast
      differentiation and maturation.
    explanation: >-
      Establishes in the human disease context that Osterix drives osteoblast
      differentiation and maturation, the function lost in OI type XII.
  downstream:
  - target: Reduced Bone Matrix, Low Bone Density, and Skeletal Fragility
    description: >-
      Deficient osteoblast-mediated bone formation yields a hypomineralized,
      mechanically weak skeleton prone to fracture.
- name: Reduced Bone Matrix, Low Bone Density, and Skeletal Fragility
  description: >-
    The osteoblast-differentiation deficit produces a quantitatively reduced and
    poorly organized bone matrix with low bone mineral density and high
    trabecular bone turnover. Bone biopsies from affected children show
    significant cortical porosity and high trabecular bone turnover. Clinically
    this manifests as recurrent low-trauma fractures, mild bone deformity, short
    stature, and, in some families, progressive hearing loss from poor
    mineralization of the ossicles and petrous temporal bone.
  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
  evidence:
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone biopsies in the proband and his male sibling revealed significant
      cortical porosity and high trabecular bone turnover.
    explanation: >-
      Documents the abnormal bone microarchitecture (cortical porosity, high
      turnover) reflecting deficient Osterix-driven bone formation.
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a novel Sp7/Osx variant in another sibship that
      presented with osteoporosis, low-trauma fractures and short stature.
    explanation: >-
      Documents the low bone density, low-trauma fractures, and short stature
      that are the clinical manifestation of the bone-formation deficit.
genetic:
- name: SP7 (Osterix) Loss-of-Function Mutation
  association: Causative
  gene_term:
    preferred_term: SP7 (OSX, Osterix; osteoblast transcription factor)
    term:
      id: hgnc:17321
      label: SP7
  notes: >-
    OI type XII is caused by a biallelic loss-of-function variant in SP7, the
    gene encoding the osteoblast-specific transcription factor Osterix (OSX).
    The defining human allele is a homozygous frameshift deletion (c.1052delA)
    that truncates the protein, removing its third zinc-finger DNA-binding motif.
    A second consanguineous sibship with a homozygous missense variant
    (c.946C>T, p.Arg316Cys) confirms SP7 as the OI type XII gene.
  evidence:
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This finding adds another locus to the spectrum of genes associated with
      osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in
      human bone development.
    explanation: >-
      Identifies SP7/OSX as the causative locus for this recessive OI, defining
      OI type XII in humans.
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in
      all affected relatives; c.946C>T (p.Arg316Cys).
    explanation: >-
      A second independent biallelic SP7 variant confirms SP7 as the OI type XII
      disease gene.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Bone fragility with recurrent low-trauma fractures, the cardinal feature of
    OI type XII.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical findings from this patient include recurrent fractures, mild
      bone deformities, delayed tooth eruption, normal hearing, and white sclera.
    explanation: >-
      Documents recurrent fractures as the cardinal clinical feature of OI type
      XII in the index patient.
- name: Reduced Bone Mineral Density
  description: >-
    Osteoporosis and low bone mineral density reflecting the deficient
    osteoblast-mediated bone formation.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a novel Sp7/Osx variant in another sibship that
      presented with osteoporosis, low-trauma fractures and short stature.
    explanation: >-
      Documents osteoporosis (reduced bone mineral density) as a feature of OI
      type XII.
- name: Short Stature
  description: >-
    Short stature / growth deficiency, part of the OI type XII phenotype.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a novel Sp7/Osx variant in another sibship that
      presented with osteoporosis, low-trauma fractures and short stature.
    explanation: >-
      Documents short stature (growth deficiency) as part of the OI type XII
      phenotype.
- name: Bone Deformity
  description: >-
    Mild bone deformity, including bowing of the long bones, accompanies the
    fragility in OI type XII.
  phenotype_term:
    preferred_term: Bone deformity (bowing of the long bones)
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical findings from this patient include recurrent fractures, mild
      bone deformities, delayed tooth eruption, normal hearing, and white sclera.
    explanation: >-
      Documents mild bone deformities (manifesting as long-bone bowing) as part
      of the OI type XII phenotype.
- name: Delayed Tooth Eruption
  description: >-
    Delayed eruption of the teeth was documented in the index OI type XII child,
    reflecting the osteoblast/odontoblast-lineage role of Osterix (SP7) in
    mineralized-tissue formation. It is distinct from the dentinogenesis
    imperfecta seen in collagen-related OI: the index patient had white (normal)
    sclera and delayed rather than dysplastic dentition.
  phenotype_term:
    preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  evidence:
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical findings from this patient include recurrent fractures, mild
      bone deformities, delayed tooth eruption, normal hearing, and white sclera.
    explanation: >-
      Documents delayed tooth eruption in the index OI type XII patient.
- name: Progressive Hearing Impairment
  description: >-
    Progressive moderate-to-severe to severe-to-profound hearing loss was
    identified in two siblings of the second SP7/Osx sibship, secondary to
    otospongiosis and poor mineralization of the ossicles and petrous temporal
    bone. This established hearing loss as a potential distinguishing feature of
    OI type XII (the index patient of the first report had normal hearing), and
    the authors recommend early audiology screening. Sp7/Osx additionally
    regulates biomineralization of the otoconia/otoliths of the inner ear in
    animal models, offering a mechanistic link to the auditory phenotype.
  phenotype_term:
    preferred_term: Progressive hearing impairment
    term:
      id: HP:0001730
      label: Progressive hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive moderate-to-severe and severe-to-profound hearing loss
      secondary to otospongiosis and poor mineralization of ossicles and petrous
      temporal bone was also noted in two of the siblings.
    explanation: >-
      Documents progressive hearing loss (from ossicle/petrous mineralization
      defects) as a distinguishing feature of OI type XII in the second sibship.
  - reference: PMID:29382611
    reference_title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it is the
      first to describe the bone histomorphometry associated with this disorder and
      identifies a significant hearing loss as a potential feature in this OI subtype.
    explanation: >-
      Confirms hearing loss as a newly recognized potential feature of the SP7/Osx
      OI subtype, warranting early audiology screening.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XII is suspected in a child with recessive OI (recurrent low-trauma
    fractures, low bone mineral density, mild deformity, short stature, with or
    without hearing loss) when COL1A1/COL1A2 and the other recessive OI genes are
    negative. Diagnosis is confirmed by identifying a biallelic SP7 (Osterix)
    loss-of-function variant by gene-panel or exome sequencing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20579626
    reference_title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using a combination of homozygosity mapping and candidate gene approach,
      we have identified a homozygous single base pair deletion (c.1052delA) in
      SP7/Osterix (OSX)
    explanation: >-
      Molecular identification of a biallelic SP7 variant establishes the
      diagnosis of OI type XII.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the
    pharmacological mainstay of more severe OI, increasing bone mineral density
    and reducing fracture frequency. They are antiresorptive and do not correct
    the underlying osteoblast-differentiation 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 XII.
- 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:20579626
  title: "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta."
- reference: PMID:29382611
  title: "Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment."
- reference: PMID:11792318
  title: "The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

4
PMID:20579626
Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:29382611
Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment.
No top-level findings curated for this source.
PMID:11792318
The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.