Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome

disease
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Also known as KOGSKosaki overgrowth syndrome

Summary

Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome (MONDO:0014704) is a disease caused by PDGFRB (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

  • Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
  • Causal gene: PDGFRB (GenCC Definitive)
  • Cohort genes: 1
  • ClinVar variants: 469
  • Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

TypeClassValueGeographyValidation
Cases/families2WorldwideValidated
Point prevalence<1 / 1 000 000WorldwideValidated

Identifiers

Disease identifiers

FieldValue
Canonical nameskeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome
Mondo IDMONDO:0014704
OMIM616592
Orphanet477831
UMLSC4225270
MedGen896409
GARD0017860
Is cancer (heuristic)no

Also known as: KOGS · Kosaki overgrowth syndrome

Data availability: 469 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary diseaseskeletal dysplasiaskeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions 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, coxopodopatellar syndrome, 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, 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

469 retrieved; paginated sample, class counts are floors:

202 likely benign, 134 uncertain significance, 59 benign, 40 conflicting classifications of pathogenicity, 25 benign/likely benign, 4 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVarVariant (HGVS)GeneClassificationReview
208692NM_002609.4(PDGFRB):c.1996A>C (p.Asn666His)PDGFRBPathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
2096300NM_002609.4(PDGFRB):c.2483C>A (p.Ala828Glu)PDGFRBPathogeniccriteria provided, single submitter
217122NM_002609.4(PDGFRB):c.1751C>G (p.Pro584Arg)PDGFRBPathogeniccriteria provided, multiple submitters, no conflicts
2925384NM_002609.4(PDGFRB):c.1679C>T (p.Pro560Leu)PDGFRBPathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
375682NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg)PDGFRBPathogeniccriteria provided, multiple submitters, no conflicts
55848NM_002609.4(PDGFRB):c.1681C>T (p.Arg561Cys)PDGFRBPathogeniccriteria provided, multiple submitters, no conflicts
1333888NM_002609.4(PDGFRB):c.1025C>T (p.Ala342Val)PDGFRBLikely pathogeniccriteria provided, single submitter
3773730NM_002609.4(PDGFRB):c.2567A>T (p.Asn856Ile)PDGFRBLikely pathogeniccriteria provided, single submitter
4794434NM_002609.4(PDGFRB):c.1A>G (p.Met1Val)PDGFRBLikely pathogeniccriteria provided, single submitter
1304805NM_002609.4(PDGFRB):c.419C>T (p.Thr140Met)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
135650NM_002609.4(PDGFRB):c.2083C>T (p.Arg695Cys)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
1486244NM_002609.4(PDGFRB):c.2905-8G>APDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
1518353NM_002609.4(PDGFRB):c.1526C>T (p.Thr509Met)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
194497NM_002609.4(PDGFRB):c.2126G>A (p.Arg709His)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
1946074NM_002609.4(PDGFRB):c.938G>A (p.Ser313Asn)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
1960043NM_002609.4(PDGFRB):c.2164G>A (p.Val722Ile)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
1961685NM_002609.4(PDGFRB):c.2122C>T (p.Arg708Cys)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
1975317NM_002609.4(PDGFRB):c.3275C>T (p.Ser1092Leu)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2042019NM_002609.4(PDGFRB):c.1535A>G (p.Asn512Ser)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2054278NM_002609.4(PDGFRB):c.338G>A (p.Arg113Gln)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2056802NM_002609.4(PDGFRB):c.3181G>A (p.Asp1061Asn)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2065779NM_002609.4(PDGFRB):c.2971C>T (p.Arg991Cys)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2144767NM_002609.4(PDGFRB):c.542G>C (p.Gly181Ala)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2146418NM_002609.4(PDGFRB):c.1399G>A (p.Gly467Arg)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2151826NM_002609.4(PDGFRB):c.1487G>A (p.Arg496His)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2178345NM_002609.4(PDGFRB):c.2243C>T (p.Ser748Leu)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2190056NM_002609.4(PDGFRB):c.2635C>A (p.Leu879Ile)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2228308NM_002609.4(PDGFRB):c.2791G>A (p.Asp931Asn)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2262363NM_002609.4(PDGFRB):c.2281G>A (p.Val761Ile)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications
2367685NM_002609.4(PDGFRB):c.1106C>T (p.Thr369Met)PDGFRBConflicting classifications of pathogenicitycriteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 7 · 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.

GeneClassificationInheritanceDiseaseRecords
PDGFRBDefinitiveAutosomal dominantacroosteolysis-keloid-like lesions-premature aging syndrome17

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
PDGFRBOrphanet:168950Myeloid/lymphoid neoplasm associated with PDGFRB rearrangement
PDGFRBOrphanet:1980Bilateral striopallidodentate calcinosis
PDGFRBOrphanet:2591Infantile myofibromatosis
PDGFRBOrphanet:314950Primary hypereosinophilic syndrome
PDGFRBOrphanet:363665Acroosteolysis-keloid-like lesions-premature aging syndrome
PDGFRBOrphanet:477831Kosaki overgrowth syndrome
PDGFRBOrphanet:86830Chronic myeloproliferative disease, unclassifiable

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence1

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
PDGFRBHGNC:8804ENSG00000113721P09619Platelet-derived growth factor receptor betagencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
PDGFRBPlatelet-derived growth factor receptor betaTyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, surviv…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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.

FamilyGenesFoldFDR
Kinase127.7×0.036

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
PDGFRBKinaseyes2.7.10.1Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_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)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)1
unknown0

Top tissues across cohort

TissueCohort genes
endocervix1
right coronary artery1
stromal cell of endometrium1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
PDGFRB270ubiquitousmarkerstromal cell of endometrium, right coronary artery, endocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
PDGFRB5,111

Structural data

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

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
PDGFRBP096198

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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.

PathwayCohort genesFoldFDRSample cohort genes
Downstream signal transduction1380.7×0.012PDGFRB
Signaling by PDGF1253.8×0.012PDGFRB
Constitutive Signaling by Aberrant PI3K in Cancer1126.9×0.015PDGFRB
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling196.8×0.015PDGFRB
PIP3 activates AKT signaling166.8×0.016PDGFRB
RAF/MAP kinase cascade161.1×0.016PDGFRB

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 termCohort genesFoldFDRSample cohort genes
cell migration involved in coronary angiogenesis116852.0×8e-04PDGFRB
metanephric glomerular mesangial cell proliferation involved in metanephros development116852.0×8e-04PDGFRB
cell migration involved in vasculogenesis18426.0×8e-04PDGFRB
smooth muscle cell chemotaxis18426.0×8e-04PDGFRB
positive regulation of metanephric mesenchymal cell migration by platelet-derived growth factor receptor-beta signaling pathway15617.3×8e-04PDGFRB
positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway15617.3×8e-04PDGFRB
metanephric glomerular capillary formation15617.3×8e-04PDGFRB
smooth muscle adaptation14213.0×1e-03PDGFRB
platelet-derived growth factor receptor-beta signaling pathway13370.4×0.001PDGFRB
retina vasculature development in camera-type eye11685.2×0.002PDGFRB
cardiac myofibril assembly11296.3×0.002PDGFRB
positive regulation of DNA biosynthetic process11123.5×0.002PDGFRB
positive regulation of smooth muscle cell migration1991.3×0.002PDGFRB
positive regulation of calcium ion import1936.2×0.002PDGFRB
aorta morphogenesis1887.0×0.002PDGFRB
positive regulation of chemotaxis1842.6×0.002PDGFRB
positive regulation of MAP kinase activity1648.1×0.003PDGFRB
platelet-derived growth factor receptor signaling pathway1561.7×0.003PDGFRB
positive regulation of mitotic nuclear division1543.6×0.003PDGFRB
positive regulation of reactive oxygen species metabolic process1510.7×0.003PDGFRB
peptidyl-tyrosine phosphorylation1421.3×0.004PDGFRB
positive regulation of calcium-mediated signaling1421.3×0.004PDGFRB
positive regulation of smooth muscle cell proliferation1330.4×0.004PDGFRB
cell chemotaxis1185.2×0.007PDGFRB
cell surface receptor protein tyrosine kinase signaling pathway1173.7×0.008PDGFRB
regulation of actin cytoskeleton organization1157.5×0.008PDGFRB
protein autophosphorylation1145.3×0.008PDGFRB
positive regulation of ERK1 and ERK2 cascade185.1×0.014PDGFRB
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction178.4×0.015PDGFRB
angiogenesis162.4×0.017PDGFRB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
PDGFRBPONATINIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
PDGFRB1024

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
PONATINIB4PDGFRB
FEDRATINIB4PDGFRB
TIVOZANIB4PDGFRB
LENVATINIB4PDGFRB
AXITINIB4PDGFRB
SORAFENIB4PDGFRB
SUNITINIB MALATE4PDGFRB
REGORAFENIB4PDGFRB
PACRITINIB4PDGFRB
VANDETANIB4PDGFRB
NILOTINIB4PDGFRB
BOSUTINIB4PDGFRB
NINTEDANIB ESYLATE4PDGFRB
GILTERITINIB4PDGFRB
TOVORAFENIB4PDGFRB
PEXIDARTINIB4PDGFRB
PAZOPANIB4PDGFRB
NINTEDANIB4PDGFRB
SUNITINIB4PDGFRB
DASATINIB4PDGFRB
ERLOTINIB4PDGFRB
LAPATINIB4PDGFRB
QUIZARTINIB4PDGFRB
MIDOSTAURIN4PDGFRB
IMATINIB4PDGFRB
VATALANIB3PDGFRB
FAMITINIB3PDGFRB
MASITINIB3PDGFRB
CRENOLANIB3PDGFRB
SARACATINIB3PDGFRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

SymbolAssaysType breakdown
PDGFRB1,237Binding:1213, Functional:16, ADMET:8

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
PDGFRB2.7.10.1receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
PDGFRB1,237

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

30 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.

CompoundMax phaseCohort target (bioactivity)
PONATINIB4PDGFRB
FEDRATINIB4PDGFRB
TIVOZANIB4PDGFRB
LENVATINIB4PDGFRB
AXITINIB4PDGFRB
SORAFENIB4PDGFRB
SUNITINIB MALATE4PDGFRB
REGORAFENIB4PDGFRB
PACRITINIB4PDGFRB
VANDETANIB4PDGFRB
NILOTINIB4PDGFRB
BOSUTINIB4PDGFRB
NINTEDANIB ESYLATE4PDGFRB
GILTERITINIB4PDGFRB
TOVORAFENIB4PDGFRB
PEXIDARTINIB4PDGFRB
PAZOPANIB4PDGFRB
NINTEDANIB4PDGFRB
SUNITINIB4PDGFRB
DASATINIB4PDGFRB
ERLOTINIB4PDGFRB
LAPATINIB4PDGFRB
QUIZARTINIB4PDGFRB
MIDOSTAURIN4PDGFRB
IMATINIB4PDGFRB
VATALANIB3PDGFRB
FAMITINIB3PDGFRB
MASITINIB3PDGFRB
CRENOLANIB3PDGFRB
SARACATINIB3PDGFRB

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1PDGFRB
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified1

Top trials by phase / activity

NCTPhaseStatusTitle
NCT05953857Not specifiedNOT_YET_RECRUITINGKnowing and Treating Kosaki/Penttinen Syndromes