Neurofibroma

Summary

Neurofibroma (MONDO:0016755) is a disease (an umbrella term covering 11 Mondo subtypes) with 2 cohort genes and 15 clinical trials. Molecularly, NF1 Mutation confers sensitivity to Tipifarnib in Neurofibroma (CIViC Level B). Top therapeutic interventions include imatinib, nilotinib, and talimogene laherparepvec.

At a glance

• Umbrella term: 11 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 19
• Phenotypes (HPO): 28
• Clinical trials: 15
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001067	Neurofibromas	Obligate (100%)
HP:0007470	Periarticular subcutaneous nodules	Frequent (30-79%)
HP:0009732	Plexiform neurofibroma	Frequent (30-79%)
HP:0012645	Enlarged peripheral nerve	Frequent (30-79%)
HP:0100698	Subcutaneous neurofibromas	Frequent (30-79%)
HP:0001291	Abnormal cranial nerve morphology	Occasional (5-29%)
HP:0003406	Peripheral nerve compression	Occasional (5-29%)
HP:0003416	Spinal canal stenosis	Occasional (5-29%)
HP:0006751	Paraspinal neurofibromas	Occasional (5-29%)
HP:0006851	Symmetric spinal nerve root neurofibromas	Occasional (5-29%)
HP:0009735	Spinal neurofibromas	Occasional (5-29%)
HP:0000995	Melanocytic nevus	Excluded (0%)
HP:0010609	Skin tags	Excluded (0%)
HP:0000256	Macrocephaly	Very rare (<1-4%)
HP:0000403	Recurrent otitis media	Very rare (<1-4%)
HP:0002584	Intestinal bleeding	Very rare (<1-4%)
HP:0002751	Kyphoscoliosis	Very rare (<1-4%)
HP:0005220	Multiple intestinal neurofibromatosis	Very rare (<1-4%)
HP:0007524	Atypical neurofibromatosis	Very rare (<1-4%)
HP:0007576	Palmar neurofibromas	Very rare (<1-4%)
HP:0009593	Peripheral schwannoma	Very rare (<1-4%)
HP:0011801	Enlargement of parotid gland	Very rare (<1-4%)
HP:0012289	Facial neoplasm	Very rare (<1-4%)
HP:0012440	Abnormal biliary tract morphology	Very rare (<1-4%)
HP:0100010	Spinal meningioma	Very rare (<1-4%)
HP:0100013	Neoplasm of the breast	Very rare (<1-4%)
HP:0100527	Neoplasia of the pleura	Very rare (<1-4%)
HP:0100551	Neoplasm of the trachea	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neurofibroma
Mondo ID	MONDO:0016755
MeSH	D009455
Orphanet	252183
DOID	DOID:962
ICD-11	221014277
NCIT	C3272
SNOMED CT	404029005
UMLS	C0027830
MedGen	45058
GARD	0007191
MedDRA	10029267
Is cancer (heuristic)	no

Also known as: neurofibroma · neurofibroma (WHO grade I) · neurofibroma, benign · NFIB

Data availability: 19 ClinVar variants · 5 cell lines.

Disease family

An umbrella term covering 11 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral nervous system neoplasm › nerve sheath neoplasm › neurofibroma

Related subtypes (5): schwannoma, granular cell tumor, neurothekeoma, malignant peripheral nerve sheath tumor, perineurioma

Subtypes (11): mediastinum neurofibroma, neurofibroma of spinal cord, Pacinian tumor, neurofibrosarcoma, epithelioid neurofibroma, neurofibroma of gallbladder, plexiform neurofibroma, cellular neurofibroma, atypical neurofibroma, neurofibroma of the heart, neurofibroma of the esophagus

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

19 retrieved; paginated sample, class counts are floors:

11 pathogenic, 5 pathogenic/likely pathogenic, 2 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1301408	NM_001042492.3(NF1):c.6858C>T (p.Asn2286=)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
186215	NM_001042492.3(NF1):c.1756_1759del (p.Thr586fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
216065	NM_001042492.3(NF1):c.5812+332A>G	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
336	NM_001042492.3(NF1):c.4330A>G (p.Lys1444Glu)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
374022	NM_001042492.3(NF1):c.2252-3T>G	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374108	NM_001042492.3(NF1):c.1721+3A>G	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40093	NM_001042492.3(NF1):c.574C>T (p.Arg192Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
457713	NM_001042492.3(NF1):c.4724+1G>A	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523344	NM_001042492.3(NF1):c.4875C>G (p.Tyr1625Ter)	NF1	Pathogenic	criteria provided, single submitter
523345	NM_001042492.3(NF1):c.4235G>C (p.Arg1412Thr)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523350	NM_001042492.3(NF1):c.6704+2del	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
635818	NM_001042492.3(NF1):c.7458-1G>C	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
635819	NM_001042492.3(NF1):c.2388del (p.Ala797fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
635820	NM_001042492.3(NF1):c.7063-2A>G	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
637012	NM_001042492.3(NF1):c.2619_2622dup (p.Gly875Ter)	NF1	Pathogenic	no assertion criteria provided
638015	NM_001042492.3(NF1):c.7448_7457del (p.Pro2483fs)	NF1	Pathogenic	no assertion criteria provided
812898	NM_001042492.3(NF1):c.2182_2196delinsT (p.Val728fs)	NF1	Likely pathogenic	no assertion criteria provided
635821	NM_001042492.3(NF1):c.1919C>T (p.Thr640Ile)	NF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
44596	NM_002834.5(PTPN11):c.1226G>C (p.Gly409Ala)	PTPN11	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

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
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar,civic_evidence
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

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
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPN11	6,009
NF1	5,540

Intra-cohort edges

A	B	Sources
NF1	PTPN11	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
NF1	P21359	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 61. 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
MET activates PTPN11	1	1142.0×	0.008	PTPN11
Co-inhibition by BTLA	1	1142.0×	0.008	PTPN11
RAS signaling downstream of NF1 loss-of-function variants	1	815.7×	0.008	NF1
STAT5 Activation	1	815.7×	0.008	PTPN11
Netrin mediated repulsion signals	1	634.4×	0.008	PTPN11
MAPK1 (ERK2) activation	1	571.0×	0.008	PTPN11
STAT5 activation downstream of FLT3 ITD mutants	1	571.0×	0.008	PTPN11
MAPK3 (ERK1) activation	1	519.1×	0.008	PTPN11
Signaling by Leptin	1	519.1×	0.008	PTPN11
Interleukin-6 signaling	1	475.8×	0.008	PTPN11
Activated NTRK2 signals through FRS2 and FRS3	1	475.8×	0.008	PTPN11
PECAM1 interactions	1	439.2×	0.008	PTPN11
Regulation of IFNG signaling	1	407.9×	0.008	PTPN11
Prolactin receptor signaling	1	380.7×	0.008	PTPN11
Signaling by FLT3 ITD and TKD mutants	1	380.7×	0.008	PTPN11
Spry regulation of FGF signaling	1	356.9×	0.008	PTPN11
Signal regulatory protein family interactions	1	335.9×	0.008	PTPN11
Platelet sensitization by LDL	1	335.9×	0.008	PTPN11
Regulation of RUNX1 Expression and Activity	1	335.9×	0.008	PTPN11
GAB1 signalosome	1	317.2×	0.008	PTPN11
PI-3K cascade:FGFR3	1	317.2×	0.008	PTPN11
Tie2 Signaling	1	300.5×	0.008	PTPN11
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	300.5×	0.008	PTPN11
PI-3K cascade:FGFR4	1	285.5×	0.008	PTPN11
Signaling by CSF3 (G-CSF)	1	285.5×	0.008	PTPN11
FRS-mediated FGFR3 signaling	1	271.9×	0.008	PTPN11
Co-inhibition by CTLA4	1	259.6×	0.008	PTPN11
Co-inhibition by PD-1	1	259.6×	0.008	PTPN11
PI-3K cascade:FGFR1	1	259.6×	0.008	PTPN11
Interleukin-37 signaling	1	259.6×	0.008	PTPN11

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
positive regulation of mast cell apoptotic process	1	8426.0×	0.003	NF1
regulation of glial cell differentiation	1	8426.0×	0.003	NF1
negative regulation of cortisol secretion	1	8426.0×	0.003	PTPN11
negative regulation of growth hormone secretion	1	8426.0×	0.003	PTPN11
observational learning	1	8426.0×	0.003	NF1
microvillus organization	1	4213.0×	0.003	PTPN11
gamma-aminobutyric acid secretion, neurotransmission	1	4213.0×	0.003	NF1
intestinal epithelial cell migration	1	4213.0×	0.003	PTPN11
Schwann cell proliferation	1	2808.7×	0.003	NF1
cerebellar cortex formation	1	2808.7×	0.003	PTPN11
forebrain astrocyte development	1	2808.7×	0.003	NF1
Schwann cell migration	1	2808.7×	0.003	NF1
glutamate secretion, neurotransmission	1	2808.7×	0.003	NF1
negative regulation of mast cell proliferation	1	2808.7×	0.003	NF1
negative regulation of Schwann cell migration	1	2808.7×	0.003	NF1
vascular associated smooth muscle cell migration	1	2808.7×	0.003	NF1
brain development	2	79.5×	0.003	NF1, PTPN11
heart development	2	78.8×	0.003	NF1, PTPN11
mast cell apoptotic process	1	2106.5×	0.003	NF1
negative regulation of Rac protein signal transduction	1	2106.5×	0.003	NF1
regulation of type I interferon-mediated signaling pathway	1	2106.5×	0.003	PTPN11
myeloid leukocyte migration	1	2106.5×	0.003	NF1
ERBB signaling pathway	1	1685.2×	0.004	PTPN11
mast cell proliferation	1	1685.2×	0.004	NF1
amygdala development	1	1404.3×	0.004	NF1
regulation of blood vessel endothelial cell migration	1	1404.3×	0.004	NF1
vascular associated smooth muscle cell proliferation	1	1404.3×	0.004	NF1
negative regulation of Schwann cell proliferation	1	1203.7×	0.004	NF1
negative regulation of neurotransmitter secretion	1	1203.7×	0.004	NF1
negative regulation of neutrophil activation	1	1203.7×	0.004	PTPN11

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTPN11	8	4
NF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PTPN11	588	Binding:585, Functional:2, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PTPN11	588

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

8 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)
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PTPN11
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	1	NF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE1	3
PHASE1/PHASE2	1
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01140360	PHASE1/PHASE2	COMPLETED	Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas
NCT06322342	PHASE2	COMPLETED	Phase 2 Ascending Dose Safety and Efficacy Study of RVP-001, a Manganese-based MRI Contrast Agent
NCT07102394	PHASE1	RECRUITING	Feasibility and Tolerability of IMLYGIC for the Treatment of Cutaneous Neurofibromas in Adults With NF1
NCT00716469	PHASE1	TERMINATED	Phase I Clinical Study of the Safety of Photodynamic Therapy (PDT) Using LS11 in Children With Plexiform Neurofibromas
NCT01031901	PHASE1	COMPLETED	Topical Rapamycin Therapy to Alleviate Cutaneous Manifestations of Tuberous Sclerosis Complex (TSC) and Neurofibromatosis I (NF1)
NCT01275586	EARLY_PHASE1	COMPLETED	Study of Tasigna®/Nilotinib (AMN107) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas
NCT00924196	Not specified	ACTIVE_NOT_RECRUITING	Natural History Study of Patients With Neurofibromatosis Type I
NCT03820778	Not specified	ACTIVE_NOT_RECRUITING	Whole Body MRI to Identify Atypical Neurofibromas in Patients With NF1
NCT05199376	Not specified	RECRUITING	Evaluation of Percutaneous Cryotherapy in the Treatment of Plexiform Neurofibromas and Unresectable Neurofibromas in Neurofibromatosis Type 1
NCT05891847	Not specified	ACTIVE_NOT_RECRUITING	Non-interventional Study of Patients With PN NF1 Starting Selumetinib in Russia
NCT06880991	Not specified	RECRUITING	Development of Patient-Reported Outcome Measures Assessing Tumor Visibility and Appearance Concerns in Neurofibromatosis Type 1: A Qualitative Study
NCT07298083	Not specified	RECRUITING	DoD Award NF230020 Identification of Metabolic Markers and Statistical Prediction of MPNST for Rapid Diagnosis and Assessment of Surgical Margins
NCT00314119	Not specified	COMPLETED	Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1
NCT01347307	Not specified	COMPLETED	Stereotactic Body Radiotherapy for Spine Tumors
NCT01567787	Not specified	WITHDRAWN	Proton Radiation Therapy for Spinal Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IMATINIB	4	1
NILOTINIB	4	1
TALIMOGENE LAHERPAREPVEC	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
NF1 Mutation	Tipifarnib	Sensitivity/Response	CIViC B	EID7426