Gorham-Stout disease

Summary

Gorham-Stout disease (MONDO:0007414) is a disease with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 36
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		300	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0010639	Elevated alkaline phosphatase of bone origin	Very frequent (80-99%)
HP:0010657	Patchy reduction of bone mineral density	Very frequent (80-99%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000969	Edema	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0002683	Abnormality of the calvaria	Frequent (30-79%)
HP:0003319	Abnormality of the cervical spine	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0005216	Impaired mastication	Frequent (30-79%)
HP:0005731	Cortical irregularity	Frequent (30-79%)
HP:0009139	Osteolysis involving bones of the lower limbs	Frequent (30-79%)
HP:0010754	Abnormality of the temporomandibular joint	Frequent (30-79%)
HP:0011384	Abnormality of the internal auditory canal	Frequent (30-79%)
HP:0011821	Abnormality of facial skeleton	Frequent (30-79%)
HP:0011849	Abnormal bone ossification	Frequent (30-79%)
HP:0012294	Abnormality of the occipital bone	Frequent (30-79%)
HP:0031417	Rhinorrhea	Frequent (30-79%)
HP:0045039	Osteolysis involving bones of the upper limbs	Frequent (30-79%)
HP:0100764	Lymphangioma	Frequent (30-79%)
HP:0200025	Mandibular pain	Frequent (30-79%)
HP:0000265	Mastoiditis	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0001167	Abnormality of finger	Occasional (5-29%)
HP:0002202	Pleural effusion	Occasional (5-29%)
HP:0002756	Pathologic fracture	Occasional (5-29%)
HP:0002823	Abnormality of femur morphology	Occasional (5-29%)
HP:0007099	Chiari type I malformation	Occasional (5-29%)
HP:0007461	Hemangiomatosis	Occasional (5-29%)
HP:0045027	Abnormality of the thoracic cavity	Occasional (5-29%)
HP:0430005	Abnormality of ethmoid bone	Occasional (5-29%)
HP:0001287	Meningitis	Very rare (<1-4%)
HP:0002176	Spinal cord compression	Very rare (<1-4%)
HP:0002754	Osteomyelitis	Very rare (<1-4%)
HP:0040163	Abnormal pelvis bone morphology	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Gorham-Stout disease
Mondo ID	MONDO:0007414
OMIM	123880
Orphanet	73
ICD-11	1318015458
SNOMED CT	1515008
UMLS	C0029438
MedGen	45248
GARD	0006542
MedDRA	10071283
NORD	1200
Is cancer (heuristic)	no

Also known as: cystic angiomatosis of bone diffuse · Gorham disease · Gorham syndrome · Gorham-Stout disease · idiopathic massive osteolysis · osteolysis massive · progressive massive osteolysis · vanishing bone disease

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › benign neoplasm › cardiovascular organ benign neoplasm › lymphangioma › Gorham-Stout disease

Related subtypes (11): colonic lymphangioma, capillary lymphangioma, lymphangioendothelioma, cystic hygroma, lymphedema-posterior choanal atresia syndrome, diffuse lymphatic malformation, mixed cystic lymphatic malformation, multifocal lymphangioendotheliomatosis-thrombocytopenia syndrome, macrocystic lymphatic malformation, microcystic lymphatic malformation, skin lymphangioma

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
15999	NM_002890.3(RASA1):c.475_476del (p.Leu159fs)	RASA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2498189	NM_014319.5(LEMD3):c.1522+11509_1522+11513del	LEMD3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LEMD3	Orphanet:166119	Isolated osteopoikilosis
LEMD3	Orphanet:1879	Melorheostosis with osteopoikilosis
LEMD3	Orphanet:94063	12q14 microdeletion syndrome
RASA1	Orphanet:693907	RASA1-related capillary malformation-arteriovenous malformation
RASA1	Orphanet:90307	Parkes Weber syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LEMD3	HGNC:28887	ENSG00000174106	Q9Y2U8	Inner nuclear membrane protein Man1	clinvar
RASA1	HGNC:9871	ENSG00000145715	P20936	Ras GTPase-activating protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LEMD3	Inner nuclear membrane protein Man1	Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins.
RASA1	Ras GTPase-activating protein 1	GTPase-activating protein (GAP) that stimulates the intrinsic GTPase activity of Ras proteins, such as NRAS, facilitating their transition from the active GTP-bound state to the inactive GDP-bound state, thereby terminating Ras signaling.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LEMD3	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, Nucleotide-bd_a/b_plait_sf
RASA1	Scaffold/PPI	no		C2_dom, SH2, SH3_domain

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	2
cerebellar vermis	1
germinal epithelium of ovary	1
choroid plexus epithelium	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LEMD3	289	ubiquitous	marker	endothelial cell, cerebellar vermis, germinal epithelium of ovary
RASA1	298	ubiquitous	marker	endothelial cell, placenta, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RASA1	4,407
LEMD3	2,735

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RASA1	P20936	15
LEMD3	Q9Y2U8	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	407.9×	0.017	RASA1
Depolymerization of the Nuclear Lamina	1	380.7×	0.017	LEMD3
Initiation of Nuclear Envelope (NE) Reformation	1	300.5×	0.017	LEMD3
VEGFR2 mediated cell proliferation	1	285.5×	0.017	RASA1
Nuclear Envelope Breakdown	1	228.4×	0.017	LEMD3
Downstream signal transduction	1	190.3×	0.017	RASA1
Mitotic Prophase	1	184.2×	0.017	LEMD3
Nuclear Envelope (NE) Reassembly	1	146.4×	0.017	LEMD3
EPHB-mediated forward signaling	1	132.8×	0.017	RASA1
RND1 GTPase cycle	1	132.8×	0.017	LEMD3
RND3 GTPase cycle	1	129.8×	0.017	LEMD3
RND2 GTPase cycle	1	129.8×	0.017	LEMD3
RHOD GTPase cycle	1	102.0×	0.020	LEMD3
Regulation of RAS by GAPs	1	96.8×	0.020	RASA1
RHOG GTPase cycle	1	74.2×	0.024	LEMD3
RAC2 GTPase cycle	1	63.4×	0.026	LEMD3
RAC3 GTPase cycle	1	59.5×	0.027	LEMD3
Mitotic Metaphase and Anaphase	1	48.4×	0.029	LEMD3
Mitotic Anaphase	1	48.4×	0.029	LEMD3
M Phase	1	33.0×	0.040	LEMD3
RAC1 GTPase cycle	1	30.5×	0.040	LEMD3
RHO GTPase cycle	1	30.1×	0.040	LEMD3
Cell Cycle, Mitotic	1	24.1×	0.048	LEMD3
Cell Cycle	1	18.0×	0.061	LEMD3
Signaling by Rho GTPases	1	17.1×	0.061	LEMD3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.061	LEMD3
Signal Transduction	1	5.1×	0.187	LEMD3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 RNA metabolic process	1	1404.3×	0.009	RASA1
negative regulation of activin receptor signaling pathway	1	702.2×	0.009	LEMD3
negative regulation of cell-matrix adhesion	1	443.5×	0.009	RASA1
regulation of intracellular signal transduction	1	443.5×	0.009	RASA1
blood vessel morphogenesis	1	401.2×	0.009	RASA1
regulation of actin filament polymerization	1	290.6×	0.010	RASA1
negative regulation of cell adhesion	1	191.5×	0.013	RASA1
ephrin receptor signaling pathway	1	172.0×	0.013	RASA1
negative regulation of BMP signaling pathway	1	145.3×	0.013	LEMD3
mitotic cytokinesis	1	129.6×	0.013	RASA1
vasculogenesis	1	127.7×	0.013	RASA1
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.017	LEMD3
regulation of cell shape	1	61.5×	0.022	RASA1
negative regulation of neuron apoptotic process	1	55.4×	0.023	RASA1
angiogenesis	1	31.2×	0.038	RASA1
intracellular signal transduction	1	19.1×	0.058	RASA1
negative regulation of apoptotic process	1	17.4×	0.060	RASA1
signal transduction	1	8.0×	0.121	RASA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
LEMD3	0	0
RASA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	LEMD3, RASA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LEMD3	0	—
RASA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02399527	Not specified	RECRUITING	Lymphatic Anomalies Registry for the Assessment of Outcome Data
NCT03001180	Not specified	RECRUITING	Identification of Biomarkers for Patients with Vascular Anomalies
NCT02744027	Not specified	COMPLETED	Imaging of Lymphatic Anomalies