Parietal foramina with cleidocranial dysplasia

Summary

Parietal foramina with cleidocranial dysplasia (MONDO:0008198) is a disease caused by MSX2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MSX2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	parietal foramina with cleidocranial dysplasia
Mondo ID	MONDO:0008198
MeSH	C566825
OMIM	168550
Orphanet	251290
UMLS	C1868597
MedGen	401479
GARD	0017207
Is cancer (heuristic)	no

Also known as: parietal foramina with cleidocranial dysostosis · parietal foramina with cleidocranial dysplasia · PFMCCD

Data availability: 3 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › parietal foramina with cleidocranial dysplasia

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, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic 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

3 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16967	NM_002449.5(MSX2):c.505_508dup (p.Ala170fs)	MSX2	Pathogenic	no assertion criteria provided
3591944	NM_002449.5(MSX2):c.380-2A>T	MSX2	Likely pathogenic	criteria provided, single submitter
4294501	NM_002449.5(MSX2):c.473dup (p.Arg159fs)	MSX2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 3 · 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
MSX2	Definitive	Autosomal dominant	parietal foramina	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSX2	Orphanet:1541	Craniosynostosis, Boston type
MSX2	Orphanet:251290	Parietal foramina with clavicular hypoplasia
MSX2	Orphanet:60015	Enlarged parietal foramina

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
MSX2	HGNC:7392	ENSG00000120149	P35548	Homeobox protein MSX-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSX2	Homeobox protein MSX-2	Acts as a transcriptional regulator in bone development.

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)
MSX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
placenta	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSX2	175	ubiquitous	marker	placenta, endometrium epithelium, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSX2	2,322

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MSX2	P35548	68.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transcriptional regulation by RUNX2	1	253.8×	0.014	MSX2
Regulation of RUNX2 expression and activity	1	181.3×	0.014	MSX2
RNA Polymerase II Transcription	1	22.5×	0.066	MSX2
Gene expression (Transcription)	1	17.8×	0.066	MSX2
Generic Transcription Pathway	1	15.1×	0.066	MSX2

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
cell surface receptor signaling pathway involved in heart development	1	8426.0×	0.002	MSX2
positive regulation of timing of catagen	1	5617.3×	0.002	MSX2
frontal suture morphogenesis	1	5617.3×	0.002	MSX2
positive regulation of mesenchymal cell apoptotic process	1	5617.3×	0.002	MSX2
activation of meiosis	1	4213.0×	0.002	MSX2
embryonic nail plate morphogenesis	1	3370.4×	0.002	MSX2
cranial suture morphogenesis	1	2808.7×	0.002	MSX2
bone trabecula formation	1	2106.5×	0.002	MSX2
endochondral bone growth	1	1685.2×	0.002	MSX2
negative regulation of keratinocyte differentiation	1	1685.2×	0.002	MSX2
embryonic morphogenesis	1	1532.0×	0.002	MSX2
mesenchymal cell apoptotic process	1	1532.0×	0.002	MSX2
epithelial to mesenchymal transition involved in endocardial cushion formation	1	1404.3×	0.002	MSX2
branching involved in mammary gland duct morphogenesis	1	1404.3×	0.002	MSX2
enamel mineralization	1	1203.7×	0.002	MSX2
cardiac conduction system development	1	1053.2×	0.002	MSX2
wound healing, spreading of epidermal cells	1	1053.2×	0.002	MSX2
osteoblast development	1	991.3×	0.002	MSX2
chondrocyte development	1	936.2×	0.002	MSX2
signal transduction involved in regulation of gene expression	1	702.2×	0.003	MSX2
outflow tract septum morphogenesis	1	648.1×	0.003	MSX2
embryonic hindlimb morphogenesis	1	581.1×	0.003	MSX2
embryonic forelimb morphogenesis	1	495.6×	0.003	MSX2
positive regulation of BMP signaling pathway	1	455.5×	0.003	MSX2
cellular response to estradiol stimulus	1	411.0×	0.004	MSX2
negative regulation of fat cell differentiation	1	312.1×	0.004	MSX2
stem cell differentiation	1	300.9×	0.004	MSX2
positive regulation of osteoblast differentiation	1	224.7×	0.006	MSX2
BMP signaling pathway	1	200.6×	0.006	MSX2
anterior/posterior pattern specification	1	181.2×	0.007	MSX2

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
MSX2	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	MSX2

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)
MSX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.