Multiple synostoses syndrome

Summary

Multiple synostoses syndrome (MONDO:0017923) is a disease caused by FGF9 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FGF9 (GenCC Definitive)
• Cohort genes: 3
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000405	Conductive hearing impairment	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0009773	Symphalangism affecting the phalanges of the hand	Very frequent (80-99%)
HP:0007598	Bilateral single transverse palmar creases	Frequent (30-79%)
HP:0010579	Cone-shaped epiphysis	Frequent (30-79%)
HP:0011304	Broad thumb	Frequent (30-79%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0001597	Abnormality of the nail	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple synostoses syndrome
Mondo ID	MONDO:0017923
OMIM	186500
Orphanet	3237
DOID	DOID:0050794
ICD-11	248917534
UMLS	C0175700
MedGen	511579
GARD	0003836
Is cancer (heuristic)	no

Also known as: deafness-Hermann type symphalangism syndrome · facio-audio-symphalangism · symphalangism-brachydactyly syndrome · WL syndrome

Data availability: 4 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › synostosis › multiple synostoses syndrome

Related subtypes (10): Banki syndrome, humeroradial synostosis, calcaneonavicular coalition, craniosynostosis, tibio-fibular synostosis, humero-radio-ulnar synostosis, congenital radioulnar synostosis, humero-ulnar synostosis, coronal synostosis, syndactyly and jejunal atresia, non-syndromic pansynostosis

Subtypes (4): multiple synostoses syndrome 1, multiple synostoses syndrome 2, multiple synostoses syndrome 3, multiple synostoses syndrome 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FGF9	Definitive	Autosomal dominant	multiple synostoses syndrome	5
NOG	Definitive	Autosomal dominant	multiple synostoses syndrome 1	10
GDF5	Strong	Autosomal dominant	multiple synostoses syndrome 2	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF9	Orphanet:3237	Multiple synostoses syndrome
GDF5	Orphanet:2098	Acromesomelic dysplasia, Grebe type
GDF5	Orphanet:2639	Fibular aplasia-complex brachydactyly syndrome
GDF5	Orphanet:3237	Multiple synostoses syndrome
GDF5	Orphanet:3250	Proximal symphalangism
GDF5	Orphanet:63442	Angel-shaped phalango-epiphyseal dysplasia
GDF5	Orphanet:93384	Brachydactyly type C
GDF5	Orphanet:93388	Brachydactyly type A1
GDF5	Orphanet:93396	Brachydactyly type A2
GDF5	Orphanet:968	Acromesomelic dysplasia, Hunter-Thompson type
NOG	Orphanet:140908	Brachydactyly type B2
NOG	Orphanet:140917	Stapes ankylosis with broad thumbs and toes
NOG	Orphanet:1412	Tarsal-carpal coalition syndrome
NOG	Orphanet:3237	Multiple synostoses syndrome
NOG	Orphanet:3250	Proximal symphalangism

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGF9	HGNC:3687	ENSG00000102678	P31371	Fibroblast growth factor 9	gencc
GDF5	HGNC:4220	ENSG00000125965	P43026	Growth/differentiation factor 5	gencc
NOG	HGNC:7866	ENSG00000183691	Q13253	Noggin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF9	Fibroblast growth factor 9	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.
GDF5	Growth/differentiation factor 5	Growth factor involved in bone and cartilage formation.
NOG	Noggin	Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF9	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
GDF5	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
NOG	Other/Unknown	no		Noggin, Cystine-knot_cytokine

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
renal medulla	1
secondary oocyte	1
cartilage tissue	1
parotid gland	1
pericardium	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF9	237	broad	marker	secondary oocyte, renal medulla, oocyte
GDF5	116	broad	yes	parotid gland, pericardium, cartilage tissue
NOG	155	broad	marker	pigmented layer of retina, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF9	4,036
NOG	2,338
GDF5	1,486

Intra-cohort edges

A	B	Sources
GDF5	NOG	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDF5	P43026	15
FGF9	P31371	3
NOG	Q13253	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR3b ligand binding and activation	1	543.8×	0.010	FGF9
Signaling by activated point mutants of FGFR1	1	317.2×	0.010	FGF9
Signaling by activated point mutants of FGFR3	1	317.2×	0.010	FGF9
FGFR3c ligand binding and activation	1	292.8×	0.010	FGF9
FGFR2c ligand binding and activation	1	292.8×	0.010	FGF9
Phospholipase C-mediated cascade; FGFR3	1	292.8×	0.010	FGF9
FGFR4 ligand binding and activation	1	271.9×	0.010	FGF9
FGFR1c ligand binding and activation	1	253.8×	0.010	FGF9
Phospholipase C-mediated cascade; FGFR4	1	253.8×	0.010	FGF9
Transcriptional regulation of testis differentiation	1	237.9×	0.010	FGF9
Activated point mutants of FGFR2	1	223.9×	0.010	FGF9
Phospholipase C-mediated cascade: FGFR1	1	223.9×	0.010	FGF9
Phospholipase C-mediated cascade; FGFR2	1	211.5×	0.010	FGF9
PI-3K cascade:FGFR3	1	211.5×	0.010	FGF9
SHC-mediated cascade:FGFR3	1	200.3×	0.010	FGF9
PI-3K cascade:FGFR4	1	190.3×	0.010	FGF9
Downstream signaling of activated FGFR1	1	181.3×	0.010	FGF9
FRS-mediated FGFR3 signaling	1	181.3×	0.010	FGF9
SHC-mediated cascade:FGFR4	1	181.3×	0.010	FGF9
PI-3K cascade:FGFR1	1	173.0×	0.010	FGF9
SHC-mediated cascade:FGFR1	1	165.5×	0.010	FGF9
PI-3K cascade:FGFR2	1	165.5×	0.010	FGF9
FRS-mediated FGFR4 signaling	1	165.5×	0.010	FGF9
Signaling by FGFR3 in disease	1	165.5×	0.010	FGF9
SHC-mediated cascade:FGFR2	1	158.6×	0.010	FGF9
FRS-mediated FGFR1 signaling	1	152.3×	0.010	FGF9
FRS-mediated FGFR2 signaling	1	146.4×	0.010	FGF9
Negative regulation of FGFR3 signaling	1	146.4×	0.010	FGF9
Negative regulation of FGFR4 signaling	1	135.9×	0.010	FGF9
Formation of paraxial mesoderm	1	135.9×	0.010	NOG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic limb morphogenesis	2	267.5×	0.001	FGF9, GDF5
embryonic skeletal system development	2	261.3×	0.001	FGF9, NOG
chondrocyte differentiation	2	200.6×	0.001	FGF9, GDF5
fibroblast growth factor receptor signaling pathway	2	190.4×	0.001	FGF9, NOG
positive regulation of epithelial cell proliferation	2	162.8×	0.001	FGF9, NOG
BMP signaling pathway	2	133.8×	0.002	GDF5, NOG
smoothened signaling pathway	2	120.8×	0.002	FGF9, NOG
negative regulation of cardiac epithelial to mesenchymal transition	1	5617.3×	0.003	NOG
osteoblast differentiation	2	80.8×	0.003	FGF9, NOG
positive regulation of glomerulus development	1	2808.7×	0.004	NOG
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	2808.7×	0.004	FGF9
neural plate morphogenesis	1	1872.4×	0.004	NOG
cell differentiation in hindbrain	1	1872.4×	0.004	NOG
neural plate anterior/posterior regionalization	1	1872.4×	0.004	NOG
ossification involved in bone remodeling	1	1872.4×	0.004	GDF5
short-term synaptic potentiation	1	1872.4×	0.004	NOG
cell-cell signaling	2	46.4×	0.004	FGF9, GDF5
regulation of timing of cell differentiation	1	1404.3×	0.005	FGF9
prostatic bud formation	1	1404.3×	0.005	NOG
axial mesoderm development	1	1123.5×	0.005	NOG
notochord morphogenesis	1	1123.5×	0.005	NOG
chondroblast differentiation	1	1123.5×	0.005	GDF5
positive regulation of activin receptor signaling pathway	1	936.2×	0.005	FGF9
hindlimb morphogenesis	1	936.2×	0.005	GDF5
Sertoli cell proliferation	1	936.2×	0.005	FGF9
ventricular compact myocardium morphogenesis	1	802.5×	0.005	NOG
regulation of fibroblast growth factor receptor signaling pathway	1	802.5×	0.005	NOG
atrial cardiac muscle tissue morphogenesis	1	802.5×	0.005	NOG
ureteric bud formation	1	802.5×	0.005	NOG
negative regulation of mesenchymal cell apoptotic process	1	802.5×	0.005	GDF5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGF9	0	0
GDF5	0	0
NOG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	FGF9, GDF5, NOG

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FGF9	0	—
GDF5	0	—
NOG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.