Coxopodopatellar syndrome

Summary

Coxopodopatellar syndrome (MONDO:0007841) is a disease caused by TBX4 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TBX4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 95
• Phenotypes (HPO): 5
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		47	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0002815	Abnormality of the knee	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0006498	Aplasia/Hypoplasia of the patella	Very frequent (80-99%)
HP:0001385	Hip dysplasia	Frequent (30-79%)
HP:0002644	Abnormality of pelvic girdle bone morphology	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	coxopodopatellar syndrome
Mondo ID	MONDO:0007841
MeSH	C535540
OMIM	147891
Orphanet	1509
DOID	DOID:0111382
ICD-11	794154672
SNOMED CT	720752007
UMLS	C1840061
MedGen	333474
GARD	0003030
Is cancer (heuristic)	no

Also known as: congenital coxa vara, patella aplasia and tarsal synostosis · Coxo-podo-patellar syndrome · coxopodopatellar syndrome · ICPPS · ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension · ischiopatellar dysplasia · patella aplasia, coxa vara, tarsal synostosis · Scott-Taor syndrome · small patella syndrome · SPS

Data availability: 95 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › coxopodopatellar syndrome

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, tricho-dento-osseous syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, SHOX-related short stature, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, osteofibrous dysplasia, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, spondylometaphyseal dysplasia, omodysplasia, Bruck syndrome, osteopetrosis, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, craniotubular dysplasia, Ikegawa type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

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

95 retrieved; paginated sample, class counts are floors:

25 benign, 24 uncertain significance, 14 pathogenic, 10 benign/likely benign, 6 conflicting classifications of pathogenicity, 6 not provided, 5 likely pathogenic, 3 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1327321	NM_001321120.2(TBX4):c.1021+1G>A	TBX4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341404	NM_001321120.2(TBX4):c.781C>T (p.Arg261Ter)	TBX4	Pathogenic	criteria provided, single submitter
1341420	NM_001321120.2(TBX4):c.1167dup (p.Arg390fs)	TBX4	Pathogenic	criteria provided, single submitter
1341445	NM_001321120.2(TBX4):c.748C>T (p.Arg250Trp)	TBX4	Pathogenic	criteria provided, multiple submitters, no conflicts
3061910	NM_001321120.2(TBX4):c.549+1G>A	TBX4	Pathogenic	criteria provided, single submitter
3900700	NM_001321120.2(TBX4):c.1104_1107dup (p.Ser370fs)	TBX4	Pathogenic	criteria provided, single submitter
620312	NM_001321120.2(TBX4):c.1018C>T (p.Arg340Ter)	TBX4	Pathogenic	criteria provided, multiple submitters, no conflicts
633610	NM_001321120.2(TBX4):c.355dup (p.Ile119fs)	TBX4	Pathogenic	no assertion criteria provided
638159	NM_001321120.2(TBX4):c.402G>A (p.Trp134Ter)	TBX4	Pathogenic	criteria provided, single submitter
7855	NM_001321120.2(TBX4):c.743G>T (p.Gly248Val)	TBX4	Pathogenic	no assertion criteria provided
7856	NM_001321120.2(TBX4):c.184C>T (p.Gln62Ter)	TBX4	Pathogenic	no assertion criteria provided
7857	NM_001321120.2(TBX4):c.1595A>G (p.Gln532Arg)	TBX4	Pathogenic	no assertion criteria provided
800703	NM_001321120.2(TBX4):c.251del (p.Gly84fs)	TBX4	Pathogenic	criteria provided, single submitter
800704	NM_001321120.2(TBX4):c.1057C>T (p.Arg353Ter)	TBX4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
805945	NM_001321120.2(TBX4):c.339T>A (p.Tyr113Ter)	TBX4	Pathogenic	criteria provided, single submitter
807511	NM_001321120.2(TBX4):c.281+1G>T	TBX4	Pathogenic	criteria provided, single submitter
812880	NM_001321120.2(TBX4):c.1115dup (p.Pro373fs)	TBX4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685462	NM_001321120.2(TBX4):c.3G>A (p.Met1Ile)	TBX4	Likely pathogenic	criteria provided, single submitter
1992375	NM_001321120.2(TBX4):c.271A>G (p.Lys91Glu)	TBX4	Likely pathogenic	criteria provided, single submitter
548695	NM_001321120.2(TBX4):c.538_547del (p.Pro180fs)	TBX4	Likely pathogenic	criteria provided, single submitter
800705	NM_001321120.2(TBX4):c.792-1G>C	TBX4	Likely pathogenic	criteria provided, single submitter
982403	NM_001321120.2(TBX4):c.979C>T (p.Gln327Ter)	TBX4	Likely pathogenic	no assertion criteria provided
1185696	NM_001321120.2(TBX4):c.292C>G (p.Pro98Ala)	TBX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1341438	NM_001321120.2(TBX4):c.316G>A (p.Gly106Ser)	TBX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324250	NM_001321120.2(TBX4):c.335A>G (p.Lys112Arg)	TBX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890660	NM_001321120.2(TBX4):c.399A>T (p.Lys133Asn)	TBX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890661	NM_001321120.2(TBX4):c.595G>A (p.Val199Ile)	TBX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891901	NM_001321120.2(TBX4):c.791+11G>T	TBX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1188835	NM_001321120.2(TBX4):c.401+3A>T	TBX4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2503113	NM_001321120.2(TBX4):c.1021G>A (p.Ala341Thr)	TBX4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · 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
TBX4	Definitive	Autosomal dominant	coxopodopatellar syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX4	Orphanet:1509	Coxopodopatellar syndrome
TBX4	Orphanet:238578	Familial clubfoot due to 17q23.1q23.2 microduplication
TBX4	Orphanet:261279	17q23.1q23.2 microdeletion syndrome
TBX4	Orphanet:275777	Heritable pulmonary arterial hypertension
TBX4	Orphanet:3301	Tetraamelia-multiple malformations syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX4	HGNC:11603	ENSG00000121075	P57082	T-box transcription factor TBX4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX4	T-box transcription factor TBX4	Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX4	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
right lung	1
upper lobe of left lung	1
upper lobe of lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX4	116	tissue_specific	yes	right lung, upper lobe of left lung, upper lobe of lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBX4	1,054

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBX4	P57082	60.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic lung development	1	8426.0×	0.001	TBX4
limb morphogenesis	1	1053.2×	0.004	TBX4
embryonic hindlimb morphogenesis	1	581.1×	0.004	TBX4
cell fate specification	1	526.6×	0.004	TBX4
skeletal system morphogenesis	1	495.6×	0.004	TBX4
morphogenesis of an epithelium	1	343.9×	0.005	TBX4
lung development	1	198.3×	0.007	TBX4
angiogenesis	1	62.4×	0.020	TBX4
positive regulation of DNA-templated transcription	1	27.9×	0.040	TBX4
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TBX4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
TBX4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TBX4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBX4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06588491	PHASE2	ACTIVE_NOT_RECRUITING	KYSA-8: A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects With Treatment Refractory Stiff Person Syndrome