Osteogenesis Imperfecta Type XXIII

Mendelian MONDO:0957988 Pathograph 2 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XXIII (OI type XXIII; OMIM 620639) is an ultra-rare, recently described autosomal recessive brittle bone disorder caused by biallelic loss-of-function variants in PHLDB1, the gene encoding pleckstrin homology-like domain family B member 1. It was first defined in 2022 in five affected children from two unrelated families carrying biallelic PHLDB1 frameshift variants. The reported phenotype is a distinctive "mild-type" OI: recurrent fractures and/or osteopenia, platyspondyly, short and bowed long bones, and widened metaphyses, with the metaphyseal and vertebral changes regressing after early childhood and no further fractures occurring under bisphosphonate treatment. The precise molecular mechanism by which PHLDB1 loss causes brittle bone is still emerging and has not been fully established. PHLDB1 protein has a reported role in insulin-dependent Akt phosphorylation; in patient blood and skin fibroblasts, PHLDB1 mRNA expression was decreased and western blot confirmed loss of PHLDB1 protein, supporting the causative role of the biallelic variants. How loss of PHLDB1 translates into the observed skeletal fragility and matrix changes remains an open question and should not be overstated.

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1
Inheritance
2
Pathophys.
6
Phenotypes
1
Gaps
2
Pathograph
1
Genes
3
Medical Actions
2
References
🏷

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from biallelic loss-of-function PHLDB1 frameshift variants; heterozygous parents are unaffected carriers.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"Two biallelic frameshift variants in the candidate gene PHLDB1 were identified in independent families with a novel, mild-type, autosomal recessive OI."
Establishes the autosomal recessive inheritance of OI type XXIII from biallelic PHLDB1 frameshift variants.
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Discussions and Knowledge Gaps

1
By what molecular mechanism does biallelic loss of PHLDB1 (pleckstrin homology-like domain family B member 1) produce brittle bone with regressive spondylometaphyseal changes? The only reported cellular role of PHLDB1 is in insulin-dependent Akt phosphorylation, and PHLDB1 has been localized to laminin-5-containing cell-adhesion sites, but neither observation has been causally connected to osteoblast function, type I collagen matrix production, or bone mineralization. Is the skeletal fragility driven by an osteoblast-autonomous PI3K/Akt signaling deficit, by an adhesion/matrix defect, by ER-stress/proteostasis dysregulation (the convergent cellular pathology proposed across OI subtypes), or by another pathway — and what explains the distinctive regression of the metaphyseal and vertebral changes after early childhood?
KNOWLEDGE GAP OPEN gap_oi23_phldb1_bone_mechanism_undefined
Attached to
pathophysiology#Biallelic PHLDB1 Loss-of-Function Eliminates PHLDB1 Protein pathophysiology#Defective Bone Formation and Skeletal Fragility
OI type XXIII is defined by a single 2022 report of five children from two unrelated families (PMID:36543534); that report establishes causation (biallelic PHLDB1 frameshift alleles, reduced PHLDB1 mRNA, and loss of PHLDB1 protein in patient fibroblasts) but explicitly leaves the intervening mechanism open, noting only PHLDB1's reported role in insulin-dependent Akt phosphorylation. Consequently the entry models the pathograph with a proximal lesion node and a downstream bone-phenotype node but no committed intermediate mechanistic node, and the description deliberately states the mechanism "should not be overstated." The gap is genuine rather than a curation omission: no independent cohort or functional study has connected PHLDB1 loss to a specific osteoblast/matrix pathway, so the intermediate step is left as an explicit open question rather than fabricated. This is a KNOWLEDGE_GAP (evidence absent), not a HUMAN_MODEL_MISMATCH (no model system yet reproduces or contradicts a proposed human mechanism to compare against).
Proposed experiments
PHLDB1-null iPSC-derived osteoblast PI3K/Akt signaling and mineralization assay
iPSC-derived osteoblast perturbation assay Relation: this experiment is of type this experiment type This experiment is of type iPSC-derived osteoblast perturbation assay.
exp_oi23_phldb1_ipsc_osteoblast_akt
Differentiate osteoblasts from PHLDB1-null (patient-derived or gene-edited) and isogenic-control human iPSCs and quantify insulin/IGF-1-stimulated Akt phosphorylation, osteoblast-differentiation markers (RUNX2, SP7, ALPL), type I collagen (COL1A1) secretion, and in-vitro matrix mineralization. This tests whether the reported PHLDB1 role in insulin-dependent Akt phosphorylation is the osteoblast-autonomous mechanism linking PHLDB1 loss to defective bone formation.
Model systems
PHLDB1-null human iPSC-derived osteoblast
Osteoblasts differentiated from patient-derived or CRISPR-edited human iPSCs lacking PHLDB1, compared to isogenic PHLDB1-intact controls.
IPSC DERIVED MODEL
ER-stress and collagen-proteostasis profiling of PHLDB1-deficient bone cells
ER-stress and proteostasis assay Relation: this experiment is of type this experiment type This experiment is of type ER-stress and proteostasis assay.
exp_oi23_phldb1_er_stress_proteostasis
Assay unfolded-protein-response activation (BiP/HSPA5, ATF4, CHOP, spliced XBP1), intracellular procollagen retention, and secreted-versus-retained type I collagen in PHLDB1-deficient osteoblasts/fibroblasts versus controls, to test whether OI type XXIII shares the ER-stress/disrupted-proteostasis convergent cellular pathology proposed across collagen and non-collagen OI subtypes, rather than acting solely through Akt signaling.
Model systems
PHLDB1-deficient patient skin fibroblast
Cultured dermal fibroblasts from OI type XXIII probands (in which reduced PHLDB1 mRNA and loss of PHLDB1 protein were already documented), used to profile ER-stress and collagen-secretion phenotypes.
PRIMARY CELL CULTURE
Resolving this gap would either add a committed intermediate pathophysiology node (e.g., an Akt-signaling or ER-stress/proteostasis mechanism) or confirm that OI type XXIII is a signaling/adhesion OI whose bone mechanism is distinct from the collagen-defect and RIP/OASIS (CREB3L1/MBTPS2) subtypes. Per issue #5079 (item 4), a deep-research pass confirmed the mechanism gap is genuine as of mid-2026; no independent functional study has closed it.
⚙

Pathophysiology

2
Biallelic PHLDB1 Loss-of-Function Eliminates PHLDB1 Protein
PHLDB1 encodes pleckstrin homology-like domain family B member 1, a protein with a reported role in insulin-dependent Akt phosphorylation. In OI type XXIII, biallelic frameshift variants reduce PHLDB1 mRNA expression in blood and skin fibroblasts and abolish the protein, as confirmed by western blot of cultured patient fibroblasts. This loss of PHLDB1 is the proximal molecular lesion; the downstream pathway by which it impairs bone is not yet established.
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. 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
Downstream
Defective Bone Formation and Skeletal Fragility Loss of PHLDB1 leads, through an as-yet-undefined mechanism, to a bone-fragility and spondylometaphyseal phenotype.
Show evidence (2 references)
PMID:36543534 SUPPORT Human Clinical
"PHLDB1 encodes pleckstrin homology-like domain family B member-1 (PHLDB1) protein, which has a role in insulin-dependent Akt phosphorylation."
Identifies PHLDB1 and its only reported molecular role (insulin-dependent Akt phosphorylation); the bone-specific role is not established.
PMID:36543534 SUPPORT In Vitro
"Compared with controls, a decrease in the expression levels of PHLDB1 in the blood and skin fibroblast samples was detected. Western blot analysis of cultured fibroblasts further confirmed the loss of PHLDB1."
Documents reduced PHLDB1 mRNA and loss of PHLDB1 protein in patient fibroblasts, supporting loss of function as the proximal lesion.
Defective Bone Formation and Skeletal Fragility
Loss of PHLDB1 produces a mild OI phenotype with recurrent fractures and/or osteopenia together with characteristic spondylometaphyseal changes (platyspondyly, short and bowed long bones, widened metaphyses). A distinctive feature is that the metaphyseal and vertebral changes regress after early childhood. Because the molecular link between PHLDB1 loss and the bone matrix defect has not been established, the mechanism connecting the proximal lesion to the skeletal phenotype remains tentative and is described here only at the level of the observed bone phenotype.
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.
ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ⚠ ABNORMAL 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:36543534 SUPPORT Human Clinical
"The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses."
Documents the bone-fragility and spondylometaphyseal skeletal phenotype that results from PHLDB1 loss of function.
PMID:36543534 SUPPORT Human Clinical
"Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment."
Documents the distinctive regressive course of the spondylometaphyseal changes and the response to bisphosphonate therapy.
⬡

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

Phenotypes

6
Limbs 2
Bowing of the Long Bones HP:0006487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bowing of the long bones (HP:0006487). HP:0006487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses."
Documents bowed long bones as a common finding in OI type XXIII patients.
Metaphyseal Widening HP:0003016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal widening (HP:0003016). HP:0003016 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses."
Documents widened metaphyses as a common metaphyseal finding in OI type XXIII.
Musculoskeletal 3
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:36543534 SUPPORT Human Clinical
"The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses."
Documents recurrent fractures as a common finding in OI type XXIII patients.
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses."
Documents osteopenia as a common finding in OI type XXIII patients.
Platyspondyly HP:0000926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Platyspondyly (HP:0000926). HP:0000926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses."
Documents platyspondyly as a common spondylometaphyseal finding in OI type XXIII.
Other 1
Short Long Bones HP:0003026 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short long bone (HP:0003026). HP:0003026 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses."
Documents short long bones as a common finding in OI type XXIII patients.
🧬

Genetic Associations

1
PHLDB1 Loss-of-Function (Frameshift) Variants (Causative)
Gene: PHLDB1 (pleckstrin homology-like domain family B member 1) hgnc:23697 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PHLDB1 (pleckstrin homology-like domain family B member 1), annotated with PHLDB1 (hgnc:23697). hgnc:23697 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"We identified biallelic NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del pathogenic variants in PHLDB1 in the affected patients, respectively, in the families; parents were heterozygous for these variants."
Identifies the causative biallelic PHLDB1 frameshift variants and their recessive segregation defining OI type XXIII.
💊

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
Bisphosphonate treatment was used in the reported OI type XXIII patients; notably, no fractures occurred under bisphosphonate treatment, consistent with the antiresorptive benefit of bisphosphonates in OI generally.
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment."
Documents that no fractures occurred under bisphosphonate treatment in OI type XXIII patients.
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 rodding and corrective orthopedic surgery are standard management options for fracture-prone, deformed long bones across OI; they may be considered in OI type XXIII for symptomatic deformity, though the mild, regressive course of this type often limits the need for surgery.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"intramedullary rodding when"
GeneReviews documents intramedullary rodding as standard orthopedic management for OI long-bone fractures and deformity, applicable to OI when surgically indicated.
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 therapy supports mobility and muscle strength and follows brief post-fracture immobilization; it is part of standard supportive OI care applicable to OI type XXIII.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"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 XXIII is suspected in a child with mild OI showing recurrent fractures and/or osteopenia together with regressive spondylometaphyseal changes (platyspondyly, short/bowed long bones, widened metaphyses). Because these features overlap other forms of OI and spondylometaphyseal dysplasia, diagnosis rests on identifying biallelic PHLDB1 loss-of-function variants by whole-exome or gene-panel sequencing; reduced PHLDB1 mRNA and loss of PHLDB1 protein in patient fibroblasts are supportive.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:36543534 SUPPORT Human Clinical
"Whole-exome sequencing and clinical evaluation were performed in five patients from two unrelated families."
Documents whole-exome sequencing as the method that established the molecular diagnosis of OI type XXIII.
📊

Prevalence

1
General (worldwide)
OI type XXIII is ultra-rare. As of the defining 2022 report, only five affected children from two unrelated families had been described; no population-level prevalence estimate is available.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XXIII
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta, type 23
  term:
    id: MONDO:0957988
    label: osteogenesis imperfecta, type 23
description: >-
  Osteogenesis imperfecta type XXIII (OI type XXIII; OMIM 620639) is an
  ultra-rare, recently described autosomal recessive brittle bone disorder
  caused by biallelic loss-of-function variants in PHLDB1, the gene encoding
  pleckstrin homology-like domain family B member 1. It was first defined in
  2022 in five affected children from two unrelated families carrying biallelic
  PHLDB1 frameshift variants. The reported phenotype is a distinctive
  "mild-type" OI: recurrent fractures and/or osteopenia, platyspondyly, short
  and bowed long bones, and widened metaphyses, with the metaphyseal and
  vertebral changes regressing after early childhood and no further fractures
  occurring under bisphosphonate treatment. The precise molecular mechanism by
  which PHLDB1 loss causes brittle bone is still emerging and has not been fully
  established. PHLDB1 protein has a reported role in insulin-dependent Akt
  phosphorylation; in patient blood and skin fibroblasts, PHLDB1 mRNA expression
  was decreased and western blot confirmed loss of PHLDB1 protein, supporting
  the causative role of the biallelic variants. How loss of PHLDB1 translates
  into the observed skeletal fragility and matrix changes remains an open
  question and should not be overstated.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic loss-of-function PHLDB1
    frameshift variants; heterozygous parents are unaffected carriers.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two biallelic frameshift variants in the candidate gene PHLDB1 were
      identified in independent families with a novel, mild-type, autosomal
      recessive OI.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type XXIII from
      biallelic PHLDB1 frameshift variants.
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.
prevalence:
- population: General (worldwide)
  notes: >-
    OI type XXIII is ultra-rare. As of the defining 2022 report, only five
    affected children from two unrelated families had been described; no
    population-level prevalence estimate is available.
pathophysiology:
- name: Biallelic PHLDB1 Loss-of-Function Eliminates PHLDB1 Protein
  description: >-
    PHLDB1 encodes pleckstrin homology-like domain family B member 1, a protein
    with a reported role in insulin-dependent Akt phosphorylation. In OI type
    XXIII, biallelic frameshift variants reduce PHLDB1 mRNA expression in blood
    and skin fibroblasts and abolish the protein, as confirmed by western blot
    of cultured patient fibroblasts. This loss of PHLDB1 is the proximal
    molecular lesion; the downstream pathway by which it impairs bone is not yet
    established.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PHLDB1 encodes pleckstrin homology-like domain family B member-1 (PHLDB1)
      protein, which has a role in insulin-dependent Akt phosphorylation.
    explanation: >-
      Identifies PHLDB1 and its only reported molecular role (insulin-dependent
      Akt phosphorylation); the bone-specific role is not established.
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared with controls, a decrease in the expression levels of PHLDB1 in
      the blood and skin fibroblast samples was detected. Western blot analysis
      of cultured fibroblasts further confirmed the loss of PHLDB1.
    explanation: >-
      Documents reduced PHLDB1 mRNA and loss of PHLDB1 protein in patient
      fibroblasts, supporting loss of function as the proximal lesion.
  downstream:
  - target: Defective Bone Formation and Skeletal Fragility
    description: >-
      Loss of PHLDB1 leads, through an as-yet-undefined mechanism, to a
      bone-fragility and spondylometaphyseal phenotype.
- name: Defective Bone Formation and Skeletal Fragility
  description: >-
    Loss of PHLDB1 produces a mild OI phenotype with recurrent fractures and/or
    osteopenia together with characteristic spondylometaphyseal changes
    (platyspondyly, short and bowed long bones, widened metaphyses). A
    distinctive feature is that the metaphyseal and vertebral changes regress
    after early childhood. Because the molecular link between PHLDB1 loss and the
    bone matrix defect has not been established, the mechanism connecting the
    proximal lesion to the skeletal phenotype remains tentative and is described
    here only at the level of the observed bone phenotype.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common findings among the five affected children were recurrent
      fractures and/or osteopaenia, platyspondyly, short and bowed long bones,
      and widened metaphyses.
    explanation: >-
      Documents the bone-fragility and spondylometaphyseal skeletal phenotype
      that results from PHLDB1 loss of function.
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal and vertebral changes regressed after early childhood, and no
      fractures occurred under bisphosphonate treatment.
    explanation: >-
      Documents the distinctive regressive course of the spondylometaphyseal
      changes and the response to bisphosphonate therapy.
discussions:
- discussion_id: gap_oi23_phldb1_bone_mechanism_undefined
  prompt: >-
    By what molecular mechanism does biallelic loss of PHLDB1 (pleckstrin
    homology-like domain family B member 1) produce brittle bone with regressive
    spondylometaphyseal changes? The only reported cellular role of PHLDB1 is in
    insulin-dependent Akt phosphorylation, and PHLDB1 has been localized to
    laminin-5-containing cell-adhesion sites, but neither observation has been
    causally connected to osteoblast function, type I collagen matrix production,
    or bone mineralization. Is the skeletal fragility driven by an
    osteoblast-autonomous PI3K/Akt signaling deficit, by an adhesion/matrix
    defect, by ER-stress/proteostasis dysregulation (the convergent cellular
    pathology proposed across OI subtypes), or by another pathway — and what
    explains the distinctive regression of the metaphyseal and vertebral changes
    after early childhood?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic PHLDB1 Loss-of-Function Eliminates PHLDB1 Protein
  - pathophysiology#Defective Bone Formation and Skeletal Fragility
  rationale: >-
    OI type XXIII is defined by a single 2022 report of five children from two
    unrelated families (PMID:36543534); that report establishes causation
    (biallelic PHLDB1 frameshift alleles, reduced PHLDB1 mRNA, and loss of PHLDB1
    protein in patient fibroblasts) but explicitly leaves the intervening
    mechanism open, noting only PHLDB1's reported role in insulin-dependent Akt
    phosphorylation. Consequently the entry models the pathograph with a proximal
    lesion node and a downstream bone-phenotype node but no committed
    intermediate mechanistic node, and the description deliberately states the
    mechanism "should not be overstated." The gap is genuine rather than a
    curation omission: no independent cohort or functional study has connected
    PHLDB1 loss to a specific osteoblast/matrix pathway, so the intermediate step
    is left as an explicit open question rather than fabricated. This is a
    KNOWLEDGE_GAP (evidence absent), not a HUMAN_MODEL_MISMATCH (no model system
    yet reproduces or contradicts a proposed human mechanism to compare against).
  proposed_experiments:
  - experiment_id: exp_oi23_phldb1_ipsc_osteoblast_akt
    name: >-
      PHLDB1-null iPSC-derived osteoblast PI3K/Akt signaling and mineralization
      assay
    description: >-
      Differentiate osteoblasts from PHLDB1-null (patient-derived or gene-edited)
      and isogenic-control human iPSCs and quantify insulin/IGF-1-stimulated Akt
      phosphorylation, osteoblast-differentiation markers (RUNX2, SP7, ALPL),
      type I collagen (COL1A1) secretion, and in-vitro matrix mineralization.
      This tests whether the reported PHLDB1 role in insulin-dependent Akt
      phosphorylation is the osteoblast-autonomous mechanism linking PHLDB1 loss
      to defective bone formation.
    experiment_type:
      preferred_term: iPSC-derived osteoblast perturbation assay
    model_systems:
    - name: PHLDB1-null human iPSC-derived osteoblast
      description: >-
        Osteoblasts differentiated from patient-derived or CRISPR-edited human
        iPSCs lacking PHLDB1, compared to isogenic PHLDB1-intact controls.
      experimental_model_type: IPSC_DERIVED_MODEL
  - experiment_id: exp_oi23_phldb1_er_stress_proteostasis
    name: >-
      ER-stress and collagen-proteostasis profiling of PHLDB1-deficient bone
      cells
    description: >-
      Assay unfolded-protein-response activation (BiP/HSPA5, ATF4, CHOP,
      spliced XBP1), intracellular procollagen retention, and
      secreted-versus-retained type I collagen in PHLDB1-deficient
      osteoblasts/fibroblasts versus controls, to test whether OI type XXIII
      shares the ER-stress/disrupted-proteostasis convergent cellular pathology
      proposed across collagen and non-collagen OI subtypes, rather than acting
      solely through Akt signaling.
    experiment_type:
      preferred_term: ER-stress and proteostasis assay
    model_systems:
    - name: PHLDB1-deficient patient skin fibroblast
      description: >-
        Cultured dermal fibroblasts from OI type XXIII probands (in which reduced
        PHLDB1 mRNA and loss of PHLDB1 protein were already documented), used to
        profile ER-stress and collagen-secretion phenotypes.
      experimental_model_type: PRIMARY_CELL_CULTURE
  notes: >-
    Resolving this gap would either add a committed intermediate pathophysiology
    node (e.g., an Akt-signaling or ER-stress/proteostasis mechanism) or confirm
    that OI type XXIII is a signaling/adhesion OI whose bone mechanism is
    distinct from the collagen-defect and RIP/OASIS (CREB3L1/MBTPS2) subtypes.
    Per issue #5079 (item 4), a deep-research pass confirmed the mechanism gap is
    genuine as of mid-2026; no independent functional study has closed it.
genetic:
- name: PHLDB1 Loss-of-Function (Frameshift) Variants
  association: Causative
  gene_term:
    preferred_term: PHLDB1 (pleckstrin homology-like domain family B member 1)
    term:
      id: hgnc:23697
      label: PHLDB1
  notes: >-
    OI type XXIII is caused by biallelic loss-of-function variants in PHLDB1.
    The defining report identified two frameshift alleles
    (NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del), each segregating
    as homozygous/biallelic within one of two unrelated families, with
    heterozygous unaffected parents. PHLDB1 is the only gene associated with this
    OI type to date and the molecular consequence is loss of PHLDB1 protein.
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified biallelic NM_001144758.3:c.2392dup and
      NM_001144758.3:c.2690_2693del pathogenic variants in PHLDB1 in the
      affected patients, respectively, in the families; parents were
      heterozygous for these variants.
    explanation: >-
      Identifies the causative biallelic PHLDB1 frameshift variants and their
      recessive segregation defining OI type XXIII.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Recurrent fractures, the cardinal feature of OI, occur in OI type XXIII,
    though the overall phenotype is mild and fractures ceased under
    bisphosphonate treatment.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common findings among the five affected children were recurrent
      fractures and/or osteopaenia, platyspondyly, short and bowed long bones,
      and widened metaphyses.
    explanation: >-
      Documents recurrent fractures as a common finding in OI type XXIII
      patients.
- name: Osteopenia
  description: >-
    Osteopenia (reduced bone mass) is a common finding in OI type XXIII,
    consistent with the mild brittle-bone phenotype.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common findings among the five affected children were recurrent
      fractures and/or osteopaenia, platyspondyly, short and bowed long bones,
      and widened metaphyses.
    explanation: >-
      Documents osteopenia as a common finding in OI type XXIII patients.
- name: Platyspondyly
  description: >-
    Platyspondyly (flattening of the vertebral bodies) is a characteristic
    vertebral change in OI type XXIII that regresses after early childhood.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common findings among the five affected children were recurrent
      fractures and/or osteopaenia, platyspondyly, short and bowed long bones,
      and widened metaphyses.
    explanation: >-
      Documents platyspondyly as a common spondylometaphyseal finding in OI
      type XXIII.
- name: Short Long Bones
  description: >-
    Short and bowed long bones are part of the spondylometaphyseal skeletal
    phenotype of OI type XXIII.
  phenotype_term:
    preferred_term: Short long bone
    term:
      id: HP:0003026
      label: Short long bone
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common findings among the five affected children were recurrent
      fractures and/or osteopaenia, platyspondyly, short and bowed long bones,
      and widened metaphyses.
    explanation: >-
      Documents short long bones as a common finding in OI type XXIII patients.
- name: Bowing of the Long Bones
  description: >-
    Bowing of the long bones accompanies the short long bones in OI type XXIII,
    reflecting the mechanically weak bone.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common findings among the five affected children were recurrent
      fractures and/or osteopaenia, platyspondyly, short and bowed long bones,
      and widened metaphyses.
    explanation: >-
      Documents bowed long bones as a common finding in OI type XXIII patients.
- name: Metaphyseal Widening
  description: >-
    Widened metaphyses are a characteristic metaphyseal change in OI type XXIII
    that, like the vertebral changes, regresses after early childhood.
  phenotype_term:
    preferred_term: Metaphyseal widening
    term:
      id: HP:0003016
      label: Metaphyseal widening
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common findings among the five affected children were recurrent
      fractures and/or osteopaenia, platyspondyly, short and bowed long bones,
      and widened metaphyses.
    explanation: >-
      Documents widened metaphyses as a common metaphyseal finding in OI type
      XXIII.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XXIII is suspected in a child with mild OI showing recurrent
    fractures and/or osteopenia together with regressive spondylometaphyseal
    changes (platyspondyly, short/bowed long bones, widened metaphyses). Because
    these features overlap other forms of OI and spondylometaphyseal dysplasia,
    diagnosis rests on identifying biallelic PHLDB1 loss-of-function variants by
    whole-exome or gene-panel sequencing; reduced PHLDB1 mRNA and loss of PHLDB1
    protein in patient fibroblasts are supportive.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing and clinical evaluation were performed in five
      patients from two unrelated families.
    explanation: >-
      Documents whole-exome sequencing as the method that established the
      molecular diagnosis of OI type XXIII.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Bisphosphonate treatment was used in the reported OI type XXIII patients;
    notably, no fractures occurred under bisphosphonate treatment, consistent
    with the antiresorptive benefit of bisphosphonates in OI generally.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:36543534
    reference_title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metaphyseal and vertebral changes regressed after early childhood, and no
      fractures occurred under bisphosphonate treatment.
    explanation: >-
      Documents that no fractures occurred under bisphosphonate treatment in OI
      type XXIII patients.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary rodding and corrective orthopedic surgery are standard
    management options for fracture-prone, deformed long bones across OI; they
    may be considered in OI type XXIII for symptomatic deformity, though the
    mild, regressive course of this type often limits the need for surgery.
  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
    explanation: >-
      GeneReviews documents intramedullary rodding as standard orthopedic
      management for OI long-bone fractures and deformity, applicable to OI when
      surgically indicated.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical therapy supports mobility and muscle strength and follows brief
    post-fracture immobilization; it is part of standard supportive OI care
    applicable to OI type XXIII.
  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: >-
      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:36543534
  title: "Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

2
PMID:36543534
Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.