Thanatophoric dysplasia type 2

Summary

Thanatophoric dysplasia type 2 (MONDO:0008547) is a disease caused by FGFR3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: FGFR3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 36
• Phenotypes (HPO): 35

Clinical features

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001582	Redundant skin	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002676	Cloverleaf skull	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0006703	Aplasia/Hypoplasia of the lungs	Very frequent (80-99%)
HP:0010306	Short thorax	Very frequent (80-99%)
HP:0012368	Flat face	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0010880	Increased nuchal translucency	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001360	Holoprosencephaly	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0002084	Encephalocele	Occasional (5-29%)
HP:0002269	Abnormality of neuronal migration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	thanatophoric dysplasia type 2
Mondo ID	MONDO:0008547
MeSH	C536508
OMIM	187601
Orphanet	93274
NCIT	C98584
SNOMED CT	389158007
UMLS	C1300257
MedGen	226975
GARD	0001402
Is cancer (heuristic)	no

Also known as: cloverleaf skull-micromelic bone dysplasia syndrome · TD2 · thanatophoric dwarfism - cloverleaf skull · thanatophoric dwarfism type 2 · thanatophoric dwarfism-cloverleaf skull syndrome · thanatophoric dysplasia type II · thanatophoric dysplasia, type 2 · thanatophoric dysplasia, type II · type 2 thanatophoric dysplasia

Data availability: 36 ClinVar variants · 5 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › thanatophoric dysplasia › thanatophoric dysplasia type 2

Related subtypes (3): thanatophoric dysplasia type 1, thanatophoric dysplasia, Glasgow variant, Kozlowski Warren Fisher syndrome

Subtypes (1): micromelic bone dysplasia with cloverleaf skull

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

36 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 10 pathogenic, 5 benign/likely benign, 5 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16327	NM_000142.5(FGFR3):c.1138G>A (p.Gly380Arg)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16331	NM_000142.5(FGFR3):c.1948A>G (p.Lys650Glu)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16332	NM_000142.5(FGFR3):c.742C>T (p.Arg248Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16335	NM_000142.5(FGFR3):c.2419T>A (p.Ter807Arg)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16338	NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16339	NM_000142.5(FGFR3):c.746C>G (p.Ser249Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16340	NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16341	NM_000142.5(FGFR3):c.1949A>T (p.Lys650Met)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16347	NM_000142.5(FGFR3):c.1950G>C (p.Lys650Asn)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16358	NM_000142.5(FGFR3):c.251C>T (p.Ser84Leu)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16359	NM_000142.5(FGFR3):c.1108G>T (p.Gly370Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
65562	NM_000142.5(FGFR3):c.2420G>T (p.Ter807Leu)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
65855	NM_000142.5(FGFR3):c.1949A>C (p.Lys650Thr)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
994395	NM_000142.5(FGFR3):c.2420G>C (p.Ter807Ser)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
1680106	NM_000142.5(FGFR3):c.1827C>G (p.Ala609=)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287276	NM_000142.5(FGFR3):c.598C>T (p.Arg200Cys)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521225	NM_000142.5(FGFR3):c.2153A>G (p.Asn718Ser)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546226	NM_000142.5(FGFR3):c.200G>A (p.Gly67Asp)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
579912	NM_000142.5(FGFR3):c.2005C>G (p.Arg669Gly)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1309951	NM_000142.5(FGFR3):c.1255C>T (p.Leu419Phe)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1310646	NM_000142.5(FGFR3):c.1547A>G (p.Asp516Gly)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1680065	NM_000142.5(FGFR3):c.1267G>C (p.Val423Leu)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1680111	NM_000142.5(FGFR3):c.1946A>G (p.Lys649Arg)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1684285	NM_000142.5(FGFR3):c.184C>T (p.Pro62Ser)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1691355	NM_000142.5(FGFR3):c.1718C>T (p.Pro573Leu)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2874249	NM_000142.5(FGFR3):c.2105A>T (p.Glu702Val)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892110	NM_000142.5(FGFR3):c.166G>A (p.Ala56Thr)	FGFR3	Uncertain significance	criteria provided, single submitter
465350	NM_000142.5(FGFR3):c.1993G>T (p.Ala665Ser)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
533891	NM_000142.5(FGFR3):c.2294C>T (p.Ala765Val)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
651478	NM_000142.5(FGFR3):c.2413C>T (p.Arg805Trp)	FGFR3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 52 · Orphanet: 13 · 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
FGFR3	Definitive	Autosomal dominant	thanatophoric dysplasia type 1	52

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGFR3	Orphanet:15	Achondroplasia
FGFR3	Orphanet:1860	Thanatophoric dysplasia type 1
FGFR3	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR3	Orphanet:251576	Gliosarcoma
FGFR3	Orphanet:251579	Giant cell glioblastoma
FGFR3	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
FGFR3	Orphanet:429	Hypochondroplasia
FGFR3	Orphanet:53271	Muenke syndrome
FGFR3	Orphanet:794	Saethre-Chotzen syndrome
FGFR3	Orphanet:85164	Camptodactyly-tall stature-scoliosis-hearing loss syndrome
FGFR3	Orphanet:85165	Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
FGFR3	Orphanet:93262	Crouzon syndrome-acanthosis nigricans syndrome
FGFR3	Orphanet:93274	Thanatophoric dysplasia type 2

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
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGFR3	Fibroblast growth factor receptor 3	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis.

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.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

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
skin of hip	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGFR3	262	broad	marker	upper leg skin, skin of hip, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGFR3	4,510

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR3	P22607	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
t(4;14) translocations of FGFR3	1	11420.0×	7e-04	FGFR3
Signaling by FGFR3 fusions in cancer	1	11420.0×	7e-04	FGFR3
FGFR3b ligand binding and activation	1	1631.4×	0.003	FGFR3
Signaling by activated point mutants of FGFR3	1	951.7×	0.003	FGFR3
FGFR3c ligand binding and activation	1	878.5×	0.003	FGFR3
Phospholipase C-mediated cascade; FGFR3	1	878.5×	0.003	FGFR3
PI-3K cascade:FGFR3	1	634.4×	0.003	FGFR3
SHC-mediated cascade:FGFR3	1	601.0×	0.003	FGFR3
FRS-mediated FGFR3 signaling	1	543.8×	0.003	FGFR3
Signaling by FGFR3 in disease	1	496.5×	0.003	FGFR3
Negative regulation of FGFR3 signaling	1	439.2×	0.003	FGFR3
PI3K Cascade	1	271.9×	0.005	FGFR3
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.010	FGFR3
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.012	FGFR3
PIP3 activates AKT signaling	1	66.8×	0.016	FGFR3
RAF/MAP kinase cascade	1	61.1×	0.016	FGFR3

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
negative regulation of developmental growth	1	16852.0×	0.001	FGFR3
fibroblast growth factor receptor apoptotic signaling pathway	1	8426.0×	0.001	FGFR3
bone maturation	1	5617.3×	0.001	FGFR3
positive regulation of phospholipase activity	1	3370.4×	0.001	FGFR3
endochondral bone growth	1	1685.2×	0.002	FGFR3
chondrocyte proliferation	1	1053.2×	0.003	FGFR3
positive regulation of tyrosine phosphorylation of STAT protein	1	732.7×	0.004	FGFR3
bone morphogenesis	1	601.9×	0.004	FGFR3
endochondral ossification	1	543.6×	0.004	FGFR3
chondrocyte differentiation	1	300.9×	0.006	FGFR3
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.006	FGFR3
fibroblast growth factor receptor signaling pathway	1	285.6×	0.006	FGFR3
bone mineralization	1	271.8×	0.006	FGFR3
MAPK cascade	1	153.2×	0.009	FGFR3
skeletal system development	1	125.8×	0.011	FGFR3
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.014	FGFR3
positive regulation of MAPK cascade	1	80.6×	0.014	FGFR3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.014	FGFR3
cell-cell signaling	1	69.6×	0.015	FGFR3
positive regulation of cell population proliferation	1	33.6×	0.030	FGFR3

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.

Symbol	Example approved molecule
FGFR3	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR3	64	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3
FEDRATINIB	4	FGFR3
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
INFIGRATINIB	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	FGFR3
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
MIDOSTAURIN	4	FGFR3
LINIFANIB	3	FGFR3
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3
ALISERTIB	3	FGFR3
CEDIRANIB	3	FGFR3
DOVITINIB	3	FGFR3
LESTAURTINIB	3	FGFR3
TANDUTINIB	2	FGFR3
FORETINIB	2	FGFR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FGFR3	975	Binding:948, Functional:18, ADMET:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR3	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FGFR3	975

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.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3
FEDRATINIB	4	FGFR3
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
INFIGRATINIB	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	FGFR3
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
MIDOSTAURIN	4	FGFR3
LINIFANIB	3	FGFR3
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3
ALISERTIB	3	FGFR3
CEDIRANIB	3	FGFR3
DOVITINIB	3	FGFR3
LESTAURTINIB	3	FGFR3
TANDUTINIB	2	FGFR3
FORETINIB	2	FGFR3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR3
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	0

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: 0.