Campomelic dysplasia

Summary

Campomelic dysplasia (MONDO:0007251) is a disease caused by SOX9 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SOX9 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 355
• Phenotypes (HPO): 38
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000	0.0003	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	1.875	Worldwide

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0000878	11 pairs of ribs	Very frequent (80-99%)
HP:0001601	Laryngomalacia	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0002779	Tracheomalacia	Very frequent (80-99%)
HP:0002786	Tracheobronchomalacia	Very frequent (80-99%)
HP:0002827	Hip dislocation	Very frequent (80-99%)
HP:0002982	Tibial bowing	Very frequent (80-99%)
HP:0003026	Short long bone	Very frequent (80-99%)
HP:0003038	Fibular hypoplasia	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0006584	Small abnormally formed scapulae	Very frequent (80-99%)
HP:0008477	Poorly ossified cervical vertebrae	Very frequent (80-99%)
HP:0008821	Hypoplastic inferior ilia	Very frequent (80-99%)
HP:0012368	Flat face	Very frequent (80-99%)
HP:0000037	Male pseudohermaphroditism	Frequent (30-79%)
HP:0000062	Ambiguous genitalia	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002980	Femoral bowing	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0010781	Skin dimple	Frequent (30-79%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0004408	Abnormality of the sense of smell	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0007036	Hypoplasia of olfactory tract	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	campomelic dysplasia
Mondo ID	MONDO:0007251
MeSH	D055036
OMIM	114290
Orphanet	140
DOID	DOID:0050463
ICD-11	913761638
NCIT	C84609
SNOMED CT	74928006
UMLS	C1861922
MedGen	354620
GARD	0010027
NORD	884
Is cancer (heuristic)	no

Also known as: acampomelic campomelic dysplasia · campomelic dwarfism · campomelic dysplasia · Campomelic Syndrome · CMD · CMPD1

Data availability: 355 ClinVar variants · 5 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › campomelic dysplasia

Related subtypes (47): autoimmune disorder of endocrine system, parathyroid gland disorder, endocrine gland neoplasm, gonadal disorder, pancreas disorder, thyroid gland disorder, pituitary gland disorder, thymus gland disorder, liver disorder, adrenal gland disorder, hyperinsulinemic hypoglycemia, non-neoplastic bile duct disorder, endocrine tuberculosis, polycystic ovary syndrome, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, genito-palato-cardiac syndrome, hypoinsulinemic hypoglycemia and body hemihypertrophy, Bamforth-Lazarus syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type, Wolfram-like syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, estrogen resistance syndrome, short stature, microcephaly, and endocrine dysfunction, polyendocrinopathy, pituitary deficiency, hereditary endocrine growth disease, diencephalic syndrome, muscular pseudohypertrophy-hypothyroidism syndrome, neonatal iodine exposure, disorders of vitamin D metabolism, rapid-onset childhood obesity-hypothalamic dysfunction-hypoventilation-autonomic dysregulation syndrome, duplication of the pituitary gland, familial hypocalciuric hypercalcemia, hypothalamic adipsic hypernatraemia syndrome, Leydig cell hypoplasia, inherited obesity, beta thalassemia, thyroid hormone metabolism, abnormal, neuroendocrine disorder, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, parneoplastic endocrine syndrome, 17,20-lyase deficiency, isolated, 17-alpha-hydroxylase/17,20-lyase deficiency, combined complete, 17-alpha-hydroxylase/17,20-lyase deficiency, combined partial, disorder of GNAS inactivation, acquired hypothalamic obesity

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

ClinVar germline variants

355 retrieved; paginated sample, class counts are floors:

122 uncertain significance, 103 likely benign, 48 pathogenic, 24 benign, 21 conflicting classifications of pathogenicity, 19 likely pathogenic, 10 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3243057	NC_000017.10:g.(?68171181)(70120528_?)del	KCNJ2	Pathogenic	criteria provided, single submitter
1254813	NM_000346.4(SOX9):c.337A>G (p.Met113Val)	LOC108021846	Pathogenic	criteria provided, multiple submitters, no conflicts
1323635	NM_000346.4(SOX9):c.124dup (p.Asp42fs)	LOC108021846	Pathogenic	criteria provided, single submitter
1422924	NM_000346.4(SOX9):c.313G>T (p.Val105Phe)	LOC108021846	Pathogenic	criteria provided, single submitter
1458092	NM_000346.4(SOX9):c.255_256del (p.Asp85fs)	LOC108021846	Pathogenic	criteria provided, single submitter
1699037	NM_000346.4(SOX9):c.218T>C (p.Ile73Thr)	LOC108021846	Pathogenic	criteria provided, single submitter
2041795	NM_000346.4(SOX9):c.334_335del (p.Phe112fs)	LOC108021846	Pathogenic	criteria provided, single submitter
2515	NM_000346.4(SOX9):c.197_226del (p.Glu66_Glu75del)	LOC108021846	Pathogenic	no assertion criteria provided
2582587	NM_000346.4(SOX9):c.326T>C (p.Met109Thr)	LOC108021846	Pathogenic	criteria provided, single submitter
3653482	NM_000346.4(SOX9):c.271_272del (p.Met91fs)	LOC108021846	Pathogenic	criteria provided, single submitter
468239	NM_000346.4(SOX9):c.252C>G (p.Tyr84Ter)	LOC108021846	Pathogenic	criteria provided, single submitter
468240	NM_000346.4(SOX9):c.349C>T (p.Gln117Ter)	LOC108021846	Pathogenic	criteria provided, single submitter
1071225	NM_000346.4(SOX9):c.1116_1117del (p.Pro374fs)	SOX9	Pathogenic	criteria provided, single submitter
1178322	t(11;17)(p15.4;q24.3)	SOX9	Pathogenic	no assertion criteria provided
1191722	NM_000346.4(SOX9):c.473C>T (p.Ala158Val)	SOX9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452379	NM_000346.4(SOX9):c.600dup (p.Asn201fs)	SOX9	Pathogenic	criteria provided, single submitter
1454687	NM_000346.4(SOX9):c.527C>T (p.Pro176Leu)	SOX9	Pathogenic	criteria provided, single submitter
1485794	NM_000346.4(SOX9):c.508C>A (p.Pro170Thr)	SOX9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1527950	NM_000346.4(SOX9):c.686-2A>G	SOX9	Pathogenic	criteria provided, single submitter
1699296	NM_000346.4(SOX9):c.517A>T (p.Lys173Ter)	SOX9	Pathogenic	criteria provided, single submitter
2008010	NC_000017.11:g.72122720_72122736del	SOX9	Pathogenic	criteria provided, single submitter
2040173	NM_000346.4(SOX9):c.683C>A (p.Ser228Ter)	SOX9	Pathogenic	criteria provided, single submitter
2047766	NM_000346.4(SOX9):c.515A>T (p.Tyr172Phe)	SOX9	Pathogenic	criteria provided, single submitter
2106821	NM_000346.4(SOX9):c.685+2T>C	SOX9	Pathogenic	criteria provided, single submitter
21163	NM_000346.4(SOX9):c.1320C>A (p.Tyr440Ter)	SOX9	Pathogenic	criteria provided, multiple submitters, no conflicts
2138102	NM_000346.4(SOX9):c.432-2A>C	SOX9	Pathogenic	criteria provided, single submitter
2138103	NM_000346.4(SOX9):c.455G>C (p.Arg152Pro)	SOX9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506	NM_000346.4(SOX9):c.583C>T (p.Gln195Ter)	SOX9	Pathogenic	criteria provided, single submitter
2507	NM_000346.4(SOX9):c.788dup (p.Arg264fs)	SOX9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2509	NM_000346.4(SOX9):c.736dup (p.Gln246fs)	SOX9	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 9 · 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
SOX9	Definitive	Autosomal dominant	campomelic dysplasia	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX9	Orphanet:140	Campomelic dysplasia
SOX9	Orphanet:2138	46,XX ovotesticular difference of sex development
SOX9	Orphanet:242	46,XY complete gonadal dysgenesis
SOX9	Orphanet:251510	46,XY partial gonadal dysgenesis
SOX9	Orphanet:393	46,XX testicular difference of sex development
SOX9	Orphanet:718	Isolated Pierre Robin sequence
KCNJ2	Orphanet:334	Hereditary atrial fibrillation
KCNJ2	Orphanet:37553	Andersen-Tawil syndrome
KCNJ2	Orphanet:51083	Congenital short QT syndrome

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
SOX9	HGNC:11204	ENSG00000125398	P48436	Transcription factor SOX-9	gencc,clinvar
FRS3	HGNC:16970	ENSG00000137218	O43559	Fibroblast growth factor receptor substrate 3	clinvar
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX9	Transcription factor SOX-9	Transcription factor that plays a key role in chondrocytes differentiation and skeletal development.
FRS3	Fibroblast growth factor receptor substrate 3	Adapter protein that links FGF and NGF receptors to downstream signaling pathways.
KCNJ2	Inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Ion channel	1	37.2×	0.080
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX9	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
FRS3	Other/Unknown	no		IRS_PTB, PH-like_dom_sf, FRS2_PTB
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N

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
cranial nerve II	1
hair follicle	1
ventricular zone	1
anterior cingulate cortex	1
cingulate cortex	1
right hemisphere of cerebellum	1
dorsal motor nucleus of vagus nerve	1
inferior vagus X ganglion	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX9	274	ubiquitous	marker	ventricular zone, cranial nerve II, hair follicle
FRS3	185	ubiquitous	yes	right hemisphere of cerebellum, anterior cingulate cortex, cingulate cortex
KCNJ2	256	ubiquitous	marker	inferior vagus X ganglion, skeletal muscle tissue of rectus abdominis, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX9	4,935
FRS3	1,044
KCNJ2	65

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FRS3	O43559	4
KCNJ2	P63252	3
SOX9	P48436	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. 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
Sensory perception of sour taste	1	1903.3×	0.020	KCNJ2
Classical Kir channels	1	951.7×	0.020	KCNJ2
G protein gated Potassium channels	1	380.7×	0.020	KCNJ2
Activated NTRK2 signals through FRS2 and FRS3	1	317.2×	0.020	FRS3
Inwardly rectifying K+ channels	1	237.9×	0.020	KCNJ2
Transcriptional regulation of testis differentiation	1	237.9×	0.020	SOX9
Phase 4 - resting membrane potential	1	200.3×	0.020	KCNJ2
Activation of GABAB receptors	1	200.3×	0.020	KCNJ2
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	200.3×	0.020	SOX9
FRS-mediated FGFR3 signaling	1	181.3×	0.020	FRS3
GABA B receptor activation	1	181.3×	0.020	KCNJ2
FRS-mediated FGFR4 signaling	1	165.5×	0.020	FRS3
FRS-mediated FGFR1 signaling	1	152.3×	0.020	FRS3
FRS-mediated FGFR2 signaling	1	146.4×	0.020	FRS3
Activation of G protein gated Potassium channels	1	131.3×	0.020	KCNJ2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	131.3×	0.020	KCNJ2
Sensory perception of taste	1	112.0×	0.023	KCNJ2
GABA receptor activation	1	105.7×	0.023	KCNJ2
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.023	SOX9
RND1 GTPase cycle	1	88.5×	0.023	FRS3
RND2 GTPase cycle	1	86.5×	0.023	FRS3
Transcriptional regulation by RUNX2	1	84.6×	0.023	SOX9
Deactivation of the beta-catenin transactivating complex	1	77.7×	0.023	SOX9
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.023	SOX9
Developmental Cell Lineages	1	74.6×	0.023	SOX9
Transcriptional and post-translational regulation of MITF-M expression and activity	1	59.5×	0.028	SOX9
Signaling by ALK fusions and activated point mutants	1	50.1×	0.032	FRS3
Potassium Channels	1	44.8×	0.034	KCNJ2
TCF dependent signaling in response to WNT	1	39.2×	0.037	SOX9
MITF-M-regulated melanocyte development	1	38.1×	0.037	SOX9

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
regulation of skeletal muscle contraction via regulation of action potential	1	5617.3×	0.004	KCNJ2
negative regulation of immune system process	1	2808.7×	0.004	SOX9
epithelial cell proliferation involved in prostatic bud elongation	1	2808.7×	0.004	SOX9
regulation of cell proliferation involved in tissue homeostasis	1	2808.7×	0.004	SOX9
regulation of branching involved in lung morphogenesis	1	2808.7×	0.004	SOX9
cell proliferation involved in heart morphogenesis	1	2808.7×	0.004	SOX9
regulation of epithelial cell proliferation involved in lung morphogenesis	1	2808.7×	0.004	SOX9
heart valve formation	1	1872.4×	0.004	SOX9
neural crest cell fate specification	1	1872.4×	0.004	SOX9
male germ-line sex determination	1	1872.4×	0.004	SOX9
intrahepatic bile duct development	1	1872.4×	0.004	SOX9
bronchus cartilage development	1	1872.4×	0.004	SOX9
lung smooth muscle development	1	1872.4×	0.004	SOX9
ureter urothelium development	1	1872.4×	0.004	SOX9
ureter smooth muscle cell differentiation	1	1872.4×	0.004	SOX9
relaxation of skeletal muscle	1	1872.4×	0.004	KCNJ2
negative regulation of beta-catenin-TCF complex assembly	1	1872.4×	0.004	SOX9
glial cell fate specification	1	1404.3×	0.004	SOX9
cellular response to heparin	1	1404.3×	0.004	SOX9
renal vesicle induction	1	1404.3×	0.004	SOX9
positive regulation of kidney development	1	1404.3×	0.004	SOX9
chondrocyte hypertrophy	1	1123.5×	0.004	SOX9
growth plate cartilage chondrocyte growth	1	1123.5×	0.004	SOX9
astrocyte fate commitment	1	1123.5×	0.004	SOX9
trachea cartilage development	1	1123.5×	0.004	SOX9
morphogenesis of a branching epithelium	1	1123.5×	0.004	SOX9
Harderian gland development	1	1123.5×	0.004	SOX9
metanephric nephron tubule formation	1	1123.5×	0.004	SOX9
positive regulation of cell proliferation involved in heart morphogenesis	1	1123.5×	0.004	SOX9
cellular response to mechanical stimulus	2	144.0×	0.004	SOX9, KCNJ2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOX9	0	0
FRS3	0	0
KCNJ2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KCNJ2	31	Binding:23, ADMET:8
SOX9	3	Binding:3

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	1	KCNJ2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SOX9, FRS3

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)
SOX9	3	—
FRS3	0	—
KCNJ2	31	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06529848	Not specified	RECRUITING	Impact of Exercise Training on Ischemia With Non-Obstructive Coronary Arteries (INOCA): The ExINOCA Study