Proximal symphalangism

Summary

Proximal symphalangism (MONDO:0008511) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• Phenotypes (HPO): 15

Clinical features

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0005048	Synostosis of carpal bones	Very frequent (80-99%)
HP:0008368	Tarsal synostosis	Very frequent (80-99%)
HP:0100264	Proximal symphalangism	Very frequent (80-99%)
HP:0100490	Camptodactyly of finger	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0003042	Elbow dislocation	Frequent (30-79%)
HP:0003070	Elbow ankylosis	Frequent (30-79%)
HP:0005880	Metacarpophalangeal synostosis	Frequent (30-79%)
HP:0005916	Abnormal metacarpal morphology	Frequent (30-79%)
HP:0040019	Finger clinodactyly	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0003019	Abnormality of the wrist	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	proximal symphalangism
Mondo ID	MONDO:0008511
MeSH	C536223
OMIM	185800
Orphanet	3250
DOID	DOID:0050788
ICD-11	49802338
UMLS	C1861385
MedGen	348856
GARD	0008182
Is cancer (heuristic)	no

Also known as: hereditary absence of proximal interphalangeal joints · proximal symphalangism · proximal symphalangism (disease) · Strasburger-Hawkins-Eldridge syndrome · Strasburger-Hawkins-Eldridge-Hargrave-McKusick syndrome · symphalangism, Cushing type · vessel’s syndrome

Data availability: 2 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › symphalangism › proximal symphalangism

Related subtypes (5): symphalangism of toes, symphalangism, C. S. Lewis type, distal symphalangism, symphalangism with multiple anomalies of hands and feet, NOG-related symphalangism spectrum disorder

Subtypes (2): symphalangism, proximal, 1B, proximal symphalangism 1A

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: 30 · Orphanet: 14 · 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
GDF5	Definitive	Autosomal dominant	symphalangism, proximal, 1B	20
NOG	Definitive	Autosomal dominant	NOG-related symphalangism spectrum disorder	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
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)
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: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
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
NOG	2,338
GDF5	1,486

Intra-cohort edges

A	B	Sources
GDF5	NOG	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDF5	P43026	15
NOG	Q13253	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of paraxial mesoderm	1	203.9×	0.006	NOG
Signaling by BMP	1	178.4×	0.006	NOG
Molecules associated with elastic fibres	1	154.3×	0.006	GDF5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
BMP signaling pathway	2	200.6×	0.002	GDF5, NOG
negative regulation of cardiac epithelial to mesenchymal transition	1	8426.0×	0.004	NOG
positive regulation of glomerulus development	1	4213.0×	0.004	NOG
neural plate morphogenesis	1	2808.7×	0.004	NOG
cell differentiation in hindbrain	1	2808.7×	0.004	NOG
neural plate anterior/posterior regionalization	1	2808.7×	0.004	NOG
ossification involved in bone remodeling	1	2808.7×	0.004	GDF5
short-term synaptic potentiation	1	2808.7×	0.004	NOG
prostatic bud formation	1	2106.5×	0.004	NOG
axial mesoderm development	1	1685.2×	0.004	NOG
notochord morphogenesis	1	1685.2×	0.004	NOG
chondroblast differentiation	1	1685.2×	0.004	GDF5
hindlimb morphogenesis	1	1404.3×	0.004	GDF5
ventricular compact myocardium morphogenesis	1	1203.7×	0.004	NOG
regulation of fibroblast growth factor receptor signaling pathway	1	1203.7×	0.004	NOG
atrial cardiac muscle tissue morphogenesis	1	1203.7×	0.004	NOG
ureteric bud formation	1	1203.7×	0.004	NOG
negative regulation of mesenchymal cell apoptotic process	1	1203.7×	0.004	GDF5
forelimb morphogenesis	1	1053.2×	0.004	GDF5
negative regulation of cartilage development	1	1053.2×	0.004	NOG
negative regulation of cardiac muscle cell proliferation	1	936.2×	0.004	NOG
heart trabecula morphogenesis	1	936.2×	0.004	NOG
membranous septum morphogenesis	1	842.6×	0.004	NOG
pharyngeal arch artery morphogenesis	1	842.6×	0.004	NOG
negative regulation of astrocyte differentiation	1	766.0×	0.004	NOG
embryonic skeletal joint morphogenesis	1	766.0×	0.004	NOG
mesenchymal cell apoptotic process	1	766.0×	0.004	GDF5
endoderm formation	1	702.2×	0.004	NOG
endocardial cushion formation	1	702.2×	0.004	NOG
nodal signaling pathway	1	561.7×	0.005	NOG

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
GDF5	0	0
NOG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	GDF5, NOG

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.