Exophthalmos

Summary

Exophthalmos (MONDO:0004770) is a disease with 4 cohort genes and 6 clinical trials. Top therapeutic interventions include linsitinib and iodine.

At a glance

• Cohort genes: 4
• ClinVar variants: 4
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	exophthalmos
Mondo ID	MONDO:0004770
MeSH	D005094
DOID	DOID:9370
NCIT	C118763
SNOMED CT	18265008
UMLS	C0015300
MedGen	41917
Is cancer (heuristic)	no

Also known as: exophthalmos · exophthalmos (disease) · proptosis

Data availability: 4 ClinVar variants · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › exophthalmos

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

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

4 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
183295	NM_001393530.1(MATN4):c.515G>C (p.Gly172Ala)	MATN4	Likely pathogenic	no assertion criteria provided
627622	NM_001365902.3(NFIX):c.440G>A (p.Gly147Glu)	NFIX	Likely pathogenic	criteria provided, single submitter
374132	NM_004006.3(DMD):c.10247G>A (p.Trp3416Ter)	DMD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
917488	NM_181336.4(LEMD2):c.1436C>T (p.Ser479Phe)	LEMD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LEMD2	Orphanet:441447	Early-onset posterior subcapsular cataract
LEMD2	Orphanet:659873	Wormian bones-micrognathia-abnormal dentition-progeroid syndrome
LEMD2	Orphanet:98994	Total early-onset cataract
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy
NFIX	Orphanet:420179	Malan overgrowth syndrome
NFIX	Orphanet:447980	19p13.3 microduplication syndrome
NFIX	Orphanet:561	Marshall-Smith syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LEMD2	HGNC:21244	ENSG00000161904	Q8NC56	LEM domain-containing protein 2	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
MATN4	HGNC:6910	ENSG00000124159	O95460	Matrilin-4	clinvar
NFIX	HGNC:7788	ENSG00000008441	Q14938	Nuclear factor 1 X-type	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LEMD2	LEM domain-containing protein 2	Nuclear lamina-associated inner nuclear membrane protein that is involved in nuclear structure organization, maintenance of nuclear envelope (NE) integrity and NE reformation after mitosis.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
MATN4	Matrilin-4	Major component of the extracellular matrix of cartilage.
NFIX	Nuclear factor 1 X-type	Recognizes and binds the palindromic sequence 5’-TTGGCNNNNNGCCAA-3’ present in viral and cellular promoters and in the origin of replication of adenovirus type 2.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LEMD2	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, Man1/Src1-like_C
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
MATN4	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, VWF_A
NFIX	Other/Unknown	no		CTF/NFI, MAD_homology1_Dwarfin-type, CTF/NFI_DNA-bd_N

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
dorsal root ganglion	1
skeletal muscle tissue of rectus abdominis	1
trigeminal ganglion	1
body of pancreas	1
buccal mucosa cell	1
cartilage tissue	1
cortical plate	1
ganglionic eminence	1
nipple	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LEMD2	186	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
MATN4	96	tissue_specific	yes	cartilage tissue, body of pancreas, buccal mucosa cell
NFIX	267	ubiquitous	marker	cortical plate, nipple, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DMD	2,479
LEMD2	2,340
NFIX	2,162
MATN4	1,168

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DMD	P11532	6
NFIX	Q14938	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MATN4	O95460	82.10
LEMD2	Q8NC56	71.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Depolymerization of the Nuclear Lamina	1	190.3×	0.026	LEMD2
Initiation of Nuclear Envelope (NE) Reformation	1	150.3×	0.026	LEMD2
RNA Polymerase III Transcription Termination	1	124.1×	0.026	NFIX
Nuclear Envelope Breakdown	1	114.2×	0.026	LEMD2
Mitotic Prophase	1	92.1×	0.026	LEMD2
Sealing of the nuclear envelope (NE) by ESCRT-III	1	86.5×	0.026	LEMD2
Striated Muscle Contraction	1	77.2×	0.026	DMD
Formation of the dystrophin-glycoprotein complex (DGC)	1	77.2×	0.026	DMD
Nuclear Envelope (NE) Reassembly	1	73.2×	0.026	LEMD2
RNA Polymerase III Abortive And Retractive Initiation	1	69.6×	0.026	NFIX
Non-integrin membrane-ECM interactions	1	38.6×	0.040	DMD
ECM proteoglycans	1	37.6×	0.040	MATN4
Mitotic Metaphase and Anaphase	1	24.2×	0.052	LEMD2
Mitotic Anaphase	1	24.2×	0.052	LEMD2
M Phase	1	16.5×	0.070	LEMD2
Extracellular matrix organization	1	15.8×	0.070	MATN4
Cell Cycle, Mitotic	1	12.1×	0.085	LEMD2
Cell Cycle	1	9.0×	0.107	LEMD2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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 muscle system process	1	4213.0×	0.005	DMD
regulation of cellular response to growth factor stimulus	1	4213.0×	0.005	DMD
cardiac muscle cell action potential	1	2106.5×	0.006	DMD
regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion	1	1053.2×	0.007	DMD
peptide biosynthetic process	1	1053.2×	0.007	DMD
heart formation	1	842.6×	0.008	LEMD2
regulation of skeletal muscle contraction	1	702.2×	0.008	DMD
nuclear membrane organization	1	601.9×	0.008	LEMD2
regulation of calcium ion transmembrane transport	1	526.6×	0.008	DMD
synaptic signaling	1	383.0×	0.010	DMD
regulation of sodium ion transmembrane transport	1	263.3×	0.013	DMD
nuclear envelope organization	1	247.8×	0.013	LEMD2
muscle cell development	1	234.1×	0.013	DMD
response to muscle stretch	1	191.5×	0.014	DMD
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	168.5×	0.014	DMD
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	168.5×	0.014	DMD
muscle cell cellular homeostasis	1	162.0×	0.014	DMD
motile cilium assembly	1	145.3×	0.014	DMD
protein localization to chromatin	1	145.3×	0.014	LEMD2
maintenance of blood-brain barrier	1	120.4×	0.016	DMD
regulation of heart rate	1	117.0×	0.016	DMD
cardiac muscle contraction	1	100.3×	0.018	DMD
skeletal muscle cell differentiation	1	86.0×	0.020	LEMD2
negative regulation of MAPK cascade	1	75.2×	0.021	LEMD2
skeletal muscle tissue development	1	72.6×	0.021	DMD
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	65.8×	0.022	LEMD2
neuron development	1	63.8×	0.022	DMD
neurogenesis	1	52.0×	0.027	LEMD2
positive regulation of neuron differentiation	1	49.6×	0.027	DMD
muscle organ development	1	41.7×	0.030	DMD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LEMD2	0	0
DMD	0	0
MATN4	0	0
NFIX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	LEMD2, DMD, MATN4, NFIX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LEMD2	0	—
DMD	0	—
MATN4	0	—
NFIX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	2
Not specified	2
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05276063	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Phase 2b, Study of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED)
NCT06112340	PHASE2/PHASE3	RECRUITING	Extension Study of Two Doses of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED)
NCT01204359	PHASE3	UNKNOWN	The Prospective Study of Standard Treatment of Graves Disease Iodine 131 and Prevention of Adverse Reactions
NCT06226545	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of LASN01 in Patients With Thyroid Eye Disease
NCT04025034	Not specified	COMPLETED	Deep Lateral Wall Partial Rim-Sparing Orbital Decompression for Treatment of Thyroid-Related Orbitopathy
NCT04704414	Not specified	UNKNOWN	Exophthalmometry With 3D Face Scanners

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LINSITINIB	3	2
IODINE	3	1