Familial multiple nevi flammei

Summary

Familial multiple nevi flammei (MONDO:0008094) is a disease with 2 cohort genes and 47 clinical trials. Top therapeutic interventions include imiquimod, talaporfin sodium, and hematoporphyrin.

At a glance

• Cohort genes: 2
• ClinVar variants: 5
• Phenotypes (HPO): 23
• Clinical trials: 47

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0001034	Hypermelanotic macule	Very frequent (80-99%)
HP:0001052	Nevus flammeus	Very frequent (80-99%)
HP:0007400	Irregular hyperpigmentation	Very frequent (80-99%)
HP:0100026	Arteriovenous malformation	Very frequent (80-99%)
HP:0200034	Papule	Frequent (30-79%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001291	Abnormal cranial nerve morphology	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002204	Pulmonary embolism	Occasional (5-29%)
HP:0002301	Hemiplegia	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002814	Abnormality of the lower limb	Occasional (5-29%)
HP:0002817	Abnormality of the upper limb	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0005293	Venous insufficiency	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0100559	Lower limb asymmetry	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial multiple nevi flammei
Mondo ID	MONDO:0008094
OMIM	163000
Orphanet	624
DOID	DOID:0111529
NCIT	C3840
SNOMED CT	416377005
UMLS	C2931029
MedGen	419699
GARD	0003986
MedDRA	10067193
Is cancer (heuristic)	no

Also known as: capillary malformations, congenital · capillary malformations, congenital, 1, somatic, mosaic · CMC · familial multiple port-wine stains · Nevus flammeus · port wine birthmark · port wine Nevus · port wine stain · port wine stain of skin · port wine stain of the skin · port wine type hemangioma · port-wine stain familial multiple · port-wine stain of skin · Salmon patch Nevus

Data availability: 5 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › capillary malformation › familial multiple nevi flammei

Related subtypes (5): stork bite, cutis marmorata telangiectatica congenita, capillary malformation-arteriovenous malformation syndrome, hereditary hemorrhagic telangiectasia, angioma serpiginosum

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172601	NM_002072.5(GNAQ):c.627A>C (p.Gln209His)	GNAQ	Pathogenic	criteria provided, multiple submitters, no conflicts
1172602	NM_002072.5(GNAQ):c.627A>T (p.Gln209His)	GNAQ	Pathogenic	criteria provided, multiple submitters, no conflicts
2664271	NM_002072.5(GNAQ):c.547C>G (p.Arg183Gly)	GNAQ	Pathogenic	criteria provided, single submitter
50853	NM_002072.5(GNAQ):c.548G>A (p.Arg183Gln)	GNAQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4279982	NM_002067.5(GNA11):c.548G>A (p.Arg183His)	GNA11	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNA11	Orphanet:101049	Familial hypocalciuric hypercalcemia type 2
GNA11	Orphanet:1556	Cutis marmorata telangiectatica congenita
GNA11	Orphanet:39044	Uveal melanoma
GNA11	Orphanet:428	Autosomal dominant hypocalcemia
GNA11	Orphanet:675359	Anastomosing haemangioma
GNA11	Orphanet:714737	Diffuse capillary malformation with overgrowth
GNA11	Orphanet:79483	Phakomatosis cesioflammea
GNA11	Orphanet:79484	Phakomatosis cesiomarmorata
GNAQ	Orphanet:3205	Sturge-Weber syndrome
GNAQ	Orphanet:39044	Uveal melanoma
GNAQ	Orphanet:624	Familial multiple nevi flammei
GNAQ	Orphanet:675359	Anastomosing haemangioma
GNAQ	Orphanet:79483	Phakomatosis cesioflammea

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
GNA11	HGNC:4379	ENSG00000088256	P29992	Guanine nucleotide-binding protein subunit alpha-11	clinvar
GNAQ	HGNC:4390	ENSG00000156052	P50148	Guanine nucleotide-binding protein G(q) subunit alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNA11	Guanine nucleotide-binding protein subunit alpha-11	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
GNAQ	Guanine nucleotide-binding protein G(q) subunit alpha	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNA11	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert
GNAQ	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert

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
ileal mucosa	1
jejunal mucosa	1
pancreatic ductal cell	1
CA1 field of hippocampus	1
dorsal motor nucleus of vagus nerve	1
postcentral gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNA11	299	ubiquitous	marker	ileal mucosa, jejunal mucosa, pancreatic ductal cell
GNAQ	302	ubiquitous	marker	CA1 field of hippocampus, dorsal motor nucleus of vagus nerve, postcentral gyrus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNAQ	3,480
GNA11	1,873

Intra-cohort edges

A	B	Sources
GNA11	GNAQ	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAQ	P50148	37
GNA11	P29992	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	2	1427.5×	4e-06	GNA11, GNAQ
Acetylcholine regulates insulin secretion	2	1142.0×	4e-06	GNA11, GNAQ
G-protein activation	2	475.8×	1e-05	GNA11, GNAQ
Thromboxane signalling through TP receptor	2	475.8×	1e-05	GNA11, GNAQ
ADP signalling through P2Y purinoceptor 1	2	456.8×	1e-05	GNA11, GNAQ
Thrombin signalling through proteinase activated receptors (PARs)	2	356.9×	1e-05	GNA11, GNAQ
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	2	356.9×	1e-05	GNA11, GNAQ
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	2	300.5×	1e-05	GNA11, GNAQ
PLC beta mediated events	2	265.6×	2e-05	GNA11, GNAQ
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	2	160.8×	4e-05	GNA11, GNAQ
G alpha (q) signalling events	2	57.4×	3e-04	GNA11, GNAQ

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
entrainment of circadian clock	2	2808.7×	3e-06	GNA11, GNAQ
phototransduction, visible light	2	1296.3×	9e-06	GNA11, GNAQ
G protein-coupled acetylcholine receptor signaling pathway	2	1053.2×	9e-06	GNA11, GNAQ
phospholipase C-activating G protein-coupled receptor signaling pathway	2	131.7×	5e-04	GNA11, GNAQ
regulation of melanocyte differentiation	1	8426.0×	8e-04	GNA11
phospholipase C-activating G protein-coupled glutamate receptor signaling pathway	1	2106.5×	0.003	GNAQ
phospholipase C-activating serotonin receptor signaling pathway	1	1404.3×	0.003	GNAQ
regulation of platelet activation	1	1404.3×	0.003	GNAQ
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	1053.2×	0.003	GNA11
developmental pigmentation	1	1053.2×	0.003	GNA11
phospholipase C-activating dopamine receptor signaling pathway	1	1053.2×	0.003	GNA11
cellular response to pH	1	1053.2×	0.003	GNA11
sensory perception of itch	1	936.2×	0.003	GNAQ
ligand-gated ion channel signaling pathway	1	936.2×	0.003	GNA11
endothelin receptor signaling pathway	1	842.6×	0.003	GNA11
response to prostaglandin E	1	702.2×	0.003	GNAQ
glutamate receptor signaling pathway	1	468.1×	0.004	GNAQ
cranial skeletal system development	1	468.1×	0.004	GNA11
cellular response to acidic pH	1	366.4×	0.005	GNAQ
mast cell degranulation	1	312.1×	0.005	GNAQ
regulation of canonical Wnt signaling pathway	1	271.8×	0.006	GNAQ
hormone-mediated signaling pathway	1	200.6×	0.007	GNAQ
action potential	1	179.3×	0.008	GNA11
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	168.5×	0.008	GNA11
positive regulation of insulin secretion	1	127.7×	0.010	GNA11
regulation of blood pressure	1	110.9×	0.011	GNA11
blood coagulation	1	86.9×	0.014	GNAQ
neuropeptide signaling pathway	1	86.0×	0.014	GNAQ
skeletal system development	1	62.9×	0.018	GNA11
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.019	GNAQ

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNA11	0	0
GNAQ	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GNAQ	27	Binding:27
GNA11	18	Binding:18

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	GNA11, GNAQ

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)
GNA11	18	—
GNAQ	27	—

Clinical trials & evidence

Clinical trials

Clinical trials: 47.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	30
PHASE1	8
PHASE4	4
PHASE2	4
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03125057	PHASE4	COMPLETED	A Pilot Study of Hemoporfin PDT in Children With Port-wine Stain
NCT03181984	PHASE4	COMPLETED	Postmarketing Safety Study of Hemoporfin in Patients With Port Wine Stain
NCT04106258	PHASE4	COMPLETED	A Pilot Study of Hemoporfin PDT in Children(2-7 Years Old) With Port-wine Stain
NCT04999618	PHASE4	COMPLETED	A New Approach in Laser Surgery Using the Regenerative Solution in Children Diagnosed With Vascular Pathology
NCT05171894	PHASE2	RECRUITING	A Study to Evaluate Efficacy and Safety of Light Dose in Subjects With PWB Treated With Hemoporfin PDT
NCT07436611	PHASE2	NOT_YET_RECRUITING	Rapamycin Dose-Ranging Efficacy Study in Port Wine Stains
NCT00540917	PHASE2	COMPLETED	Measurement Skin Temperature During Pulsed Laser Exposure
NCT00969397	PHASE1/PHASE2	WITHDRAWN	Combined Use of Pulsed Dye Laser and Topical Antiangiogenic Agents for Treatment of Port Wine Stain Birthmarks
NCT00979550	PHASE2	TERMINATED	The Effects of Aldara as an Adjunct to Laser Treatment
NCT00573729	PHASE1	COMPLETED	Pulsed Dye Laser Treatment of Port Wine Stain Birthmarks: Comparison of 577 nm Versus 595 nm Wavelengths
NCT00580736	PHASE1	COMPLETED	Optical Clearing of the Skin in Conjunction With Laser Treatments
NCT00580944	PHASE1	WITHDRAWN	Combined Alexandrite and Pulsed Dye Laser Treatment of Port Wine Stain Birthmarks
NCT00667472	PHASE1	WITHDRAWN	Combined Pulsed Dye Laser and Topical Ranibizumab for Treatment of Port Wine Stain Birthmarks
NCT00800722	PHASE1	COMPLETED	A Randomized Trial to Study Combined Pulsed Dye Laser and Rapamycin Treatment of Port Wine Stain Birthmarks.
NCT00830466	PHASE1	COMPLETED	A Randomized Trial to Study Combined Pulsed Dye Laser and Rapamycin Treatment of Port Wine Stain Birthmarks.
NCT01166919	PHASE1	WITHDRAWN	Pilot Study on the Use of the Matrix Radiofrequencyfor Treatment of Port Wine Stain Birthmarks
NCT01924273	PHASE1	COMPLETED	Novel Treatment for Port Wine Stain Birthmarks
NCT05841628	Not specified	RECRUITING	Tolerability of 532 nm Laser Treatment of Port Wine Stains
NCT07183644	Not specified	NOT_YET_RECRUITING	Maximizing Laser Therapy Success for Port-Wine Birthmarks in Pediatric Patients
NCT07290426	Not specified	NOT_YET_RECRUITING	Vbeam Pro Pulse Dye Laser for the Treatment of Vascular Conditions
NCT00247299	Not specified	UNKNOWN	Evaluation and Optimization of the Technical and Clinical Performance of the Lumenis ONE Platform
NCT00365118	Not specified	COMPLETED	Treatment of Naevus Flammeus Using Intense Pulsed Light and Pulsed Dye Laser
NCT00540371	Not specified	COMPLETED	Dynamic Epidermal Cooling During Pulsed Dye Laser Treatment of Port Wine Stain Birthmark at High Fluences
NCT00540566	Not specified	COMPLETED	Optical Biopsy of Human Skin in Conjunction With Laser Treatment
NCT00556946	Not specified	COMPLETED	Combined Photodynamic and Pulsed Dye Laser Treatment of Port Wine Stains
NCT00585247	Not specified	COMPLETED	Combining Topical Imiquimod 5% Cream With a Pulsed Dye Laser to Treat Port Wine Stain Birthmarks
NCT00782483	Not specified	TERMINATED	Personalized Interactive Laser Therapy of Port Wine Stain
NCT01101360	Not specified	COMPLETED	Port Wine Stains Treatment Matrix RF Study
NCT01333553	Not specified	COMPLETED	Monitoring the Response of Port Wine Stain Birthmarks to Laser Therapy With Wide-field Functional Imaging Technologies
NCT01364857	Not specified	COMPLETED	French National Cohort of Children With Port Wine Stain
NCT01438047	Not specified	WITHDRAWN	Optical Frequency Domain Imaging (OFDI) in Dermatology
NCT01774552	Not specified	COMPLETED	Evaluate the Port-wine Stain Birthmark Treatment Before and After Pulsed Dye Laser Treatment
NCT01775722	Not specified	COMPLETED	Combined Bipolar Radiofrequency&Pulsed Dye Laser Treatment
NCT01968681	Not specified	COMPLETED	Treatment of Nevus Flammeus With Alexandrite Laser
NCT02035319	Not specified	WITHDRAWN	Effect of Laser Treatment on Capillary Malformations
NCT02051101	Not specified	COMPLETED	Pathogenic Mechanisms of Port Wine Stain and Repository of Port Wine Stain Biopsy Samples
NCT02214706	Not specified	TERMINATED	Treatment of Port Wine Stains Using Pulsed Dye Laser, Erbium Yag Laser and Topical Sirolimus
NCT03736252	Not specified	COMPLETED	Effectiveness of a Neoprene CMC Joint Orthosis
NCT03948997	Not specified	COMPLETED	The Role of Angiogenesis-related Pathways in the Development of Port Wine Stains
NCT04103164	Not specified	SUSPENDED	Pilot Study to Evaluate the Effect of Multiple Passes on Port Wine Stain Treatments With the Cutera Excel V™ Laser.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IMIQUIMOD	4	2
TALAPORFIN SODIUM	4	1
HEMATOPORPHYRIN	-1	1