Multiple Synostoses Syndrome

Mendelian MONDO:0017923 Pathograph 15 Show in embeddings browser Joint Disorders

Multiple synostoses syndrome (SYNS) is an autosomal dominant disorder characterized by progressive joint fusion (synostosis) affecting proximal interphalangeal joints, carpal and tarsal bones, and the cervical spine. It is caused by mutations in genes involved in BMP signaling, primarily NOG (encoding noggin, a BMP antagonist) and GDF5 (encoding growth/differentiation factor 5, a BMP ligand). The disorder typically presents in childhood with progressive stiffness and conductive hearing loss from stapes fixation.

Ask OpenScientist

Ask a research question about Multiple Synostoses Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

4
Mappings
1
Inheritance
3
Pathophys.
8
Phenotypes
15
Pathograph
4
Genes
3
Medical Actions
5
References
2
Deep Research
🏷

Classifications

ISDS Skeletal Nosology
defects in joint formation and synostoses
🔗

Mappings

MONDO
MONDO:0008519 multiple synostoses syndrome 1 Not Yet Curated
skos:narrowMatch MONDO
MONDO:0008519 (multiple synostoses syndrome 1, SYNS1) is MONDO's gene-stratified subtype for the NOG-caused form, already curated here under genetic[].name: NOG Mutations (SYNS1).
MONDO:0012394 multiple synostoses syndrome 2 Not Yet Curated
skos:narrowMatch MONDO
MONDO:0012394 (multiple synostoses syndrome 2, SYNS2) is MONDO's gene-stratified subtype for the GDF5-caused form, already curated here under genetic[].name: GDF5 Mutations (SYNS2).
MONDO:0013064 multiple synostoses syndrome 3 Not Yet Curated
skos:narrowMatch MONDO
MONDO:0013064 (multiple synostoses syndrome 3, SYNS3) is MONDO's gene-stratified subtype for the FGF9-caused form, already curated here under genetic[].name: FGF9.
MONDO:0054752 multiple synostoses syndrome 4 Not Yet Curated
skos:narrowMatch MONDO
MONDO:0054752 (multiple synostoses syndrome 4, SYNS4) is MONDO's gene-stratified subtype for the GDF6-caused form, already curated here under genetic[].name: GDF6 Mutations (SYNS4).
👪

Inheritance

1
Autosomal Dominant
Autosomal dominant inheritance with variable expressivity.
Show evidence (1 reference)
PMID:16532400 SUPPORT
"Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism."
Confirms autosomal dominant inheritance of SYNS.
⚙

Pathophysiology

3
BMP Signaling Dysregulation
NOG mutations reduce noggin's ability to antagonize BMPs (particularly BMP2, BMP4, and GDF5), leading to excessive BMP signaling in developing joints. This causes progressive ossification and fusion of joints that would normally remain separate. GDF5 mutations cause gain-of-function changes that similarly enhance BMP pathway activity in joint development, and the SYNS4 GDF6 p.Y444N variant raises BMP signaling by the same route, resisting noggin-mediated antagonism.
Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
NOG hgnc:7866 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOG (hgnc:7866). hgnc:7866 is a gene from the HUGO Gene Nomenclature Committee. GDF5 hgnc:4220 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDF5 (hgnc:4220). hgnc:4220 is a gene from the HUGO Gene Nomenclature Committee. GDF6 hgnc:4221 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDF6 (hgnc:4221). hgnc:4221 is a gene from the HUGO Gene Nomenclature Committee.
BMP Signaling Pathway GO:0030509 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves BMP Signaling Pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology. Limb Development GO:0060173 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Limb Development (GO:0060173). GO:0060173 is a biological process from the Gene Ontology. Chondrocyte Differentiation GO:0002062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Chondrocyte Differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology.
Downstream
Abnormal Joint Cavitation Excess BMP signaling disrupts normal joint-space formation during skeletal development.
Show evidence (2 references)
PMID:11562478 SUPPORT In Vitro
"The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells."
Shows that SYNS1-causing NOG mutations abolish functional noggin dimer secretion, explaining the loss of BMP antagonism.
PMID:21976273 SUPPORT In Vitro
"this gain of function is caused by strongly reduced affinity of GDF5-S94N to the BMP/GDF antagonist noggin and the consequential lack of noggin inhibition."
Demonstrates that GDF5 mutations in SYNS cause noggin resistance, resulting in excessive BMP signaling during chondrogenesis.
FGF9 Signaling Loss in the Joint Interzone
SYNS3 is caused by the FGF9 p.S99N substitution, which is secreted normally but binds FGFR poorly, so FGF signaling in the developing joint is reduced rather than increased. FGF9 normally restrains mesenchymal cells from differentiating into chondrocytes at the prospective joint site and sustains Gdf5 expression there; the mutant protein does neither, and the interzone fails to form. This is a separate route to the same synostoses from the BMP-side lesions in SYNS1, SYNS2 and SYNS4, and it converges on the same failure of joint separation.
Mesenchymal stem cell CL:0000134 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Mesenchymal stem cell (CL:0000134). CL:0000134 is a cell type from the Cell Ontology.
FGF9 hgnc:3687 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGF9 (hgnc:3687). hgnc:3687 is a gene from the HUGO Gene Nomenclature Committee.
FGF receptor signaling in the joint interzone GO:0008543 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased FGF receptor signaling in the joint interzone, annotated with fibroblast growth factor receptor signaling pathway (GO:0008543). GO:0008543 is a biological process from the Gene Ontology. Embryonic skeletal joint morphogenesis GO:0060272 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Embryonic skeletal joint morphogenesis (GO:0060272). GO:0060272 is a biological process from the Gene Ontology. Mesenchymal cell differentiation at the prospective joint GO:0048762 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Mesenchymal cell differentiation at the prospective joint, annotated with mesenchymal cell differentiation (GO:0048762). GO:0048762 is a biological process from the Gene Ontology.
Downstream
Abnormal Joint Cavitation Failure of interzone formation removes the cell population from which the joint space would be carved, so cavitation never occurs.
Show evidence (3 references)
PMID:19589401 SUPPORT In Vitro
"Importantly, the binding of FGF9(S99N) to its receptor is severely impaired although the dimerization ability of mutant FGF9 itself or with wild-type FGF9 is not detectably affected, providing a basis for the defective FGFR signaling."
Identifies impaired receptor binding, not impaired dimerization or secretion, as the molecular defect behind reduced FGF signaling in SYNS3.
PMID:28169396 SUPPORT Model Organism
"Further study reveals that the S99N mutation in Fgf9 disrupts joint interzone formation by affecting the chondrogenic differentiation of mesenchymal cells at the early stage of joint development."
Places the SYNS3 lesion at interzone formation in a mouse carrying the human allele, which is the step this node names.
PMID:28169396 SUPPORT Model Organism
"We also show that Fgf9 is required for normal expression of Gdf5 in the prospective elbow and knee joints through its activation of Gdf5 promoter activity."
Links the FGF9 lesion to the same GDF5-dependent joint program that the BMP-side subtypes disturb, supporting convergence on one cavitation defect.
Abnormal Joint Cavitation
Normal joint formation requires interzone specification and subsequent cavitation. Both routes above disrupt this process: excess BMP signaling from loss of noggin antagonism (SYNS1) or from noggin-resistant GDF5/GDF6 ligands (SYNS2, SYNS4), and loss of FGF9 receptor signaling at the prospective joint (SYNS3). Either way joint space formation fails and synostosis is progressive.
Ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology.
Downstream
Proximal Symphalangism Failed joint separation produces proximal interphalangeal synostosis.
Carpal and Tarsal Fusion Abnormal cavitation and ossification extend to carpal and tarsal joints.
Humeroradial Synostosis Abnormal skeletal joint separation can include humeroradial fusion.
Vertebral Fusion Abnormal joint morphogenesis can involve cervical spine joint fusion.
Joint stiffness Progressive synostosis limits joint range of motion and produces stiffness.
Conductive Hearing Loss Middle-ear ossicular fixation in the synostosis spectrum produces conductive hearing impairment.
Brachydactyly Altered BMP signaling in limb development contributes to shortened digits.
Broad thumb Altered BMP signaling in limb development contributes to broad thumbs.
Show evidence (2 references)
PMID:10080184 SUPPORT Model Organism
"Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton."
Loss of noggin in mice leads to skeletal fusion, confirming the role of noggin in preventing joint ossification.
PMID:11562478 SUPPORT In Vitro
"noggin has both species-specific and joint-specific dosage-dependent roles during joint formation."
Establishes that noggin dosage is critical for joint formation and that haploinsufficiency causes joint-specific pathology.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Multiple Synostoses Syndrome 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

8
Ear 1
Conductive Hearing Loss Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16532400 SUPPORT
"Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism."
Lists deafness (conductive hearing loss from stapes fixation) as a characteristic feature of SYNS.
ORPHA:3237 SUPPORT Other
"HP:0000405 | Conductive hearing impairment | Very frequent (99-80%)"
Orphanet reports conductive hearing impairment as a very frequent MSS phenotype.
Limbs 4
Carpal and Tarsal Fusion Carpal synostosis HP:0009702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carpal synostosis (HP:0009702). HP:0009702 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16532400 SUPPORT
"Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism."
Lists carpal/tarsal fusions as a characteristic feature of SYNS.
PMID:21976273 SUPPORT
"SYNS is characterized by progressive symphalangism, carpal/tarsal fusions, deafness and mild facial dysmorphism."
Confirms carpal/tarsal fusions as a core feature of SYNS.
Humeroradial Synostosis HP:0003041 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Humeroradial synostosis (HP:0003041). HP:0003041 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3237 SUPPORT Other
"Multiple synostoses syndrome (MSS) is a rare developmental bone disorder characterized by proximal symphalangism of the fingers and/or toes often associated with fusion of carpal and tarsal, humeroradial, and cervical spine joints."
Orphanet lists humeroradial joint fusion among the characteristic fusions in multiple synostoses syndrome.
Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3237 SUPPORT Other
"HP:0001156 | Brachydactyly | Very frequent (99-80%)"
Orphanet reports brachydactyly as a very frequent MSS phenotype.
Broad thumb HP:0011304 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad thumb (HP:0011304). HP:0011304 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3237 SUPPORT Other
"HP:0011304 | Broad thumb | Frequent (79-30%)"
Orphanet reports broad thumb as a frequent MSS phenotype.
Musculoskeletal 3
Proximal Symphalangism HP:0100264 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal symphalangism (HP:0100264). HP:0100264 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10080184 SUPPORT
"We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800)"
NOG mutations segregate with proximal symphalangism in affected families, establishing the genetic basis.
PMID:16532400 SUPPORT
"Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism."
Lists progressive symphalangism as a defining feature of SYNS.
Vertebral Fusion HP:0002948 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertebral fusion (HP:0002948). HP:0002948 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3237 SUPPORT Other
"Multiple synostoses syndrome (MSS) is a rare developmental bone disorder characterized by proximal symphalangism of the fingers and/or toes often associated with fusion of carpal and tarsal, humeroradial, and cervical spine joints."
Orphanet states that cervical spine joint fusion is part of the MSS fusion pattern.
Joint stiffness HP:0001387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint stiffness (HP:0001387). HP:0001387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3237 SUPPORT Other
"HP:0001387 | Joint stiffness | Very frequent (99-80%)"
Orphanet reports joint stiffness as a very frequent MSS phenotype.
🧬

Genetic Associations

4
NOG Mutations (SYNS1) (Causative)
Gene: NOG hgnc:7866 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOG (hgnc:7866). hgnc:7866 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:10080184 SUPPORT
"We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature."
Identifies NOG as the causative gene for SYNS1.
PMID:10080184 SUPPORT
"All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation."
Confirms that NOG mutations affect conserved residues critical for joint formation.
PMID:11562478 SUPPORT In Vitro
"these data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin."
Demonstrates that SYNS/SYM1 NOG mutations are hypomorphic, reducing functional noggin dimer secretion.
GDF5 Mutations (SYNS2) (Causative)
Gene: GDF5 hgnc:4220 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDF5 (hgnc:4220). hgnc:4220 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:16532400 SUPPORT
"These data establish locus heterogeneity in multiple-synostosis syndrome and demonstrate that the disorder can result from mutations in either the NOGGIN or the GDF5 gene."
Identifies GDF5 as a second causative locus for SYNS, establishing genetic heterogeneity.
PMID:21976273 SUPPORT In Vitro
"GDF5-S94N exhibits impaired binding to BMPRII causing alleviated Smad and non-Smad signaling and reduced chondrogenic differentiation of ATDC5 cells."
Shows the GDF5 SYNS mutation has impaired BMPRII binding in vitro, but gains function via noggin resistance in chondrogenic contexts.
GDF6 Mutations (SYNS4) (Causative)
Gene: GDF6 hgnc:4221 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDF6 (hgnc:4221). hgnc:4221 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:26643732 SUPPORT Human Clinical
"Using genetic data obtained from a six-generation Chinese family, we identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4."
Establishes GDF6 as the SYNS4 locus by segregation in a large pedigree.
PMID:26643732 SUPPORT In Vitro
"Further, we determine that the enhanced BMP activity exhibited by mutant GDF6 is attributable to resistance to NOG-mediated antagonism."
Gives the mechanism by which the SYNS4 GDF6 variant raises BMP signaling, the same noggin-resistance route as the SYNS2 GDF5 variant.
PMID:34573339 SUPPORT Human Clinical
"Here we report a five-generation SYNS4 family with a reduction in GDF6 expression resulting from a chromosomal breakpoint 3' of GDF6."
Records a SYNS4 family in which GDF6 dosage is reduced rather than the ligand being hyperactive, so the allelic spectrum is not uniformly gain-of-function.
FGF9 (Pathogenic Variants)
Gene: FGF9 hgnc:3687 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FGF9 (hgnc:3687). hgnc:3687 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
CGGV:assertion_1fd535ba-f5b4-469b-8866-894cf9e4e1d0-2025-06-24T040000.000Z SUPPORT Other
"FGF9 | HGNC:3687 | multiple synostoses syndrome | MONDO:0017923 | AD | Definitive"
ClinGen classifies the FGF9-multiple synostoses syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Medical Actions

3
Hearing Aid
Hearing aids for conductive hearing loss from stapes fixation.
Stapedectomy
Surgical replacement of the fixed stapes to restore hearing.
Orthopedic Management
Occupational therapy and adaptive devices for joint stiffness and limited range of motion.
📊

Prevalence

1
Published SYNS kindreds
Cases In Literature Ultra-rare; 18 reported individuals with FGF9-related SYNS3 and a recently described five-generation SYNS4 family Ultra Rare
No population-based prevalence estimate was identified in PubMed-indexed literature; current evidence is limited to reported multigenerational families and small kindreds across SYNS subtypes.
Show evidence (2 references)
PMID:36980996 SUPPORT Human Clinical
"So far, only five different missense variants in FGF9 that cause SYNS3 have been reported in 18 affected individuals."
This recent SYNS3 report quantifies the very small number of published affected individuals for one multiple-synostoses subtype.
PMID:34573339 SUPPORT Human Clinical
"Here we report a five-generation SYNS4 family with a reduction in GDF6 expression resulting from a chromosomal breakpoint 3' of GDF6."
This recent SYNS4 report supports that multiple synostoses syndrome remains documented largely through rare multigenerational kindreds.
{ }

Source YAML

click to show 
name: Multiple Synostoses Syndrome
creation_date: '2026-02-13T00:31:42Z'
category: Mendelian
description: >
  Multiple synostoses syndrome (SYNS) is an autosomal dominant disorder characterized
  by progressive joint fusion (synostosis) affecting proximal interphalangeal joints,
  carpal and tarsal bones, and the cervical spine. It is caused by mutations in genes
  involved in BMP signaling, primarily NOG (encoding noggin, a BMP antagonist) and
  GDF5 (encoding growth/differentiation factor 5, a BMP ligand). The disorder
  typically presents in childhood with progressive stiffness and conductive hearing
  loss from stapes fixation.
disease_term:
  preferred_term: Multiple synostoses syndrome
  term:
    id: MONDO:0017923
    label: multiple synostoses syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008519
      label: multiple synostoses syndrome 1
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0008519 (multiple synostoses syndrome 1, SYNS1) is MONDO's
      gene-stratified subtype for the NOG-caused form, already curated here
      under genetic[].name: NOG Mutations (SYNS1).
  - term:
      id: MONDO:0012394
      label: multiple synostoses syndrome 2
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0012394 (multiple synostoses syndrome 2, SYNS2) is MONDO's
      gene-stratified subtype for the GDF5-caused form, already curated here
      under genetic[].name: GDF5 Mutations (SYNS2).
  - term:
      id: MONDO:0013064
      label: multiple synostoses syndrome 3
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0013064 (multiple synostoses syndrome 3, SYNS3) is MONDO's
      gene-stratified subtype for the FGF9-caused form, already curated here
      under genetic[].name: FGF9.
  - term:
      id: MONDO:0054752
      label: multiple synostoses syndrome 4
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0054752 (multiple synostoses syndrome 4, SYNS4) is MONDO's
      gene-stratified subtype for the GDF6-caused form, already curated here
      under genetic[].name: GDF6 Mutations (SYNS4).
parents:
- Joint Disorders
inheritance:
- name: Autosomal Dominant
  description: >
    Autosomal dominant inheritance with variable expressivity.
  evidence:
  - reference: PMID:16532400
    reference_title: "GDF5 is a second locus for multiple-synostosis syndrome."
    supports: SUPPORT
    snippet: >-
      Multiple-synostosis syndrome is an autosomal dominant disorder
      characterized by progressive symphalangism, carpal/tarsal fusions,
      deafness, and mild facial dysmorphism.
    explanation: >-
      Confirms autosomal dominant inheritance of SYNS.
classifications:
  isds_skeletal_category:
  - classification_value: defects_in_joint_formation_and_synostoses
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 42 "Defects in joint
      formation and synostoses"; listed as "Multiple synostoses syndrome".
prevalence:
- population: Published SYNS kindreds
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  percentage: Ultra-rare; 18 reported individuals with FGF9-related SYNS3 and a recently described five-generation SYNS4 family
  notes: >-
    No population-based prevalence estimate was identified in PubMed-indexed
    literature; current evidence is limited to reported multigenerational
    families and small kindreds across SYNS subtypes.
  evidence:
  - reference: PMID:36980996
    reference_title: "FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, only five different missense variants in FGF9 that cause SYNS3 have been reported in 18 affected individuals."
    explanation: This recent SYNS3 report quantifies the very small number of published affected individuals for one multiple-synostoses subtype.
  - reference: PMID:34573339
    reference_title: "GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a five-generation SYNS4 family with a reduction in GDF6 expression resulting from a chromosomal breakpoint 3' of GDF6."
    explanation: This recent SYNS4 report supports that multiple synostoses syndrome remains documented largely through rare multigenerational kindreds.
pathophysiology:
- name: BMP Signaling Dysregulation
  description: >
    NOG mutations reduce noggin's ability to antagonize BMPs (particularly BMP2,
    BMP4, and GDF5), leading to excessive BMP signaling in developing joints.
    This causes progressive ossification and fusion of joints that would normally
    remain separate. GDF5 mutations cause gain-of-function changes that similarly
    enhance BMP pathway activity in joint development, and the SYNS4 GDF6
    p.Y444N variant raises BMP signaling by the same route, resisting
    noggin-mediated antagonism.
  biological_processes:
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
  - preferred_term: Limb Development
    term:
      id: GO:0060173
      label: limb development
  - preferred_term: Chondrocyte Differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
  genes:
  - preferred_term: NOG
    term:
      id: hgnc:7866
      label: NOG
  - preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  - preferred_term: GDF6
    term:
      id: hgnc:4221
      label: GDF6
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:11562478
    reference_title: "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding."
    supports: SUPPORT
    snippet: >-
      The SYNS1 mutation abolished, and the SYM1 mutations reduced, the
      secretion of functional noggin dimers in transiently transfected COS-7
      cells.
    explanation: >-
      Shows that SYNS1-causing NOG mutations abolish functional noggin
      dimer secretion, explaining the loss of BMP antagonism.
    evidence_source: IN_VITRO
  - reference: PMID:21976273
    reference_title: "New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance."
    supports: SUPPORT
    snippet: >-
      this gain of function is caused by strongly reduced affinity of
      GDF5-S94N to the BMP/GDF antagonist noggin and the consequential lack
      of noggin inhibition.
    explanation: >-
      Demonstrates that GDF5 mutations in SYNS cause noggin resistance,
      resulting in excessive BMP signaling during chondrogenesis.
    evidence_source: IN_VITRO
  downstream:
  - target: Abnormal Joint Cavitation
    description: Excess BMP signaling disrupts normal joint-space formation during skeletal development.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: FGF9 Signaling Loss in the Joint Interzone
  description: >
    SYNS3 is caused by the FGF9 p.S99N substitution, which is secreted normally
    but binds FGFR poorly, so FGF signaling in the developing joint is reduced
    rather than increased. FGF9 normally restrains mesenchymal cells from
    differentiating into chondrocytes at the prospective joint site and
    sustains Gdf5 expression there; the mutant protein does neither, and the
    interzone fails to form. This is a separate route to the same synostoses
    from the BMP-side lesions in SYNS1, SYNS2 and SYNS4, and it converges on
    the same failure of joint separation.
  biological_processes:
  - preferred_term: FGF receptor signaling in the joint interzone
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
    modifier: DECREASED
  - preferred_term: Embryonic skeletal joint morphogenesis
    term:
      id: GO:0060272
      label: embryonic skeletal joint morphogenesis
  - preferred_term: Mesenchymal cell differentiation at the prospective joint
    term:
      id: GO:0048762
      label: mesenchymal cell differentiation
  genes:
  - preferred_term: FGF9
    term:
      id: hgnc:3687
      label: FGF9
  cell_types:
  - preferred_term: Mesenchymal stem cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  evidence:
  - reference: PMID:19589401
    reference_title: "Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, the binding of FGF9(S99N) to its receptor is severely
      impaired although the dimerization ability of mutant FGF9 itself or with
      wild-type FGF9 is not detectably affected, providing a basis for the
      defective FGFR signaling.
    explanation: >-
      Identifies impaired receptor binding, not impaired dimerization or
      secretion, as the molecular defect behind reduced FGF signaling in SYNS3.
  - reference: PMID:28169396
    reference_title: "A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further study reveals that the S99N mutation in Fgf9 disrupts joint
      interzone formation by affecting the chondrogenic differentiation of
      mesenchymal cells at the early stage of joint development.
    explanation: >-
      Places the SYNS3 lesion at interzone formation in a mouse carrying the
      human allele, which is the step this node names.
  - reference: PMID:28169396
    reference_title: "A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We also show that Fgf9 is required for normal expression of Gdf5 in the
      prospective elbow and knee joints through its activation of Gdf5 promoter
      activity.
    explanation: >-
      Links the FGF9 lesion to the same GDF5-dependent joint program that the
      BMP-side subtypes disturb, supporting convergence on one cavitation
      defect.
  downstream:
  - target: Abnormal Joint Cavitation
    description: >-
      Failure of interzone formation removes the cell population from which the
      joint space would be carved, so cavitation never occurs.
    causal_link_type: DIRECT
- name: Abnormal Joint Cavitation
  description: >
    Normal joint formation requires interzone specification and subsequent
    cavitation. Both routes above disrupt this process: excess BMP signaling
    from loss of noggin antagonism (SYNS1) or from noggin-resistant GDF5/GDF6
    ligands (SYNS2, SYNS4), and loss of FGF9 receptor signaling at the
    prospective joint (SYNS3). Either way joint space formation fails and
    synostosis is progressive.
  biological_processes:
  - preferred_term: Ossification
    term:
      id: GO:0001503
      label: ossification
  evidence:
  - reference: PMID:10080184
    reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
    supports: SUPPORT
    snippet: >-
      Nog-/- mice die at birth from multiple defects that include bony
      fusion of the appendicular skeleton.
    explanation: >-
      Loss of noggin in mice leads to skeletal fusion, confirming the
      role of noggin in preventing joint ossification.
    evidence_source: MODEL_ORGANISM
  - reference: PMID:11562478
    reference_title: "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding."
    supports: SUPPORT
    snippet: >-
      noggin has both species-specific and joint-specific dosage-dependent
      roles during joint formation.
    explanation: >-
      Establishes that noggin dosage is critical for joint formation and
      that haploinsufficiency causes joint-specific pathology.
    evidence_source: IN_VITRO
  downstream:
  - target: Proximal Symphalangism
    description: Failed joint separation produces proximal interphalangeal synostosis.
    causal_link_type: DIRECT
  - target: Carpal and Tarsal Fusion
    description: Abnormal cavitation and ossification extend to carpal and tarsal joints.
    causal_link_type: DIRECT
  - target: Humeroradial Synostosis
    description: Abnormal skeletal joint separation can include humeroradial fusion.
    causal_link_type: DIRECT
  - target: Vertebral Fusion
    description: Abnormal joint morphogenesis can involve cervical spine joint fusion.
    causal_link_type: DIRECT
  - target: Joint stiffness
    description: Progressive synostosis limits joint range of motion and produces stiffness.
    causal_link_type: DIRECT
  - target: Conductive Hearing Loss
    description: Middle-ear ossicular fixation in the synostosis spectrum produces conductive hearing impairment.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Brachydactyly
    description: Altered BMP signaling in limb development contributes to shortened digits.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Broad thumb
    description: Altered BMP signaling in limb development contributes to broad thumbs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Proximal Symphalangism
  description: >
    Fusion of proximal interphalangeal joints, causing inability to flex
    the fingers. One of the earliest and most consistent findings.
  phenotype_term:
    preferred_term: Proximal symphalangism
    term:
      id: HP:0100264
      label: Proximal symphalangism
  evidence:
  - reference: PMID:10080184
    reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
    supports: SUPPORT
    snippet: >-
      We have identified five dominant human NOG mutations in unrelated
      families segregating proximal symphalangism (SYM1; OMIM 185800)
    explanation: >-
      NOG mutations segregate with proximal symphalangism in affected
      families, establishing the genetic basis.
  - reference: PMID:16532400
    reference_title: "GDF5 is a second locus for multiple-synostosis syndrome."
    supports: SUPPORT
    snippet: >-
      Multiple-synostosis syndrome is an autosomal dominant disorder
      characterized by progressive symphalangism, carpal/tarsal fusions,
      deafness, and mild facial dysmorphism.
    explanation: >-
      Lists progressive symphalangism as a defining feature of SYNS.
- name: Carpal and Tarsal Fusion
  description: >
    Progressive fusion of carpal (wrist) and tarsal (ankle) bones.
  phenotype_term:
    preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
  evidence:
  - reference: PMID:16532400
    reference_title: "GDF5 is a second locus for multiple-synostosis syndrome."
    supports: SUPPORT
    snippet: >-
      Multiple-synostosis syndrome is an autosomal dominant disorder
      characterized by progressive symphalangism, carpal/tarsal fusions,
      deafness, and mild facial dysmorphism.
    explanation: >-
      Lists carpal/tarsal fusions as a characteristic feature of SYNS.
  - reference: PMID:21976273
    reference_title: "New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance."
    supports: SUPPORT
    snippet: >-
      SYNS is characterized by progressive symphalangism, carpal/tarsal
      fusions, deafness and mild facial dysmorphism.
    explanation: >-
      Confirms carpal/tarsal fusions as a core feature of SYNS.
- name: Humeroradial Synostosis
  description: >
    Fusion of the humerus and radius at the elbow, part of the broader multiple
    synostoses pattern.
  phenotype_term:
    preferred_term: Humeroradial synostosis
    term:
      id: HP:0003041
      label: Humeroradial synostosis
  evidence:
  - reference: ORPHA:3237
    reference_title: "Multiple synostoses syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Multiple synostoses syndrome (MSS) is a rare developmental bone disorder characterized by proximal symphalangism of the fingers and/or toes often associated with fusion of carpal and tarsal, humeroradial, and cervical spine joints."
    explanation: Orphanet lists humeroradial joint fusion among the characteristic fusions in multiple synostoses syndrome.
- name: Conductive Hearing Loss
  description: >
    Conductive hearing loss resulting from stapes fixation or fusion
    of the ossicular chain in the middle ear.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:16532400
    reference_title: "GDF5 is a second locus for multiple-synostosis syndrome."
    supports: SUPPORT
    snippet: >-
      Multiple-synostosis syndrome is an autosomal dominant disorder
      characterized by progressive symphalangism, carpal/tarsal fusions,
      deafness, and mild facial dysmorphism.
    explanation: >-
      Lists deafness (conductive hearing loss from stapes fixation)
      as a characteristic feature of SYNS.
  - reference: ORPHA:3237
    reference_title: "Multiple synostoses syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000405 | Conductive hearing impairment | Very frequent (99-80%)"
    explanation: Orphanet reports conductive hearing impairment as a very frequent MSS phenotype.
- name: Vertebral Fusion
  description: >
    Fusion of vertebrae, particularly cervical, limiting neck mobility.
  phenotype_term:
    preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  evidence:
  - reference: ORPHA:3237
    reference_title: "Multiple synostoses syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Multiple synostoses syndrome (MSS) is a rare developmental bone disorder characterized by proximal symphalangism of the fingers and/or toes often associated with fusion of carpal and tarsal, humeroradial, and cervical spine joints."
    explanation: Orphanet states that cervical spine joint fusion is part of the MSS fusion pattern.
- name: Joint stiffness
  description: >
    Progressive synostosis produces stiff joints and limited range of motion.
  phenotype_term:
    preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  evidence:
  - reference: ORPHA:3237
    reference_title: "Multiple synostoses syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001387 | Joint stiffness | Very frequent (99-80%)"
    explanation: Orphanet reports joint stiffness as a very frequent MSS phenotype.
- name: Brachydactyly
  description: >
    Short digits are part of the multiple synostoses limb phenotype.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: ORPHA:3237
    reference_title: "Multiple synostoses syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001156 | Brachydactyly | Very frequent (99-80%)"
    explanation: Orphanet reports brachydactyly as a very frequent MSS phenotype.
- name: Broad thumb
  description: >
    Broad thumbs are reported in the symphalangism-brachydactyly MSS spectrum.
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
  evidence:
  - reference: ORPHA:3237
    reference_title: "Multiple synostoses syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011304 | Broad thumb | Frequent (79-30%)"
    explanation: Orphanet reports broad thumb as a frequent MSS phenotype.
genetic:
- name: NOG Mutations (SYNS1)
  gene_term:
    preferred_term: NOG
    term:
      id: hgnc:7866
      label: NOG
  association: Causative
  notes: >
    Heterozygous loss-of-function mutations in NOG encoding noggin,
    a BMP antagonist. Mutations reduce noggin's ability to bind and
    inhibit BMP ligands, resulting in excessive BMP signaling during
    joint development. NOG mutations also cause proximal symphalangism
    and stapes ankylosis with broad thumbs and toes.
  evidence:
  - reference: PMID:10080184
    reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
    supports: SUPPORT
    snippet: >-
      We also found a dominant NOG mutation in a family segregating multiple
      synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have
      multiple joint fusion as their principal feature.
    explanation: >-
      Identifies NOG as the causative gene for SYNS1.
  - reference: PMID:10080184
    reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
    supports: SUPPORT
    snippet: >-
      All seven NOG mutations alter evolutionarily conserved amino acid
      residues. The findings reported here confirm that NOG is essential
      for joint formation.
    explanation: >-
      Confirms that NOG mutations affect conserved residues critical
      for joint formation.
  - reference: PMID:11562478
    reference_title: "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding."
    supports: SUPPORT
    snippet: >-
      these data indicate that the human disease-causing mutations are
      hypomorphic alleles that reduce secretion of functional dimeric
      noggin.
    explanation: >-
      Demonstrates that SYNS/SYM1 NOG mutations are hypomorphic,
      reducing functional noggin dimer secretion.
    evidence_source: IN_VITRO
- name: GDF5 Mutations (SYNS2)
  gene_term:
    preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  association: Causative
  notes: >
    Heterozygous gain-of-function mutations in GDF5 encoding growth
    differentiation factor 5, a BMP family ligand. GDF5 mutations
    increase BMP signaling activity in joint development through
    noggin resistance.
  evidence:
  - reference: PMID:16532400
    reference_title: "GDF5 is a second locus for multiple-synostosis syndrome."
    supports: SUPPORT
    snippet: >-
      These data establish locus heterogeneity in multiple-synostosis
      syndrome and demonstrate that the disorder can result from mutations
      in either the NOGGIN or the GDF5 gene.
    explanation: >-
      Identifies GDF5 as a second causative locus for SYNS, establishing
      genetic heterogeneity.
  - reference: PMID:21976273
    reference_title: "New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance."
    supports: SUPPORT
    snippet: >-
      GDF5-S94N exhibits impaired binding to BMPRII causing alleviated
      Smad and non-Smad signaling and reduced chondrogenic differentiation
      of ATDC5 cells.
    explanation: >-
      Shows the GDF5 SYNS mutation has impaired BMPRII binding in vitro,
      but gains function via noggin resistance in chondrogenic contexts.
    evidence_source: IN_VITRO
- name: GDF6 Mutations (SYNS4)
  gene_term:
    preferred_term: GDF6
    term:
      id: hgnc:4221
      label: GDF6
  association: Causative
  notes: >
    GDF6 encodes growth/differentiation factor 6, a BMP-family ligand. The
    SYNS4 subtype was defined by a GDF6 missense variant (p.Y444N) segregating
    in a six-generation Chinese pedigree; the substitution lies in the region
    that binds GDF6 receptors and the BMP antagonist noggin, and the mutant
    ligand resists noggin antagonism and signals more strongly than wild-type
    GDF6. A separate five-generation family with SYNS4 carries a chromosomal
    breakpoint 3' of GDF6 that reduces GDF6 expression rather than a coding
    gain-of-function change.
  evidence:
  - reference: PMID:26643732
    reference_title: "A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using genetic data obtained from a six-generation Chinese family, we
      identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully
      segregates with a novel autosomal dominant synostoses (SYNS) phenotype,
      which we designate as SYNS4.
    explanation: >-
      Establishes GDF6 as the SYNS4 locus by segregation in a large pedigree.
  - reference: PMID:26643732
    reference_title: "A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Further, we determine that the enhanced BMP activity exhibited by mutant
      GDF6 is attributable to resistance to NOG-mediated antagonism.
    explanation: >-
      Gives the mechanism by which the SYNS4 GDF6 variant raises BMP signaling,
      the same noggin-resistance route as the SYNS2 GDF5 variant.
  - reference: PMID:34573339
    reference_title: "GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a five-generation SYNS4 family with a reduction in GDF6
      expression resulting from a chromosomal breakpoint 3' of GDF6.
    explanation: >-
      Records a SYNS4 family in which GDF6 dosage is reduced rather than the
      ligand being hyperactive, so the allelic spectrum is not uniformly
      gain-of-function.
- name: FGF9
  gene_term:
    preferred_term: FGF9
    term:
      id: hgnc:3687
      label: FGF9
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_1fd535ba-f5b4-469b-8866-894cf9e4e1d0-2025-06-24T040000.000Z
    reference_title: "FGF9 / multiple synostoses syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FGF9 | HGNC:3687 | multiple synostoses syndrome | MONDO:0017923 | AD | Definitive"
    explanation: ClinGen classifies the FGF9-multiple synostoses syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Hearing Aid
  description: >
    Hearing aids for conductive hearing loss from stapes fixation.
- name: Stapedectomy
  description: >
    Surgical replacement of the fixed stapes to restore hearing.
- name: Orthopedic Management
  description: >
    Occupational therapy and adaptive devices for joint stiffness
    and limited range of motion.
datasets: []
references:
- reference: DOI:10.1002/ajmg.a.38503
  title: Further delineation of the GDF6 related multiple synostoses syndrome
  findings: []
- reference: DOI:10.1002/jbmr.2761
  title: A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in <i>GDF6</i> That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal
  findings: []
- reference: DOI:10.1016/j.ajhg.2009.06.007
  title: Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene
  findings: []
- reference: DOI:10.1093/hmg/ddx029
  title: A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome
  findings: []
- reference: DOI:10.3390/genes14030724
  title: FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family
  findings: []
📚

References & Deep Research

References

5
DOI:10.1002/ajmg.a.38503
Further delineation of the GDF6 related multiple synostoses syndrome
No top-level findings curated for this source.
DOI:10.1002/jbmr.2761
A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in <i>GDF6</i> That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal
No top-level findings curated for this source.
DOI:10.1016/j.ajhg.2009.06.007
Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene
No top-level findings curated for this source.
DOI:10.1093/hmg/ddx029
A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome
No top-level findings curated for this source.
DOI:10.3390/genes14030724
FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Multiple Synostoses Syndrome
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 20

Key Pathophysiology Nodes

  • BMP Signaling Dysregulation
  • Abnormal Joint Cavitation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1002/ajmg.a.38503
  • DOI:10.1002/jbmr.2761
  • DOI:10.1016/j.ajhg.2009.06.007
  • DOI:10.1093/hmg/ddx029
  • DOI:10.3390/genes14030724
Falcon ▸
Disease Pathophysiology Research Template
Edison Scientific Literature 18 citations 2026-02-10T07:49:13.977549

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Multiple Synostoses Syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Multiple Synostoses Syndrome. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Disease Pathophysiology Research Report: Multiple Synostoses Syndrome (SYNS1–4)

Target Disease - Disease Name: Multiple Synostoses Syndrome (SYNS) - MONDO ID: Not specified in source set - Category: Mendelian, autosomal dominant

Scope and nomenclature Multiple synostoses syndromes comprise a genetically heterogeneous group characterized by progressive or congenital joint fusions involving hands/feet (carpal–tarsal coalitions, symphalangism), large joints (e.g., elbow, knee), vertebrae, and sometimes conductive hearing loss due to stapes ankylosis. Four principal subtypes are recognized by causal genes: SYNS1 (NOG), SYNS2 (GDF5), SYNS3 (FGF9), SYNS4 (GDF6). Mechanistically, they converge on dysregulation of BMP and FGF signaling during joint morphogenesis and maintenance. (wu2009multiplesynostosessyndrome pages 7-8, tang2017apointmutation pages 9-10, wang2016anewsubtype pages 3-5, terhal2018furtherdelineationof pages 1-2)

1) Core Pathophysiology - Primary mechanisms: - Excess BMP pathway activity due to ligand gain-of-function and/or resistance to the BMP antagonist noggin (SYNS1/NOG, SYNS2/GDF5, SYNS4/GDF6) leading to ectopic chondrogenesis and failure of joint interzone formation/maintenance. Wang et al.: “a mutation in GDF6 … decreases its sensitivity to noggin and enhances its potency as a BMP signal” (J Bone Miner Res, Apr 2016; https://doi.org/10.1002/jbmr.2761). (wang2016anewsubtype pages 5-7, wang2016anewsubtype pages 3-5) - Impaired FGF9 signaling and altered FGF–BMP balance (SYNS3/FGF9), which disrupt joint interzone cell fate by failing to restrain chondrogenic differentiation and to support Gdf5 expression at nascent joints, producing synostosis. Tang et al.: “A point mutation in Fgf9 impedes joint interzone formation” (Hum Mol Genet, Apr 2017; https://doi.org/10.1093/hmg/ddx029). (tang2017apointmutation pages 9-10, tang2017apointmutation pages 1-2) - Dysregulated pathways: - Canonical BMP/SMAD signaling is increased by GDF6 Y444N and analogous GDF5 knuckle-epitope variants that are noggin-resistant; enhanced ALP activity, SMAD1/5/8 reporter activation, and increased chondrogenesis are documented. “Increased BMP signaling resulting from reduced sensitivity to NOG” (Wang 2016). (wang2016anewsubtype pages 5-7, wang2016anewsubtype pages 3-5) - FGF signaling via FGF9 is reduced with S99N: diminished ERK activation, reduced FGFR3 binding, and impaired Wnt/β-catenin support, shifting interzone mesenchyme toward chondrogenesis and ossification. Wu et al. report that the S99N mutant “shows impaired signaling … and markedly reduced binding to FGFR3,” contextualized within SYNS genetics. (Am J Hum Genet, Jul 2009; https://doi.org/10.1016/j.ajhg.2009.06.007). (wu2009multiplesynostosessyndrome pages 7-8) - Affected cellular processes: - Joint interzone formation and maintenance fail, with excess chondrogenesis at would-be joint spaces (FGF9 S99N) and exaggerated BMP-driven chondro-ossification (GDF6 Y444N; likely similar in NOG/GDF5). (tang2017apointmutation pages 9-10, wang2016anewsubtype pages 3-5) - Postnatal progression includes ectopic ossification and vertebral calcification/fusion with age in Fgf9 mutant models, consistent with progressive synostosis. (tang2017apointmutation pages 9-10)

2) Key Molecular Players - Genes/Proteins (HGNC): - NOG (HGNC:7858; protein: Noggin) – extracellular BMP antagonist; heterozygous variants cause SYNS1 and related NOG-spectrum disorders; mechanistic axis is loss of BMP inhibition → increased BMP activity. (Summary context within Wu 2009 and cross-referenced in Wang 2016). (wu2009multiplesynostosessyndrome pages 7-8, wang2016anewsubtype pages 8-8) - GDF5 (HGNC:4221; BMP14) – BMP-family ligand critical for joint patterning; SYNS2 variants include noggin-resistant mutations in the knuckle epitope causing enhanced signaling. “Mutation within the GDF5 knuckle epitope causes noggin-resistance.” (cited within Wang 2016 synopsis). (wang2016anewsubtype pages 8-8) - FGF9 (HGNC:3680) – paracrine FGF controlling interzone cell fate; S99N (human) impairs signaling, reduces FGFR3 binding, and diminishes ERK/Wnt outputs; SYNS3 is FGF9-associated. (wu2009multiplesynostosessyndrome pages 7-8, tang2017apointmutation pages 1-2) - GDF6 (HGNC:4228; BMP13) – BMP-family ligand; SYNS4 Y444N decreases sensitivity to NOG and “enhances its potency as a BMP signal,” producing gain-of-function. (wang2016anewsubtype pages 5-7, wang2016anewsubtype pages 3-5, terhal2018furtherdelineationof pages 1-2) - Chemical Entities (CHEBI) and modulators: - BMP ligands (class); antagonism by Noggin; FGF9–FGFR interactions regulate MAPK/ERK. Specific small-molecule therapeutics were not detailed in the source set; mechanistic chemicals are signaling proteins rather than small-molecule metabolites. (wu2009multiplesynostosessyndrome pages 7-8, wang2016anewsubtype pages 5-7) - Cell Types (CL): - Interzone mesenchymal cells (joint progenitors) and chondrocytes are primary targets; osteoblasts/osteoclasts contribute to ossification outcomes and vertebral fusion. FGF9 normally “inhibits mesenchymal differentiation into chondrocytes … maintaining an undifferentiated interzone” and S99N causes “excess chondrogenesis within the interzone.” (tang2017apointmutation pages 9-10, tang2017apointmutation pages 1-2) - Anatomical Locations (UBERON): - Distal appendicular skeleton: hand/foot (carpal/tarsal coalitions, symphalangism), large joints (elbow, knee), axial skeleton (vertebrae), middle ear (stapes) – consistent across SYNS subtypes with locus-specific variability. (wang2016anewsubtype pages 3-5, tang2017apointmutation pages 9-10, terhal2018furtherdelineationof pages 1-2)

3) Biological Processes (GO-style annotations) - BMP signaling pathway; positive regulation of chondrocyte differentiation; cartilage development; joint morphogenesis; regulation by BMP antagonist (Noggin). Empirically supported by functional assays: “enhanced BMP signaling” with GDF6 Y444N and noggin resistance (ALP, SMAD1/5/8 reporter, micromass chondrogenesis). (wang2016anewsubtype pages 5-7, wang2016anewsubtype pages 3-5) - FGF receptor signaling pathway; negative regulation of chondrogenesis in joint interzone; promotion of Gdf5 expression at nascent joints; MAPK/ERK cascade; crosstalk with Wnt/β-catenin. Demonstrated by FGF9 S99N effects on ERK, FGFR3 binding, and interzone gene programs. (wu2009multiplesynostosessyndrome pages 7-8, tang2017apointmutation pages 9-10) - Ossification and endochondral bone development; ectopic chondrogenesis leading to synostosis when regulatory balance is perturbed. (tang2017apointmutation pages 9-10, wang2016anewsubtype pages 3-5)

4) Cellular Components - Extracellular region: Noggin–BMP ligand interactions (NOG with GDF5/GDF6) governing receptor availability. (wang2016anewsubtype pages 3-5, terhal2018furtherdelineationof pages 1-2) - Plasma membrane: BMP type I/II receptors and FGFRs on chondrogenic/interzone cells mediating SMAD and MAPK cascades. (tang2017apointmutation pages 9-10, terhal2018furtherdelineationof pages 1-2) - ECM microenvironment at nascent joints (interzone) where ligand diffusion and receptor engagement set spatial signaling domains. (tang2017apointmutation pages 9-10)

5) Disease Progression - Initiation (prenatal): - SYNS3 (FGF9 S99N): failure to establish/maintain an undifferentiated interzone at selected joints, “imped[ing] joint interzone formation,” with reduced Gdf5 expression at elbow/knee, leading to patterning defects and early fusion. (Hum Mol Genet, Apr 2017; https://doi.org/10.1093/hmg/ddx029). (tang2017apointmutation pages 9-10, tang2017apointmutation pages 1-2) - SYNS4 (GDF6 Y444N): heightened BMP signaling due to noggin resistance drives ectopic chondrogenesis where joints should form; carpal/tarsal fusions prominent. (J Bone Miner Res, Apr 2016; https://doi.org/10.1002/jbmr.2761). (wang2016anewsubtype pages 5-7, wang2016anewsubtype pages 3-5) - Progression (postnatal): - Progressive vertebral fusion and increased ossification with age in Fgf9 mutant models; clinical SYNS cohorts show progressive ankylosis beyond congenital coalitions. (tang2017apointmutation pages 9-10) - Tissue spectrum: - Digits (symphalangism), carpals/tarsals, elbows/knees, vertebrae, and middle ear ossicles (stapes ankylosis in subsets), reflecting locus-specific expressivity. (wang2016anewsubtype pages 3-5, tang2017apointmutation pages 9-10, terhal2018furtherdelineationof pages 1-2)

6) Phenotypic Manifestations (HPO terms/examples) - Symphalangism (HP:0004691) and carpal–tarsal coalition (HP:0005048) with variable large-joint synostoses (e.g., elbow/knee; HP:0003031/HP:0010584). (tang2017apointmutation pages 9-10, wang2016anewsubtype pages 3-5) - Vertebral fusion (HP:0002948) with progressive involvement in some FGF9-associated cases. (tang2017apointmutation pages 9-10) - Conductive hearing loss due to stapes ankylosis (HP:0000405) – common in NOG/GDF6 subtypes; historically “unreported” in SYNS3 but 2023 family with FGF9 variant extends the spectrum to include conductive loss and cleft palate: “We extend the phenotypic spectrum of SYNS3 by suggesting that cleft palate and conductive hearing loss are part of the syndrome.” (Genes, Mar 2023; https://doi.org/10.3390/genes14030724). (schmetz2023fgf9associatedmultiplesynostoses pages 11-12, terhal2018furtherdelineationof pages 1-2)

Key Evidence Items (primary data, quotes, and dates) - GDF6 SYNS4 mechanism and phenotype: - “A new subtype of multiple synostoses syndrome is caused by a mutation in GDF6 that decreases its sensitivity to noggin and enhances its potency as a BMP signal” (Journal of Bone and Mineral Research, Apr 2016; DOI:10.1002/jbmr.2761; URL: https://doi.org/10.1002/jbmr.2761). Functional assays: increased ALP, SMAD1/5/8 reporter activity, and chondrogenesis; clinical: bilateral wrist/ankle deformities at birth and progressive conductive deafness after age 40. (wang2016anewsubtype pages 5-7, wang2016anewsubtype pages 3-5) - FGF9 SYNS3 mechanism and interzone biology: - “A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome” (Human Molecular Genetics, Apr 2017; DOI:10.1093/hmg/ddx029; URL: https://doi.org/10.1093/hmg/ddx029). S99N disrupts FGF signaling, fails to repress Sox6/Sox9 in interzone, reduces Gdf5 at elbow/knee, and causes site-specific synostosis; progressive axial changes with age. (tang2017apointmutation pages 9-10, tang2017apointmutation pages 1-2) - Original human genetics of SYNS3: “Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9” (American Journal of Human Genetics, Jul 2009; DOI:10.1016/j.ajhg.2009.06.007; URL: https://doi.org/10.1016/j.ajhg.2009.06.007). Shows S99N impairs ERK signaling, reduces FGFR3 binding, and alters Wnt/β-catenin context; delineates clinical spectrum. (wu2009multiplesynostosessyndrome pages 7-8) - GDF6-related SYNS4 delineation and hearing loss: - “Further delineation of the GDF6 related multiple synostoses syndrome” (Am J Med Genet A, Jan 2018; DOI:10.1002/ajmg.a.38503; URL: https://doi.org/10.1002/ajmg.a.38503). Confirms gain-of-function and noggin-resistance mechanisms with variable conductive hearing loss (otosclerosis/stapes fixation can occur in childhood). (terhal2018furtherdelineationof pages 1-2) - SYNS3 phenotype expansion and statistics: - “FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family” (Genes, Mar 2023; DOI:10.3390/genes14030724; URL: https://doi.org/10.3390/genes14030724). Reports a novel p.Trp144Arg variant; “only five different missense variants in FGF9 … reported in 18 affected individuals” previously; extends spectrum to include conductive hearing loss and cleft palate, with marked intrafamilial variability. (schmetz2023fgf9associatedmultiplesynostoses pages 11-12)

Expert perspectives and integrative analysis - Convergent model: Three subtypes (SYNS1/NOG; SYNS2/GDF5; SYNS4/GDF6) feature excessive BMP activity—by reduced noggin inhibition or ligand hypermorphs—driving ectopic chondrogenesis and joint failure; SYNS3/FGF9 features reduced local FGF signaling that fails to preserve an interzone progenitor state and to support Gdf5 expression, further tilting the BMP–FGF balance toward chondro-ossification. Wang et al. explicitly note: “3 of the 4 SYNS identified are the result of increased BMP signaling (SYNS1, SYNS2, and here SYNS4), whereas SYNS3 is caused by a loss-of-function mutation in FGF9.” (J Bone Miner Res, 2016; https://doi.org/10.1002/jbmr.2761). (wang2016anewsubtype pages 8-8) - Tissue selectivity and progression reflect spatially restricted expression (e.g., Fgf9 at elbow/knee), ligand diffusion/receptor context, and mechanical environments that modulate ossification postnatally (e.g., progressive vertebral involvement in Fgf9 S99N models). (tang2017apointmutation pages 9-10) - Hearing loss biology: Whereas conductive hearing loss is classically linked to NOG/GDF6 subtypes via stapes fixation/otosclerosis, recent SYNS3 evidence suggests FGF9 perturbation can also affect middle-ear development or maintenance, broadening counseling/management considerations. (schmetz2023fgf9associatedmultiplesynostoses pages 11-12, terhal2018furtherdelineationof pages 1-2)

Applications and real-world implementations - Genetic diagnosis and counseling: Gene-specific expectations guide surveillance—e.g., carpal/tarsal and vertebral imaging for all subtypes; audiologic monitoring prioritized for NOG/GDF6 and now considered in FGF9 families per 2023 report. (schmetz2023fgf9associatedmultiplesynostoses pages 11-12, terhal2018furtherdelineationof pages 1-2) - Surgical/rehabilitative care: Although not detailed extensively in the current evidence set, mechanistic and anatomical insights underpin orthopedic management of coalitions/synostoses and stapes surgery timing in conductive loss. The recognition that interzone failure and ectopic ossification are ongoing processes supports staged, individualized orthopedic interventions. (tang2017apointmutation pages 9-10, terhal2018furtherdelineationof pages 1-2)

Structured annotations (ontology cross-references; examples) - Genes/Proteins (HGNC): NOG (HGNC:7858); GDF5 (HGNC:4221); FGF9 (HGNC:3680); GDF6 (HGNC:4228). (wu2009multiplesynostosessyndrome pages 7-8, wang2016anewsubtype pages 8-8, tang2017apointmutation pages 9-10, terhal2018furtherdelineationof pages 1-2) - Biological Processes (GO): BMP signaling pathway; joint morphogenesis; chondrocyte differentiation; FGF receptor signaling pathway; MAPK cascade; regulation by BMP antagonist activity. (wang2016anewsubtype pages 3-5, tang2017apointmutation pages 9-10) - Cellular Components (GO): extracellular region (ligand–antagonist interactions); plasma membrane (BMPRs, FGFRs); extracellular matrix at nascent joint interzone. (terhal2018furtherdelineationof pages 1-2, tang2017apointmutation pages 9-10) - Cell Types (CL): interzone mesenchymal progenitors; chondrocytes; osteoblasts; osteoclasts. (tang2017apointmutation pages 9-10) - Anatomical Locations (UBERON): hand (carpal bones), foot (tarsal bones), elbow, knee, vertebral column, middle ear (stapes). (wang2016anewsubtype pages 3-5, tang2017apointmutation pages 9-10, terhal2018furtherdelineationof pages 1-2) - Phenotypes (HPO): symphalangism (HP:0004691); carpal–tarsal coalition (HP:0005048); elbow ankylosis/synostosis (HP:0003031); vertebral fusion (HP:0002948); conductive hearing loss (HP:0000405). (tang2017apointmutation pages 9-10, wang2016anewsubtype pages 3-5, terhal2018furtherdelineationof pages 1-2)

Recent developments (2023–2024 priority) - FGF9/SYNS3 spectrum expanded: conductive hearing loss and cleft palate reported in a large multigenerational family; total known FGF9 missense variants and affected individuals summarized, underscoring rarity and variable expressivity (Genes, Mar 2023; https://doi.org/10.3390/genes14030724). (schmetz2023fgf9associatedmultiplesynostoses pages 11-12)

Limitations and open questions - Though noggin-resistance is clearly demonstrated for selected GDF5/GDF6 variants, quantitative maps of NOG–BMP–FGF crosstalk across all human SYNS alleles remain incomplete. Site-specific vulnerability (e.g., elbow/knee) needs deeper integration of spatiotemporal expression and biomechanics to predict phenotype. (tang2017apointmutation pages 9-10, wang2016anewsubtype pages 3-5)

References with URLs and dates (subset, keyed to citations above) - Wang et al., Journal of Bone and Mineral Research, Apr 2016. “A new subtype of multiple synostoses syndrome is caused by a mutation in GDF6 that decreases its sensitivity to noggin and enhances its potency as a BMP signal.” DOI:10.1002/jbmr.2761. URL: https://doi.org/10.1002/jbmr.2761 (wang2016anewsubtype pages 5-7, wang2016anewsubtype pages 3-5) - Tang et al., Human Molecular Genetics, Apr 2017. “A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome.” DOI:10.1093/hmg/ddx029. URL: https://doi.org/10.1093/hmg/ddx029 (tang2017apointmutation pages 9-10, tang2017apointmutation pages 1-2) - Wu et al., American Journal of Human Genetics, Jul 2009. “Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene.” DOI:10.1016/j.ajhg.2009.06.007. URL: https://doi.org/10.1016/j.ajhg.2009.06.007 (wu2009multiplesynostosessyndrome pages 7-8) - Terhal et al., American Journal of Medical Genetics Part A, Jan 2018. “Further delineation of the GDF6 related multiple synostoses syndrome.” DOI:10.1002/ajmg.a.38503. URL: https://doi.org/10.1002/ajmg.a.38503 (terhal2018furtherdelineationof pages 1-2) - Schmetz et al., Genes, Mar 2023. “FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family.” DOI:10.3390/genes14030724. URL: https://doi.org/10.3390/genes14030724 (schmetz2023fgf9associatedmultiplesynostoses pages 11-12)

References

  1. (wu2009multiplesynostosessyndrome pages 7-8): Xiao-lin Wu, Ming-min Gu, Lei Huang, Xue-song Liu, Hong-xin Zhang, Xiao-yi Ding, Jian-qiang Xu, Bin Cui, Long Wang, Shun-yuan Lu, Xiao-yi Chen, Hai-guo Zhang, Wei Huang, Wen-tao Yuan, Jiang-ming Yang, Qun Gu, Jian Fei, Zhu Chen, Zhi-min Yuan, and Zhu-gang Wang. Multiple synostoses syndrome is due to a missense mutation in exon 2 of fgf9 gene. American journal of human genetics, 85 1:53-63, Jul 2009. URL: https://doi.org/10.1016/j.ajhg.2009.06.007, doi:10.1016/j.ajhg.2009.06.007. This article has 104 citations and is from a highest quality peer-reviewed journal.

  2. (tang2017apointmutation pages 9-10): Lingyun Tang, Xiaolin Wu, Hongxing Zhang, Shun-yuan Lu, Min Wu, Chunling Shen, Xuejiao Chen, Yicheng Wang, Wei-gang Wang, Yan Shen, Ming-min Gu, Xiaoyi Ding, Xiaolong Jin, J. Fei, and Zhugang Wang. A point mutation in fgf9 impedes joint interzone formation leading to multiple synostoses syndrome. Human Molecular Genetics, 26:1280–1293, Apr 2017. URL: https://doi.org/10.1093/hmg/ddx029, doi:10.1093/hmg/ddx029. This article has 34 citations and is from a domain leading peer-reviewed journal.

  3. (wang2016anewsubtype pages 3-5): Jian Wang, Tingting Yu, Zhigang Wang, Satoshi Ohte, Ru-en Yao, Zhaojing Zheng, Juan Geng, Haiqing Cai, Yihua Ge, Yuchan Li, Yunlan Xu, Qinghua Zhang, James F Gusella, Qihua Fu, Steven Pregizer, Vicki Rosen, and Yiping Shen. A new subtype of multiple synostoses syndrome is caused by a mutation in gdf6 that decreases its sensitivity to noggin and enhances its potency as a bmp signal. Journal of Bone and Mineral Research, Apr 2016. URL: https://doi.org/10.1002/jbmr.2761, doi:10.1002/jbmr.2761. This article has 40 citations and is from a highest quality peer-reviewed journal.

  4. (terhal2018furtherdelineationof pages 1-2): Paulien A. Terhal, Nienke E. Verbeek, Nine Knoers, Rutger J. A. J. Nievelstein, Ans van den Ouweland, Ralph J. Sakkers, Lucienne Speleman, and Gijs van Haaften. Further delineation of the gdf6 related multiple synostoses syndrome. American Journal of Medical Genetics Part A, 176:225-229, Jan 2018. URL: https://doi.org/10.1002/ajmg.a.38503, doi:10.1002/ajmg.a.38503. This article has 15 citations.

  5. (wang2016anewsubtype pages 5-7): Jian Wang, Tingting Yu, Zhigang Wang, Satoshi Ohte, Ru-en Yao, Zhaojing Zheng, Juan Geng, Haiqing Cai, Yihua Ge, Yuchan Li, Yunlan Xu, Qinghua Zhang, James F Gusella, Qihua Fu, Steven Pregizer, Vicki Rosen, and Yiping Shen. A new subtype of multiple synostoses syndrome is caused by a mutation in gdf6 that decreases its sensitivity to noggin and enhances its potency as a bmp signal. Journal of Bone and Mineral Research, Apr 2016. URL: https://doi.org/10.1002/jbmr.2761, doi:10.1002/jbmr.2761. This article has 40 citations and is from a highest quality peer-reviewed journal.

  6. (tang2017apointmutation pages 1-2): Lingyun Tang, Xiaolin Wu, Hongxing Zhang, Shun-yuan Lu, Min Wu, Chunling Shen, Xuejiao Chen, Yicheng Wang, Wei-gang Wang, Yan Shen, Ming-min Gu, Xiaoyi Ding, Xiaolong Jin, J. Fei, and Zhugang Wang. A point mutation in fgf9 impedes joint interzone formation leading to multiple synostoses syndrome. Human Molecular Genetics, 26:1280–1293, Apr 2017. URL: https://doi.org/10.1093/hmg/ddx029, doi:10.1093/hmg/ddx029. This article has 34 citations and is from a domain leading peer-reviewed journal.

  7. (wang2016anewsubtype pages 8-8): Jian Wang, Tingting Yu, Zhigang Wang, Satoshi Ohte, Ru-en Yao, Zhaojing Zheng, Juan Geng, Haiqing Cai, Yihua Ge, Yuchan Li, Yunlan Xu, Qinghua Zhang, James F Gusella, Qihua Fu, Steven Pregizer, Vicki Rosen, and Yiping Shen. A new subtype of multiple synostoses syndrome is caused by a mutation in gdf6 that decreases its sensitivity to noggin and enhances its potency as a bmp signal. Journal of Bone and Mineral Research, Apr 2016. URL: https://doi.org/10.1002/jbmr.2761, doi:10.1002/jbmr.2761. This article has 40 citations and is from a highest quality peer-reviewed journal.

  8. (schmetz2023fgf9associatedmultiplesynostoses pages 11-12): Ariane Schmetz, Jörg Schaper, Simon Thelen, Majeed Rana, Thomas Klenzner, Katharina Schaumann, Jasmin Beygo, Harald Surowy, Hermann-Josef Lüdecke, and Dagmar Wieczorek. Fgf9-associated multiple synostoses syndrome type 3 in a multigenerational family. Genes, 14:724, Mar 2023. URL: https://doi.org/10.3390/genes14030724, doi:10.3390/genes14030724. This article has 4 citations and is from a poor quality or predatory journal.