Osteogenesis Imperfecta Type XVIII

Mendelian MONDO:0044329 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XVIII (OI type XVIII; OMIM 617952) is a severe autosomal recessive brittle bone disease caused by biallelic loss-of-function variants in TENT5A (terminal nucleotidyltransferase 5A; previously named FAM46A). TENT5A is a non-canonical cytoplasmic poly(A) polymerase that is induced during osteoblast differentiation and polyadenylates mRNAs encoding type I collagen (Col1a1, Col1a2) and other secreted bone extracellular-matrix proteins, thereby stabilizing those transcripts and increasing their expression. Biallelic TENT5A loss removes this post-transcriptional support, destabilizing the osteoblast secretome mRNAs and reducing production of bone matrix proteins, including type I collagen. The resulting quantitative and qualitative collagen defect yields a defective, hypomineralized bone matrix and skeletal fragility, clinically manifesting as congenital bowing of the long bones, recurrent fractures, vertebral collapse, blue sclerae, wormian bones, and bone deformity in the first years of life. The disorder was defined in consanguineous human kindreds (Doyard et al., 2018) and is recapitulated by the Tent5a-knockout mouse, which displays bone fragility and skeletal hypomineralization from quantitative and qualitative collagen defects.

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🏷

Classifications

ISDS Skeletal Nosology

👪

Inheritance

Autosomal Recessive HP:0000007

Autosomal recessive inheritance from biallelic (homozygous) loss-of-function TENT5A (FAM46A) variants; heterozygous carriers are clinically unaffected.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:29358272 SUPPORT Human Clinical

"We conclude that FAM46A mutations are responsible for a severe form of OI with congenital bowing of the lower limbs"

Establishes that biallelic FAM46A (TENT5A) mutations cause autosomal recessive OI (type XVIII).

⚙

Pathophysiology

TENT5A (FAM46A) Loss Eliminates Cytoplasmic Polyadenylation of Osteoblast ECM mRNAs

TENT5A (terminal nucleotidyltransferase 5A, previously FAM46A) is a non-canonical cytoplasmic poly(A) polymerase that is induced during osteoblast differentiation and polyadenylates mRNAs encoding type I collagen (Col1a1, Col1a2) and other secreted proteins involved in osteogenesis, stabilizing them and increasing their expression. FAM46A/TENT5A is specifically expressed in human osteoblasts. Biallelic loss-of-function TENT5A variants eliminate this cytoplasmic polyadenylation activity, the proximal molecular lesion of the disorder.

osteoblast CL:0000062 fibroblast CL:0000057

cytoplasmic polyadenylation of secretome mRNAs (mRNA stabilization) GO:0048255 ↓ DECREASED

Downstream

Destabilized Collagen/ECM Transcripts and Reduced Bone Matrix Protein Output Without TENT5A-dependent cytoplasmic polyadenylation, the collagen and secreted-matrix mRNAs are no longer stabilized, so production of type I collagen and other bone matrix proteins falls.

Show evidence (3 references)

PMID:33882302 SUPPORT In Vitro

"TENT5A, whose mutations were found in congenital bone disease osteogenesis imperfecta patients, is a cytoplasmic poly(A) polymerase playing a crucial role in regulating bone mineralization."

Identifies TENT5A as the cytoplasmic poly(A) polymerase whose loss causes OI, the proximal lesion of type XVIII.

PMID:33882302 SUPPORT In Vitro

"TENT5A is induced during osteoblast differentiation and polyadenylates mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in osteogenesis, increasing their expression."

Documents the molecular function lost in OI type XVIII: TENT5A polyadenylates collagen and secretome mRNAs in differentiating osteoblasts to increase their expression.

PMID:29358272 SUPPORT Human Clinical

"By RT-PCR analysis, we detected specific expression of FAM46A in human osteoblasts"

Documents osteoblast-specific expression of FAM46A/TENT5A, consistent with its osteoblast-restricted role in bone matrix mRNA regulation.

Destabilized Collagen/ECM Transcripts and Reduced Bone Matrix Protein Output

Loss of TENT5A cytoplasmic polyadenylation removes the post-transcriptional support for osteoblast secretome transcripts, reducing expression of type I collagen (Col1a1, Col1a2) and other matrix proteins. The result is a quantitative and qualitative deficit in collagen and bone matrix protein output by osteoblasts, the post-transcriptional counterpart of the collagen defects seen in classical (COL1A1/COL1A2) OI.

osteoblast CL:0000062

collagen biosynthetic process GO:0032964 ↓ DECREASED regulation of mRNA stability (collagen/secretome transcripts) GO:0043488 ⚠ ABNORMAL

Downstream

Defective Hypomineralized Bone Matrix and Skeletal Fragility Reduced and qualitatively abnormal collagen yields a defective bone extracellular matrix that fails to mineralize normally, producing skeletal fragility.

Show evidence (2 references)

PMID:33882302 SUPPORT Model Organism

"the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects."

Links loss of TENT5A polyadenylation to quantitative and qualitative collagen defects in osteoblasts, the matrix-protein deficit underlying OI type XVIII.

PMID:33882302 SUPPORT In Vitro

"Osteoblasts orchestrate bone formation through the secretion of type I collagen and other constituents of the matrix on which hydroxyapatite crystals mineralize."

Establishes that osteoblast secretion of type I collagen and matrix proteins is the function impaired when TENT5A-stabilized transcripts are lost.

Defective Hypomineralized Bone Matrix and Skeletal Fragility

The quantitative and qualitative collagen deficit yields a defective bone extracellular matrix with impaired (hypo)mineralization and reduced mechanical strength. Clinically this manifests as congenital bowing of the long bones, recurrent fractures, vertebral collapse, reduced bone mineral density, and bone deformity in the first years of life.

osteoblast CL:0000062

bone mineralization GO:0030282 ↓ DECREASED ossification GO:0001503 ⚠ ABNORMAL

Show evidence (2 references)

PMID:33882302 SUPPORT Model Organism

"the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects."

Demonstrates that TENT5A loss produces bone fragility and skeletal hypomineralization, the bone-matrix endpoint of OI type XVIII.

PMID:29358272 SUPPORT Model Organism

"a nonsense mutation in Fam46a has been recently identified in an ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities and reduced cortical thickness in long bones."

An independent Fam46a mutant mouse recapitulates skeletal deformity and reduced cortical bone, supporting the defective-bone-matrix endpoint.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Eye 1

Blue Sclerae HP:0000592

Show evidence (1 reference)

PMID:29358272 SUPPORT Human Clinical

"The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae."

Documents blue sclerae as a defining clinical feature that, together with vertebral collapses, established the OI diagnosis in the index FAM46A/TENT5A (type XVIII) case.

Limbs 1

Congenital Bowing of the Long Bones HP:0006487

Show evidence (1 reference)

PMID:29358272 SUPPORT Human Clinical

"We conclude that FAM46A mutations are responsible for a severe form of OI with congenital bowing of the lower limbs"

Documents congenital long-bone (lower-limb) bowing as a defining feature of FAM46A/TENT5A OI type XVIII.

Musculoskeletal 3

Recurrent Fractures HP:0002757

Show evidence (1 reference)

PMID:29358272 SUPPORT Human Clinical

"Survivors develop progressive scoliosis and spontaneous fractures."

Documents spontaneous fractures in the clinical spectrum of patients, consistent with the bone fragility of OI type XVIII.

Reduced Bone Mineral Density HP:0004349

Show evidence (1 reference)

PMID:33882302 SUPPORT Model Organism

"the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects."

The Tent5a-null mouse shows skeletal hypomineralization, the model correlate of reduced bone mineral density in OI type XVIII. Human reduced bone density is also implied by the vertebral collapses reported in patients.

Vertebral Collapse Vertebral compression fracture HP:0002953

Show evidence (1 reference)

PMID:29358272 SUPPORT Human Clinical

"The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae."

Documents vertebral collapses (compression) as a feature establishing the OI diagnosis in FAM46A/TENT5A disease.

Growth 1

Growth Deficiency Growth delay HP:0001510

Show evidence (1 reference)

PMID:29358272 SUPPORT Model Organism

"an ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities"

The Fam46a mutant mouse shows decreased body length (growth deficiency), a model correlate of the growth phenotype in OI type XVIII.

🧬

Genetic Associations

TENT5A (FAM46A) Loss-of-Function Mutations (Causative)

Gene: TENT5A (terminal nucleotidyltransferase 5A; cytoplasmic poly(A) polymerase) hgnc:18345

Show evidence (2 references)

PMID:29358272 SUPPORT Human Clinical

"We identified a homozygous deleterious variant in FAM46A in two affected sibs with typical OI"

Documents a causative homozygous FAM46A (TENT5A) variant segregating with OI, defining the disease gene for type XVIII.

PMID:29358272 SUPPORT Human Clinical

"FAM46A is a member of the superfamily of nucleotidyltransferase fold proteins"

Classifies FAM46A/TENT5A as a nucleotidyltransferase-fold protein, consistent with its later-defined poly(A) polymerase activity.

💊

Medical Actions

Bisphosphonate Therapy

Action: Bisphosphonate Therapy 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 post-transcriptional collagen 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 XVIII.

Orthopedic Surgery and Intramedullary Rodding

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize fracture-prone, bowed 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 therapy Ontology label: Physical Therapy NCIT:C15302

Physical and occupational therapy improve mobility and muscle strength and reduce fracture risk; 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

Molecular Genetic Diagnosis

OI type XVIII is suspected in an infant with severe recessive OI (congenital long-bone bowing, recurrent fractures, vertebral collapse, blue sclerae, wormian bones) when COL1A1/COL1A2 and other known OI genes are negative. Diagnosis is confirmed by identifying a biallelic TENT5A (FAM46A) loss-of-function variant by gene-panel or exome sequencing; screening of FAM46A/TENT5A is recommended in unexplained OI forms.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:29358272 SUPPORT Human Clinical

"suggest screening this gene in unexplained OI forms."

Recommends molecular screening of FAM46A/TENT5A to diagnose this form of OI in otherwise unexplained cases.

{ }

Source YAML

click to show

name: Osteogenesis Imperfecta Type XVIII
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 18
  term:
    id: MONDO:0044329
    label: osteogenesis imperfecta, type 18
description: >-
  Osteogenesis imperfecta type XVIII (OI type XVIII; OMIM 617952) is a severe
  autosomal recessive brittle bone disease caused by biallelic loss-of-function
  variants in TENT5A (terminal nucleotidyltransferase 5A; previously named
  FAM46A). TENT5A is a non-canonical cytoplasmic poly(A) polymerase that is
  induced during osteoblast differentiation and polyadenylates mRNAs encoding
  type I collagen (Col1a1, Col1a2) and other secreted bone extracellular-matrix
  proteins, thereby stabilizing those transcripts and increasing their
  expression. Biallelic TENT5A loss removes this post-transcriptional support,
  destabilizing the osteoblast secretome mRNAs and reducing production of bone
  matrix proteins, including type I collagen. The resulting quantitative and
  qualitative collagen defect yields a defective, hypomineralized bone matrix
  and skeletal fragility, clinically manifesting as congenital bowing of the
  long bones, recurrent fractures, vertebral collapse, blue sclerae, wormian
  bones, and bone deformity in the first years of life. The disorder was defined
  in consanguineous human kindreds (Doyard et al., 2018) and is recapitulated by
  the Tent5a-knockout mouse, which displays bone fragility and skeletal
  hypomineralization from quantitative and qualitative collagen defects.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic (homozygous) loss-of-function
    TENT5A (FAM46A) variants; heterozygous carriers are clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that FAM46A mutations are responsible for a severe form of OI
      with congenital bowing of the lower limbs
    explanation: >-
      Establishes that biallelic FAM46A (TENT5A) mutations cause autosomal
      recessive OI (type XVIII).
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: TENT5A (FAM46A) Loss Eliminates Cytoplasmic Polyadenylation of Osteoblast ECM mRNAs
  description: >-
    TENT5A (terminal nucleotidyltransferase 5A, previously FAM46A) is a
    non-canonical cytoplasmic poly(A) polymerase that is induced during
    osteoblast differentiation and polyadenylates mRNAs encoding type I collagen
    (Col1a1, Col1a2) and other secreted proteins involved in osteogenesis,
    stabilizing them and increasing their expression. FAM46A/TENT5A is
    specifically expressed in human osteoblasts. Biallelic loss-of-function
    TENT5A variants eliminate this cytoplasmic polyadenylation activity, the
    proximal molecular lesion of the disorder.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: cytoplasmic polyadenylation of secretome mRNAs (mRNA stabilization)
    term:
      id: GO:0048255
      label: mRNA stabilization
    modifier: DECREASED
  evidence:
  - reference: PMID:33882302
    reference_title: "Cytoplasmic polyadenylation by TENT5A is required for proper bone formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TENT5A, whose mutations were found in congenital bone disease osteogenesis
      imperfecta patients, is a cytoplasmic poly(A) polymerase playing a crucial
      role in regulating bone mineralization.
    explanation: >-
      Identifies TENT5A as the cytoplasmic poly(A) polymerase whose loss causes
      OI, the proximal lesion of type XVIII.
  - reference: PMID:33882302
    reference_title: "Cytoplasmic polyadenylation by TENT5A is required for proper bone formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TENT5A is induced during osteoblast differentiation and polyadenylates
      mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in
      osteogenesis, increasing their expression.
    explanation: >-
      Documents the molecular function lost in OI type XVIII: TENT5A
      polyadenylates collagen and secretome mRNAs in differentiating osteoblasts
      to increase their expression.
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By RT-PCR analysis, we detected specific expression of FAM46A in human
      osteoblasts
    explanation: >-
      Documents osteoblast-specific expression of FAM46A/TENT5A, consistent with
      its osteoblast-restricted role in bone matrix mRNA regulation.
  downstream:
  - target: Destabilized Collagen/ECM Transcripts and Reduced Bone Matrix Protein Output
    description: >-
      Without TENT5A-dependent cytoplasmic polyadenylation, the collagen and
      secreted-matrix mRNAs are no longer stabilized, so production of type I
      collagen and other bone matrix proteins falls.
- name: Destabilized Collagen/ECM Transcripts and Reduced Bone Matrix Protein Output
  description: >-
    Loss of TENT5A cytoplasmic polyadenylation removes the post-transcriptional
    support for osteoblast secretome transcripts, reducing expression of type I
    collagen (Col1a1, Col1a2) and other matrix proteins. The result is a
    quantitative and qualitative deficit in collagen and bone matrix protein
    output by osteoblasts, the post-transcriptional counterpart of the collagen
    defects seen in classical (COL1A1/COL1A2) OI.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: DECREASED
  - preferred_term: regulation of mRNA stability (collagen/secretome transcripts)
    term:
      id: GO:0043488
      label: regulation of mRNA stability
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33882302
    reference_title: "Cytoplasmic polyadenylation by TENT5A is required for proper bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the Tent5a knockout (KO) mouse line displays bone fragility and skeletal
      hypomineralization phenotype resulting from quantitative and qualitative
      collagen defects.
    explanation: >-
      Links loss of TENT5A polyadenylation to quantitative and qualitative
      collagen defects in osteoblasts, the matrix-protein deficit underlying OI
      type XVIII.
  - reference: PMID:33882302
    reference_title: "Cytoplasmic polyadenylation by TENT5A is required for proper bone formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Osteoblasts orchestrate bone formation through the secretion of type I
      collagen and other constituents of the matrix on which hydroxyapatite
      crystals mineralize.
    explanation: >-
      Establishes that osteoblast secretion of type I collagen and matrix
      proteins is the function impaired when TENT5A-stabilized transcripts are
      lost.
  downstream:
  - target: Defective Hypomineralized Bone Matrix and Skeletal Fragility
    description: >-
      Reduced and qualitatively abnormal collagen yields a defective bone
      extracellular matrix that fails to mineralize normally, producing skeletal
      fragility.
- name: Defective Hypomineralized Bone Matrix and Skeletal Fragility
  description: >-
    The quantitative and qualitative collagen deficit yields a defective bone
    extracellular matrix with impaired (hypo)mineralization and reduced
    mechanical strength. Clinically this manifests as congenital bowing of the
    long bones, recurrent fractures, vertebral collapse, reduced bone mineral
    density, and bone deformity in the first years of life.
  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: ABNORMAL
  evidence:
  - reference: PMID:33882302
    reference_title: "Cytoplasmic polyadenylation by TENT5A is required for proper bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the Tent5a knockout (KO) mouse line displays bone fragility and skeletal
      hypomineralization phenotype resulting from quantitative and qualitative
      collagen defects.
    explanation: >-
      Demonstrates that TENT5A loss produces bone fragility and skeletal
      hypomineralization, the bone-matrix endpoint of OI type XVIII.
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a nonsense mutation in Fam46a has been recently identified in an
      ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by decreased
      body length, limb, rib, pelvis, and skull deformities and reduced cortical
      thickness in long bones.
    explanation: >-
      An independent Fam46a mutant mouse recapitulates skeletal deformity and
      reduced cortical bone, supporting the defective-bone-matrix endpoint.
genetic:
- name: TENT5A (FAM46A) Loss-of-Function Mutations
  association: Causative
  gene_term:
    preferred_term: TENT5A (terminal nucleotidyltransferase 5A; cytoplasmic poly(A) polymerase)
    term:
      id: hgnc:18345
      label: TENT5A
  notes: >-
    OI type XVIII is caused by biallelic loss-of-function variants in TENT5A.
    The gene was previously named FAM46A (family with sequence similarity 46
    member A) and is the symbol used in the original disease-gene report.
    Reported alleles include a frameshift (p.Ser205Tyrfs*13) and homozygous
    missense variants classed as deleterious (p.His127Arg in two affected sibs;
    p.Asp231Gly in a type III OI patient of consanguineous parents). TENT5A is a
    member of the nucleotidyltransferase fold superfamily.
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a homozygous deleterious variant in FAM46A in two affected
      sibs with typical OI
    explanation: >-
      Documents a causative homozygous FAM46A (TENT5A) variant segregating with
      OI, defining the disease gene for type XVIII.
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FAM46A is a member of the superfamily of nucleotidyltransferase fold
      proteins
    explanation: >-
      Classifies FAM46A/TENT5A as a nucleotidyltransferase-fold protein,
      consistent with its later-defined poly(A) polymerase activity.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with multiple fractures, occurring in the first years
    of life, a cardinal feature of OI type XVIII.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survivors develop progressive scoliosis and spontaneous fractures.
    explanation: >-
      Documents spontaneous fractures in the clinical spectrum of patients,
      consistent with the bone fragility of OI type XVIII.
- name: Congenital Bowing of the Long Bones
  description: >-
    Congenital bowing and deformity of the long bones (notably the lower limbs)
    is a hallmark presenting feature of OI type XVIII, reflecting the fragile,
    deformable bone matrix.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that FAM46A mutations are responsible for a severe form of OI
      with congenital bowing of the lower limbs
    explanation: >-
      Documents congenital long-bone (lower-limb) bowing as a defining feature
      of FAM46A/TENT5A OI type XVIII.
- name: Reduced Bone Mineral Density
  description: >-
    Skeletal hypomineralization with reduced bone mineral density, reflecting
    the defective, collagen-deficient bone matrix.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:33882302
    reference_title: "Cytoplasmic polyadenylation by TENT5A is required for proper bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the Tent5a knockout (KO) mouse line displays bone fragility and skeletal
      hypomineralization phenotype resulting from quantitative and qualitative
      collagen defects.
    explanation: >-
      The Tent5a-null mouse shows skeletal hypomineralization, the model
      correlate of reduced bone mineral density in OI type XVIII. Human reduced
      bone density is also implied by the vertebral collapses reported in
      patients.
- name: Growth Deficiency
  description: >-
    Growth deficiency with decreased body length, part of the severe skeletal
    phenotype; the Fam46a mutant mouse shows decreased body length.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      an ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by
      decreased body length, limb, rib, pelvis, and skull deformities
    explanation: >-
      The Fam46a mutant mouse shows decreased body length (growth deficiency),
      a model correlate of the growth phenotype in OI type XVIII.
- name: Vertebral Collapse
  description: >-
    Vertebral body collapse develops in OI type XVIII, reflecting the fragile,
    low-density axial skeleton, and was part of the clinical picture that
    established the OI diagnosis in the index FAM46A case.
  phenotype_term:
    preferred_term: Vertebral compression fracture
    term:
      id: HP:0002953
      label: Vertebral compression fracture
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The follow-up of this case supported a final diagnosis of osteogenesis
      imperfecta (OI), based on vertebral collapses and blue sclerae.
    explanation: >-
      Documents vertebral collapses (compression) as a feature establishing the
      OI diagnosis in FAM46A/TENT5A disease.
- name: Blue Sclerae
  description: >-
    Blue sclerae, a classic extraskeletal hallmark of osteogenesis imperfecta,
    are documented in TENT5A (FAM46A) disease and were part of the clinical
    picture that established the OI diagnosis in the index FAM46A case.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The follow-up of this case supported a final diagnosis of osteogenesis
      imperfecta (OI), based on vertebral collapses and blue sclerae.
    explanation: >-
      Documents blue sclerae as a defining clinical feature that, together with
      vertebral collapses, established the OI diagnosis in the index
      FAM46A/TENT5A (type XVIII) case.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XVIII is suspected in an infant with severe recessive OI (congenital
    long-bone bowing, recurrent fractures, vertebral collapse, blue sclerae,
    wormian bones) when COL1A1/COL1A2 and other known OI genes are negative.
    Diagnosis is confirmed by identifying a biallelic TENT5A (FAM46A)
    loss-of-function variant by gene-panel or exome sequencing; screening of
    FAM46A/TENT5A is recommended in unexplained OI forms.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:29358272
    reference_title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suggest screening this gene in unexplained OI forms.
    explanation: >-
      Recommends molecular screening of FAM46A/TENT5A to diagnose this form of
      OI in otherwise unexplained cases.
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 post-transcriptional collagen 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 XVIII.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, bowed 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 improve mobility and muscle strength and
    reduce fracture risk; 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:29358272
  title: "FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta."
- reference: PMID:33882302
  title: "Cytoplasmic polyadenylation by TENT5A is required for proper bone formation."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews

📚

References & Deep Research

References

PMID:29358272

FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta.

No top-level findings curated for this source.

PMID:33882302

Cytoplasmic polyadenylation by TENT5A is required for proper 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.

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