Neurofibromatosis Type 1

MONDO:0018975 Pathograph 22 hereditary cancer-predisposing syndrome

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome caused by germline pathogenic variants in the NF1 tumor suppressor gene encoding neurofibromin. It is characterized by cafe-au-lait macules, neurofibromas, Lisch nodules, skeletal abnormalities, and increased risk of malignancy including optic pathway gliomas and malignant peripheral nerve sheath tumors (MPNST). NF1 exemplifies the RASopathy spectrum, with neurofibromin functioning as a RAS-GAP that normally negatively regulates RAS-MAPK signaling.

Ask OpenScientist

Ask a research question about Neurofibromatosis Type 1. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

2
Mappings
1
Inheritance
12
Pathophys.
16
Phenotypes
22
Pathograph
1
Genes
4
Medical Actions
1
Deep Research
🔗

Mappings

MONDO
MONDO:0018975 neurofibromatosis type 1
skos:exactMatch ORPHA:636 ORPHA:636: CONSISTENT
Orphanet lists MONDO:0018975 as an exact cross-reference for neurofibromatosis type 1.
ICD-11 Foundation
icd11f:337970533 Neurofibromatosis type 1
skos:exactMatch ORPHA:636 ORPHA:636: CONSISTENT
Orphanet lists ICD-11 LD2D.10 as an exact cross-reference; the local ICD-11 Foundation ontology represents this as icd11f:337970533.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Orphanet classifies neurofibromatosis type 1 as autosomal dominant, consistent with heterozygous germline pathogenic variants in NF1.
Autosomal dominant inheritance
Show evidence (1 reference)
ORPHA:636 SUPPORT Other
"Autosomal dominant"
Orphanet directly lists autosomal dominant inheritance for ORPHA:636.
⚙

Pathophysiology

12
NF1 Tumor Suppressor Loss
Germline heterozygous NF1 pathogenic variants reduce neurofibromin dosage across tissues. In focal lesions such as neurofibromas, cafe-au-lait macules, optic pathway gliomas, and tibial pseudoarthrosis, somatic loss or mutation of the remaining allele can create cell-specific biallelic NF1 inactivation. Loss of neurofibromin removes RAS-GAP restraint, allowing hyperactive RAS effector signaling and tissue-specific developmental or neoplastic outcomes.
NF1 hgnc:7765
regulation of Ras protein signal transduction GO:0046578 ↓ DECREASED
Downstream
RAS-MAPK Pathway Hyperactivation Loss of neurofibromin RAS-GAP activity increases RAS effector signaling.
PI3K-AKT-mTOR Pathway Hyperactivation NF1 loss also activates PI3K-AKT-mTOR signaling in susceptible tumor cells.
cAMP-PKA Signaling Dysregulation NF1 loss alters cAMP-PKA signaling in melanocytes and optic glioma biology.
Show evidence (2 references)
PMID:25877329 SUPPORT Human Clinical
"The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS-MAPK signalling, causing related diseases collectively known as RASopathies."
This review establishes NF1 as a neurofibromin/RAS-GAP disorder in the RASopathy spectrum.
PMID:24932921 SUPPORT Human Clinical
"Genomewide analysis identified multiple genetic mechanisms resulting in somatic biallelic NF1 inactivation; no other genes with recurring somatic mutations were identified."
Patient pseudoarthrosis tissue demonstrates a second-hit NF1 mechanism in an NF1 skeletal lesion.
RAS-MAPK Pathway Hyperactivation
Neurofibromin normally accelerates GTP hydrolysis on RAS proteins, promoting the inactive GDP-bound state. Loss of neurofibromin results in prolonged RAS-GTP accumulation and constitutive activation of the RAS-RAF-MEK-ERK cascade. In NF1, this branch drives Schwann-cell tumor initiation, melanocyte pigmentation programs, glial proliferation, skeletal remodeling defects, and neurodevelopmental plasticity abnormalities.
Ras protein signal transduction GO:0007265 ↑ INCREASED MAPK cascade GO:0000165 ↑ INCREASED
Downstream
Schwann Cell Neurofibroma Initiation Biallelic NF1 loss in Schwann lineage cells initiates neurofibroma formation.
Melanocyte Pigmentation Program Activation NF1-deficient melanocytes activate ERK-associated pigmentation programs.
Glial Progenitor Hyperproliferation NF1 loss in CNS glial lineages increases progenitor proliferation.
Neurodevelopmental GABAergic Plasticity Defect Excessive Ras activity perturbs inhibitory tone and synaptic plasticity.
Osteoblast-Osteoclast Remodeling Defect Hyperactive Ras/MAPK signaling disrupts bone-forming and bone-resorbing lineages.
Show evidence (1 reference)
PMID:25877329 SUPPORT Human Clinical
"The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS-MAPK signalling, causing related diseases collectively known as RASopathies."
This supports RAS-MAPK pathway hyperactivation as the central biochemical consequence of NF1 mutation.
PI3K-AKT-mTOR Pathway Hyperactivation
NF1 loss activates PI3K-AKT-mTOR signaling in susceptible glial and Schwann lineage tumors. In optic glioma models, PI3K/Akt and MEK/ERK converge on mTOR to maintain tumor cell proliferation. During peripheral nerve sheath tumor progression, reduced PTEN restraint cooperates with Nf1 loss to accelerate transition toward high-grade malignant PNST.
PI3K/AKT signal transduction GO:0043491 ↑ INCREASED mTOR signaling pathway GO:0031929 ↑ INCREASED
Downstream
Optic Glioma mTOR-Dependent Maintenance MEK and Akt signaling converge on mTOR to sustain Nf1 optic glioma growth.
Malignant Peripheral Nerve Sheath Tumor Progression PTEN pathway loss cooperates with Nf1 loss during malignant progression.
Show evidence (1 reference)
PMID:25534823 SUPPORT Model Organism
"Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo."
This demonstrates MEK and Akt pathway hyperactivation downstream of Nf1 loss in astrocyte and optic glioma models.
cAMP-PKA Signaling Dysregulation
NF1 loss perturbs cAMP-PKA signaling in cell-type-specific contexts. In melanocytes, increased cAMP-mediated PKA activity cooperates with ERK1/2 to drive MITF and melanogenic enzyme expression, producing the pigmentation branch of the NF1 pathograph.
cAMP/PKA signal transduction GO:0141156 ⚠ ABNORMAL
Downstream
Melanocyte Pigmentation Program Activation Increased cAMP-PKA and ERK1/2 signaling induce MITF and melanogenic enzymes.
Show evidence (1 reference)
PMID:26150484 SUPPORT In Vitro
"Molecular mechanisms associated with these pathological phenotypes correlate with an increased activity of cAMP-mediated PKA and ERK1/2 signaling pathways, leading to overexpression of the transcription factor MITF and of the melanogenic enzymes tyrosinase and dopachrome tautomerase, all major..."
This directly supports abnormal cAMP-PKA signaling as a contributor to the melanocyte pigmentation branch.
Melanocyte Pigmentation Program Activation
NF1-deficient melanocytes reproduce the cafe-au-lait hyperpigmentation phenotype in vitro. Increased cAMP-PKA and ERK1/2 signaling induces MITF and melanogenic enzymes, increasing melanin synthesis and supporting the pigmentary manifestations of NF1.
melanocyte CL:0000148
melanin biosynthetic process GO:0042438 ↑ INCREASED developmental pigmentation GO:0048066 ↑ INCREASED
Downstream
Cafe-au-lait Macules Increased melanogenic signaling produces multiple hyperpigmented cafe-au-lait macules.
Lisch Nodules Melanocytic hamartoma formation in iris stroma produces Lisch nodules.
Show evidence (1 reference)
PMID:26150484 SUPPORT In Vitro
"In the present study, we demonstrate that NF1 melanocytes reproduce the hyperpigmentation phenotype in vitro, and further characterize the link between loss of heterozygosity and the typical CALMs that appear over the general hyperpigmentation."
NF1 melanocyte models reproduce cafe-au-lait macule hyperpigmentation and connect it to NF1 loss of heterozygosity.
Schwann Cell Neurofibroma Initiation
Biallelic NF1 loss in Schwann cells or Schwann-cell precursors is the initiating lesion for peripheral nerve sheath tumor formation. Schwann lineage NF1 loss creates the tumor cell compartment, while the NF1 heterozygous microenvironment supplies cooperating stromal, immune, and paracrine signals.
Schwann cell CL:0002573
cell population proliferation GO:0008283 ↑ INCREASED
Downstream
Mast Cell-Rich Neurofibroma Microenvironment Nf1-deficient Schwann cells secrete Kit ligand that recruits Nf1+/- mast cells.
Cutaneous Neurofibromas Schwann-cell-dominant peripheral nerve sheath overgrowth produces cutaneous neurofibromas.
Plexiform Neurofibromas Expanded Schwann cell clones in major nerves form plexiform tumors.
Show evidence (1 reference)
PMID:22700876 SUPPORT Model Organism
"Schwann cells and/or their precursor cells are believed to be the primary pathogenic cell in neurofibromas because they harbor biallelic neurofibromin 1 (NF1) gene mutations."
This supports Schwann lineage cells as the core NF1-biallelic tumor cell compartment.
Mast Cell-Rich Neurofibroma Microenvironment
Nf1-deficient Schwann cells secrete soluble Kit ligand, attracting Nf1+/- mast cells that can remodel extracellular matrix and support angiogenesis. This paracrine Schwann cell-mast cell loop helps convert cell-autonomous NF1 loss into multicellular neurofibroma growth.
Schwann cell CL:0002573 mast cell CL:0000097
cell population proliferation GO:0008283 ↑ INCREASED
Downstream
Cutaneous Neurofibromas Multicellular Schwann-cell-dominant tumor growth produces cutaneous neurofibromas.
Plexiform Neurofibromas The same Schwann-cell and microenvironment program expands along major nerves.
Malignant Peripheral Nerve Sheath Tumor Progression Plexiform neurofibromas create the precursor tumor population at risk for malignant transformation.
Show evidence (1 reference)
PMID:14679180 SUPPORT Model Organism
"Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in neurofibroma formation."
This supports the paracrine microenvironment mechanism for neurofibroma formation.
Malignant Peripheral Nerve Sheath Tumor Progression
Most neurofibromas remain benign, but cooperating tumor-suppressor pathway lesions can convert NF1-deficient peripheral nerve sheath tumors into MPNST. Experimental Nf1/Pten inactivation accelerates low-grade PNST development and promotes progression to high-grade tumors, matching the PI3K-AKT-mTOR branch of the NF1 pathograph.
Schwann cell CL:0002573
NF1 hgnc:7765 PTEN hgnc:9588
PI3K/AKT signal transduction GO:0043491 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED
Downstream
Malignant Peripheral Nerve Sheath Tumor Cooperating PI3K-pathway deregulation promotes high-grade malignant PNST.
Show evidence (1 reference)
PMID:22700876 SUPPORT Model Organism
"Haploinsufficiency or complete loss of Pten dramatically accelerated neurofibroma development and led to the development of higher grade PNSTs in the context of Nf1 loss."
Nf1 and Pten cooperate in peripheral nerve sheath tumor development and malignant progression.
Glial Progenitor Hyperproliferation
NF1 inactivation in CNS glial lineages produces reactive astrogliosis and increased glial progenitor proliferation. Enlarged optic nerves with hyperplastic lesions can progress to optic pathway glioma, and MEK/Akt-mTOR signaling maintains subsequent Nf1 optic glioma growth.
astrocyte CL:0000127
cell population proliferation GO:0008283 ↑ INCREASED
Downstream
Optic Glioma mTOR-Dependent Maintenance Hyperproliferative glial lineage lesions are maintained by MEK/Akt-mTOR signaling.
Show evidence (1 reference)
PMID:16314489 SUPPORT Model Organism
"These data point to hyperproliferative glial progenitors as the source of the optic tumors and provide a genetic model for NF1-associated astrogliosis and optic glioma."
This directly supports hyperproliferative glial progenitors as the source of optic tumors.
Optic Glioma mTOR-Dependent Maintenance
In Nf1 optic glioma models, MEK and Akt pathways converge on mTOR to sustain astrocyte and optic glioma proliferation. This maintenance branch connects NF1-loss glial progenitor hyperproliferation to clinical optic pathway glioma risk.
astrocyte CL:0000127
mTOR signaling pathway GO:0031929 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED
Downstream
Optic Pathway Glioma Maintained proliferative glial lesions manifest clinically as optic pathway gliomas.
Show evidence (1 reference)
PMID:25534823 SUPPORT Model Organism
"These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials."
This supports mTOR-dependent maintenance of Nf1 optic glioma growth.
Neurodevelopmental GABAergic Plasticity Defect
NF1-associated learning problems are modeled as excessive Ras activity increasing GABA-mediated inhibition and decreasing long-term potentiation. This branch links the same proximal RAS dysregulation that drives tumors to neurodevelopmental circuit-level learning impairment.
neuron CL:0000540
learning or memory GO:0007612 ⚠ ABNORMAL Ras protein signal transduction GO:0007265 ↑ INCREASED
Downstream
Learning Difficulties Impaired synaptic plasticity and increased inhibition produce the learning phenotype.
Show evidence (1 reference)
PMID:28256688 SUPPORT Model Organism
"Studies in animal models suggest that the learning disabilities associated with NF1 are caused by excessive Ras activity that leads to increased gamma-aminobutyric acid (GABA) inhibition and to decreased long-term potentiation."
This summarizes the accepted animal-model mechanism for NF1 learning disability.
Osteoblast-Osteoclast Remodeling Defect
Neurofibromin deficiency in skeletal progenitors and bone-resorbing lineages disrupts osteoblast differentiation, osteoclast maturation, fracture repair, and bone remodeling. This skeletal branch links NF1 Ras/MAPK hyperactivation to scoliosis and focal dysplasia/pseudoarthrosis phenotypes.
osteoblast CL:0000062 osteoclast CL:0000092
bone remodeling GO:0046849 ⚠ ABNORMAL osteoblast differentiation GO:0001649 ⚠ ABNORMAL
Downstream
Scoliosis Abnormal vertebral growth and bone remodeling promote progressive spinal curvature.
Tibial Pseudarthrosis Focal tibial dysplasia and defective fracture repair produce persistent tibial pseudoarthrosis/nonunion.
Show evidence (2 references)
PMID:23863460 SUPPORT Model Organism
"Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis related to NF1 mutations."
This supports Ras/MAPK-driven skeletal remodeling defects in NF1.
PMID:24932921 SUPPORT Human Clinical
"Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways."
Human pseudoarthrosis tissue shows neurofibromin-deficiency-associated pathway dysregulation in a skeletal NF1 lesion.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neurofibromatosis Type 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Endocrine 1
Pheochromocytoma OCCASIONAL Pheochromocytoma HP:0002666
Show evidence (1 reference)
ORPHA:636 SUPPORT Other
"HP:0002666 | Pheochromocytoma | Occasional (29-5%)"
Orphanet's curated HPO table classifies pheochromocytoma as occasional in NF1.
Eye 2
Lisch Nodules VERY_FREQUENT Lisch nodules HP:0009737
Show evidence (2 references)
PMID:9874851 SUPPORT Human Clinical
"The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
Review identifies Lisch nodules (iris hamartomas) as a cardinal feature of NF1.
ORPHA:636 SUPPORT Other
"HP:0009737 | Lisch nodules | Very frequent (99-80%)"
Orphanet's curated HPO table classifies Lisch nodules as very frequent in NF1.
Choroidal Abnormalities VERY_FREQUENT Abnormal choroid morphology HP:0000610
Show evidence (1 reference)
PMID:34012067 SUPPORT Human Clinical
"Choroidal abnormalities were added as an ophthalmologic criterion because of the high specificity and sensitivity for NF1"
The revised NF1 diagnostic criteria include choroidal abnormalities as an ophthalmologic criterion because they are sensitive and specific for NF1.
Head and Neck 1
Macrocephaly OCCASIONAL Macrocephaly HP:0000256
Show evidence (1 reference)
ORPHA:636 SUPPORT Other
"HP:0000256 | Macrocephaly | Occasional (29-5%)"
Orphanet's curated HPO table classifies macrocephaly as occasional in NF1.
Integument 3
Cafe-au-lait Macules OBLIGATE Multiple cafe-au-lait spots HP:0007565
Show evidence (2 references)
PMID:9874851 SUPPORT Human Clinical
"The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
Review identifies cafe-au-lait spots as a cardinal feature of NF1.
ORPHA:636 PARTIAL Other
"HP:0007565 | Multiple cafe-au-lait spots | Very frequent (99-80%)"
Orphanet's curated HPO table confirms multiple cafe-au-lait spots as a very frequent NF1 phenotype, while this entry keeps the stronger diagnostic/near-obligate classification supported by clinical criteria.
Cutaneous Neurofibromas VERY_FREQUENT Neurofibroma HP:0001067
Show evidence (1 reference)
PMID:9874851 SUPPORT Human Clinical
"The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
Review identifies cutaneous neurofibromas as a cardinal feature of NF1.
Plexiform Neurofibromas FREQUENT Plexiform neurofibroma HP:0009732
Show evidence (2 references)
PMID:33395032 PARTIAL Human Clinical
"Given the potential of MEK inhibition as an effective and overall well tolerated medical treatment, the use of targeted agents in the NF1 population is likely to increase considerably."
Review confirms plexiform neurofibromas are a significant clinical problem in NF1 amenable to MEK inhibitor therapy.
ORPHA:636 SUPPORT Other
"HP:0009732 | Plexiform neurofibroma | Very frequent (99-80%)"
Orphanet's curated HPO table lists plexiform neurofibroma among NF1 phenotypes.
Musculoskeletal 1
Scoliosis FREQUENT Scoliosis HP:0002650
Show evidence (1 reference)
PMID:9874851 SUPPORT Human Clinical
"Common complications include learning disability, scoliosis, and optic gliomas."
Review identifies scoliosis as a common complication of NF1.
Nervous System 1
Attention Deficit Hyperactivity Disorder FREQUENT Attention deficit hyperactivity disorder HP:0007018
Show evidence (1 reference)
ORPHA:636 SUPPORT Other
"HP:0007018 | Attention deficit hyperactivity disorder | Frequent (79-30%)"
Orphanet's curated HPO table classifies ADHD as frequent in NF1.
Neoplasm 2
Optic Pathway Glioma FREQUENT Optic nerve glioma HP:0009734
The local HPO snapshot does not contain a distinct optic pathway glioma term; HP:0009734 is used as the closest available term because its definition covers glioma originating in the optic nerve or optic chiasm.
Show evidence (2 references)
PMID:9874851 SUPPORT Human Clinical
"Common complications include learning disability, scoliosis, and optic gliomas."
Review identifies optic gliomas as a common complication of NF1.
ORPHA:636 PARTIAL Other
"HP:0009734 | Optic nerve glioma | Occasional (29-5%)"
Orphanet confirms optic nerve glioma as an NF1 phenotype, but its curated frequency class is occasional rather than this entry's broader frequent optic-pathway-glioma framing.
Malignant Peripheral Nerve Sheath Tumor OCCASIONAL Neurofibrosarcoma HP:0100697
Show evidence (1 reference)
PMID:32234870 SUPPORT Human Clinical
"Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10% of PNSTs will undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs)."
Review confirms approximately 10% of peripheral nerve sheath tumors in NF1 undergo malignant transformation to MPNST.
Other 5
Axillary and Inguinal Freckling VERY_FREQUENT Axillary freckling HP:0000997
This phenotype aggregates the NF1 diagnostic criterion of axillary or inguinal freckling. The local HPO snapshot contains separate terms for axillary freckling (HP:0000997) and inguinal freckling (HP:0030052), so the axillary term is used as the representative mapped descriptor.
Show evidence (4 references)
PMID:34012067 SUPPORT Human Clinical
"Freckling in the axillary or inguinal region"
The international consensus diagnostic criteria include axillary or inguinal freckling as an NF1 criterion.
PMID:9874851 SUPPORT Human Clinical
"The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
Review identifies axillary freckling as a cardinal NF1 feature.
ORPHA:636 PARTIAL Other
"HP:0000997 | Axillary freckling | Frequent (79-30%)"
Orphanet confirms axillary freckling as an NF1 phenotype, but classifies it as frequent rather than very frequent.
+ 1 more reference
Tibial Pseudarthrosis OCCASIONAL Tibial pseudarthrosis HP:0009736
Show evidence (2 references)
PMID:24932921 SUPPORT Human Clinical
"About 5% of individuals with NF1 will present with anterolateral bowing (dysplasia) leading to fracture that fails to achieve proper union, often after repeated surgical correction."
Human NF1 pseudoarthrosis tissue study summarizes the approximate frequency and nonunion phenotype.
PMID:34012067 SUPPORT Human Clinical
"anterolateral bowing of the tibia, or pseudarthrosis of a long bone"
Consensus diagnostic criteria include tibial bowing and long-bone pseudarthrosis as distinctive NF1 osseous lesions.
Learning Difficulties FREQUENT Specific learning disability HP:0001328
Most NF1 patients have normal IQ but specific learning disabilities, attention deficits, or executive function problems.
Show evidence (2 references)
PMID:9874851 SUPPORT Human Clinical
"Common complications include learning disability, scoliosis, and optic gliomas."
Review identifies learning disability as a common complication of NF1.
ORPHA:636 SUPPORT Other
"HP:0001328 | Specific learning disability | Very frequent (99-80%)"
Orphanet's curated HPO table lists specific learning disability among very frequent NF1 phenotypes.
Gastrointestinal Stromal Tumor OCCASIONAL Gastrointestinal stroma tumor HP:0100723
Show evidence (1 reference)
ORPHA:636 SUPPORT Other
"HP:0100723 | Gastrointestinal stroma tumor | Occasional (29-5%)"
Orphanet's curated HPO table classifies gastrointestinal stroma tumor as occasional in NF1.
Breast Neoplasm OCCASIONAL Neoplasm of the breast HP:0100013
Show evidence (1 reference)
ORPHA:636 SUPPORT Other
"HP:0100013 | Neoplasm of the breast | Occasional (29-5%)"
Orphanet's curated HPO table classifies neoplasm of the breast as occasional in NF1.
🧬

Genetic Associations

1
NF1 (Germline Loss-of-Function Mutations)
Autosomal Dominant
Show evidence (1 reference)
CGGV:assertion_367a3958-ce81-47fa-a505-a451ca67aab5-2019-03-05T170000.000Z SUPPORT Other
"NF1 | HGNC:7765 | neurofibromatosis type 1 | MONDO:0018975 | AD | Definitive"
ClinGen classifies the NF1-neurofibromatosis type 1 gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Medical Actions

4
MEK Inhibitors
Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352
Selumetinib is FDA-approved for symptomatic, inoperable plexiform neurofibromas in children aged 2 years and older. As a MEK inhibitor, it targets the downstream effector of hyperactive RAS signaling. Shrinkage of plexiform neurofibromas observed in clinical trials.
Show evidence (1 reference)
PMID:33395032 SUPPORT Human Clinical
"The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20% reduction in the size of pNF from baseline in 71% of patients and was associated with clinically meaningful improvements. On the basis of this trial, selumetinib (Koselugo) received FDA approval for children 2 years of age..."
SPRINT trial demonstrated selumetinib efficacy in plexiform neurofibromas leading to FDA approval for pediatric NF1 patients.
Surgical Management
Action: surgical procedure MAXO:0000004
Surgery for symptomatic neurofibromas causing pain, functional impairment, or disfigurement. Complete resection of plexiform neurofibromas often impossible due to infiltrative nature. Surgery is primary treatment for operable MPNST.
Surveillance Protocol
Action: cancer screening MAXO:0000126
Annual clinical evaluation including skin, skeletal, neurologic, and ophthalmologic examination. Annual ophthalmologic evaluation in children (optic glioma screening). MRI for symptomatic lesions or suspected MPNST. Blood pressure monitoring for renovascular disease or pheochromocytoma.
Show evidence (1 reference)
PMID:9874851 SUPPORT Human Clinical
"The mainstay of care for patients with NF1 is anticipatory guidance, and the early detection and symptomatic treatment of disease complications."
Review emphasizes surveillance and early detection as the foundation of NF1 management.
Genetic Counseling
Action: genetic counseling MAXO:0000079
Genetic counseling for affected individuals and at-risk family members. Children of affected parents have 50% risk. High rate of de novo mutations means negative family history does not exclude NF1. Variable expressivity makes predicting severity difficult.
Show evidence (1 reference)
PMID:9874851 SUPPORT Human Clinical
"Counseling of patients and their families should provide a realistic overview of possible disease complications, while emphasizing that most individuals with NF1 lead healthy and productive lives."
Review discusses the importance of genetic counseling for NF1 families, addressing both disease complications and positive prognosis.
🔬

Biochemical Markers

1
NF1 Genetic Testing
{ }

Source YAML

click to show 
name: Neurofibromatosis Type 1
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-28T03:57:10Z'
description: >-
  Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome
  caused by germline pathogenic variants in the NF1 tumor suppressor gene encoding
  neurofibromin. It is characterized by cafe-au-lait macules, neurofibromas, Lisch
  nodules, skeletal abnormalities, and increased risk of malignancy including optic
  pathway gliomas and malignant peripheral nerve sheath tumors (MPNST). NF1 exemplifies
  the RASopathy spectrum, with neurofibromin functioning as a RAS-GAP that normally
  negatively regulates RAS-MAPK signaling.
mappings:
  icd11f_mappings:
  - term:
      id: icd11f:337970533
      label: Neurofibromatosis type 1
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:636
    mapping_justification: Orphanet lists ICD-11 LD2D.10 as an exact cross-reference; the local ICD-11 Foundation ontology represents this as icd11f:337970533.
    consistency:
    - reference: ORPHA:636
      consistent: CONSISTENT
      notes: "ICD-11:LD2D.10 | Exact"
  mondo_mappings:
  - term:
      id: MONDO:0018975
      label: neurofibromatosis type 1
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:636
    mapping_justification: Orphanet lists MONDO:0018975 as an exact cross-reference for neurofibromatosis type 1.
    consistency:
    - reference: ORPHA:636
      consistent: CONSISTENT
      notes: "MONDO:0018975 | Exact"
external_assertions:
- name: Orphanet Neurofibromatosis type 1 record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:636
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=636
  description: >
    Orphanet identifies neurofibromatosis type 1 as ORPHA:636 and provides
    curated cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA,
    and UMLS identifiers.
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0018975 | Exact"
    explanation: Orphanet maps ORPHA:636 exactly to the MONDO term used as the disease anchor in this file.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-11:LD2D.10 | Exact"
    explanation: Orphanet provides an exact ICD-11 cross-reference for NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:Q85.0 | Narrower"
    explanation: Orphanet lists ICD-10 Q85.0 among the NF1 cross-references.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:162200 | Broader"
    explanation: Orphanet lists OMIM 162200 among the broader OMIM cross-references for NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MeSH:D009456 | Exact"
    explanation: Orphanet provides an exact MeSH cross-reference for NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C0027831 | Exact"
    explanation: Orphanet provides an exact UMLS cross-reference for NF1.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Orphanet classifies neurofibromatosis type 1 as autosomal dominant,
    consistent with heterozygous germline pathogenic variants in NF1.
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet directly lists autosomal dominant inheritance for ORPHA:636.
prevalence:
- population: Worldwide
  percentage: "1-5 / 10 000"
  notes: Orphanet worldwide prevalence-at-birth class for neurofibromatosis type 1.
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Worldwide | Prevalence at birth | PMID:20301288"
    explanation: Orphanet reports the worldwide birth-prevalence class for NF1.
- population: Europe
  percentage: "1-5 / 10 000"
  notes: Orphanet European point-prevalence class for neurofibromatosis type 1.
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Europe | Point prevalence | PMID:10991696,PMID:20082463,PMID:2511318,PMID:6807042"
    explanation: Orphanet reports the European point-prevalence class for NF1.
progression:
- phase: Onset
  age_range: Neonatal to infancy
  notes: Orphanet lists both neonatal and infancy onset categories for NF1.
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset for NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infancy onset for NF1.
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Neurocutaneous Syndrome
- RASopathy
parents:
- hereditary cancer-predisposing syndrome
pathophysiology:
- name: NF1 Tumor Suppressor Loss
  description: >-
    Germline heterozygous NF1 pathogenic variants reduce neurofibromin dosage
    across tissues. In focal lesions such as neurofibromas, cafe-au-lait macules,
    optic pathway gliomas, and tibial pseudoarthrosis, somatic loss or mutation
    of the remaining allele can create cell-specific biallelic NF1 inactivation.
    Loss of neurofibromin removes RAS-GAP restraint, allowing hyperactive RAS
    effector signaling and tissue-specific developmental or neoplastic outcomes.
  biological_processes:
  - preferred_term: regulation of Ras protein signal transduction
    modifier: DECREASED
    term:
      id: GO:0046578
      label: regulation of Ras protein signal transduction
  genes:
  - preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  evidence:
  - reference: PMID:25877329
    reference_title: "A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin
      and is one of several genes that (when mutant) affect RAS-MAPK signalling,
      causing related diseases collectively known as RASopathies.
    explanation: >-
      This review establishes NF1 as a neurofibromin/RAS-GAP disorder in the
      RASopathy spectrum.
  - reference: PMID:24932921
    reference_title: "Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomewide analysis identified multiple genetic mechanisms resulting in
      somatic biallelic NF1 inactivation; no other genes with recurring somatic
      mutations were identified.
    explanation: >-
      Patient pseudoarthrosis tissue demonstrates a second-hit NF1 mechanism in
      an NF1 skeletal lesion.
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: Loss of neurofibromin RAS-GAP activity increases RAS effector signaling.
    causal_link_type: DIRECT
  - target: PI3K-AKT-mTOR Pathway Hyperactivation
    description: NF1 loss also activates PI3K-AKT-mTOR signaling in susceptible tumor cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - RAS effector signaling
  - target: cAMP-PKA Signaling Dysregulation
    description: NF1 loss alters cAMP-PKA signaling in melanocytes and optic glioma biology.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - RAS effector signaling
- name: RAS-MAPK Pathway Hyperactivation
  description: >-
    Neurofibromin normally accelerates GTP hydrolysis on RAS proteins, promoting
    the inactive GDP-bound state. Loss of neurofibromin results in prolonged
    RAS-GTP accumulation and constitutive activation of the RAS-RAF-MEK-ERK
    cascade. In NF1, this branch drives Schwann-cell tumor initiation,
    melanocyte pigmentation programs, glial proliferation, skeletal remodeling
    defects, and neurodevelopmental plasticity abnormalities.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  evidence:
  - reference: PMID:25877329
    reference_title: "A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin
      and is one of several genes that (when mutant) affect RAS-MAPK signalling,
      causing related diseases collectively known as RASopathies.
    explanation: >-
      This supports RAS-MAPK pathway hyperactivation as the central biochemical
      consequence of NF1 mutation.
  downstream:
  - target: Schwann Cell Neurofibroma Initiation
    description: Biallelic NF1 loss in Schwann lineage cells initiates neurofibroma formation.
    causal_link_type: DIRECT
  - target: Melanocyte Pigmentation Program Activation
    description: NF1-deficient melanocytes activate ERK-associated pigmentation programs.
    causal_link_type: DIRECT
  - target: Glial Progenitor Hyperproliferation
    description: NF1 loss in CNS glial lineages increases progenitor proliferation.
    causal_link_type: DIRECT
  - target: Neurodevelopmental GABAergic Plasticity Defect
    description: Excessive Ras activity perturbs inhibitory tone and synaptic plasticity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased GABA-mediated inhibition
    - decreased long-term potentiation
  - target: Osteoblast-Osteoclast Remodeling Defect
    description: Hyperactive Ras/MAPK signaling disrupts bone-forming and bone-resorbing lineages.
    causal_link_type: DIRECT
- name: PI3K-AKT-mTOR Pathway Hyperactivation
  description: >-
    NF1 loss activates PI3K-AKT-mTOR signaling in susceptible glial and Schwann
    lineage tumors. In optic glioma models, PI3K/Akt and MEK/ERK converge on
    mTOR to maintain tumor cell proliferation. During peripheral nerve sheath
    tumor progression, reduced PTEN restraint cooperates with Nf1 loss to
    accelerate transition toward high-grade malignant PNST.
  biological_processes:
  - preferred_term: PI3K/AKT signal transduction
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  - preferred_term: mTOR signaling pathway
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  evidence:
  - reference: PMID:25534823
    reference_title: "Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro
      and in Nf1 murine optic gliomas in vivo.
    explanation: >-
      This demonstrates MEK and Akt pathway hyperactivation downstream of Nf1
      loss in astrocyte and optic glioma models.
  downstream:
  - target: Optic Glioma mTOR-Dependent Maintenance
    description: MEK and Akt signaling converge on mTOR to sustain Nf1 optic glioma growth.
    causal_link_type: DIRECT
  - target: Malignant Peripheral Nerve Sheath Tumor Progression
    description: PTEN pathway loss cooperates with Nf1 loss during malignant progression.
    causal_link_type: DIRECT
- name: cAMP-PKA Signaling Dysregulation
  description: >-
    NF1 loss perturbs cAMP-PKA signaling in cell-type-specific contexts. In
    melanocytes, increased cAMP-mediated PKA activity cooperates with ERK1/2 to
    drive MITF and melanogenic enzyme expression, producing the pigmentation
    branch of the NF1 pathograph.
  biological_processes:
  - preferred_term: cAMP/PKA signal transduction
    modifier: ABNORMAL
    term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
  evidence:
  - reference: PMID:26150484
    reference_title: "In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Molecular mechanisms associated with these pathological phenotypes
      correlate with an increased activity of cAMP-mediated PKA and ERK1/2
      signaling pathways, leading to overexpression of the transcription factor
      MITF and of the melanogenic enzymes tyrosinase and dopachrome tautomerase,
      all major players in melanogenesis.
    explanation: >-
      This directly supports abnormal cAMP-PKA signaling as a contributor to the
      melanocyte pigmentation branch.
  downstream:
  - target: Melanocyte Pigmentation Program Activation
    description: Increased cAMP-PKA and ERK1/2 signaling induce MITF and melanogenic enzymes.
    causal_link_type: DIRECT
- name: Melanocyte Pigmentation Program Activation
  description: >-
    NF1-deficient melanocytes reproduce the cafe-au-lait hyperpigmentation
    phenotype in vitro. Increased cAMP-PKA and ERK1/2 signaling induces MITF and
    melanogenic enzymes, increasing melanin synthesis and supporting the
    pigmentary manifestations of NF1.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: melanin biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0042438
      label: melanin biosynthetic process
  - preferred_term: developmental pigmentation
    modifier: INCREASED
    term:
      id: GO:0048066
      label: developmental pigmentation
  evidence:
  - reference: PMID:26150484
    reference_title: "In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In the present study, we demonstrate that NF1 melanocytes reproduce the
      hyperpigmentation phenotype in vitro, and further characterize the link
      between loss of heterozygosity and the typical CALMs that appear over the
      general hyperpigmentation.
    explanation: >-
      NF1 melanocyte models reproduce cafe-au-lait macule hyperpigmentation and
      connect it to NF1 loss of heterozygosity.
  downstream:
  - target: Cafe-au-lait Macules
    description: Increased melanogenic signaling produces multiple hyperpigmented cafe-au-lait macules.
    causal_link_type: DIRECT
  - target: Lisch Nodules
    description: Melanocytic hamartoma formation in iris stroma produces Lisch nodules.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Schwann Cell Neurofibroma Initiation
  description: >-
    Biallelic NF1 loss in Schwann cells or Schwann-cell precursors is the
    initiating lesion for peripheral nerve sheath tumor formation. Schwann
    lineage NF1 loss creates the tumor cell compartment, while the NF1
    heterozygous microenvironment supplies cooperating stromal, immune, and
    paracrine signals.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:22700876
    reference_title: "PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Schwann cells and/or their precursor cells are believed to be the primary
      pathogenic cell in neurofibromas because they harbor biallelic
      neurofibromin 1 (NF1) gene mutations.
    explanation: >-
      This supports Schwann lineage cells as the core NF1-biallelic tumor cell
      compartment.
  downstream:
  - target: Mast Cell-Rich Neurofibroma Microenvironment
    description: Nf1-deficient Schwann cells secrete Kit ligand that recruits Nf1+/- mast cells.
    causal_link_type: DIRECT
  - target: Cutaneous Neurofibromas
    description: Schwann-cell-dominant peripheral nerve sheath overgrowth produces cutaneous neurofibromas.
    causal_link_type: DIRECT
  - target: Plexiform Neurofibromas
    description: Expanded Schwann cell clones in major nerves form plexiform tumors.
    causal_link_type: DIRECT
- name: Mast Cell-Rich Neurofibroma Microenvironment
  description: >-
    Nf1-deficient Schwann cells secrete soluble Kit ligand, attracting Nf1+/-
    mast cells that can remodel extracellular matrix and support angiogenesis.
    This paracrine Schwann cell-mast cell loop helps convert cell-autonomous NF1
    loss into multicellular neurofibroma growth.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:14679180
    reference_title: "Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, these studies identify a novel interaction between Nf1-/- Schwann
      cells and Nf1+/- mast cells that is likely to be important in neurofibroma
      formation.
    explanation: >-
      This supports the paracrine microenvironment mechanism for neurofibroma
      formation.
  downstream:
  - target: Cutaneous Neurofibromas
    description: Multicellular Schwann-cell-dominant tumor growth produces cutaneous neurofibromas.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Schwann cell proliferation
    - mast cell recruitment
    - extracellular matrix remodeling
  - target: Plexiform Neurofibromas
    description: The same Schwann-cell and microenvironment program expands along major nerves.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Schwann cell proliferation
    - mast cell recruitment
    - nerve-sheath matrix remodeling
  - target: Malignant Peripheral Nerve Sheath Tumor Progression
    description: Plexiform neurofibromas create the precursor tumor population at risk for malignant transformation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - plexiform neurofibroma growth
    - acquisition of additional tumor-suppressor pathway defects
- name: Malignant Peripheral Nerve Sheath Tumor Progression
  description: >-
    Most neurofibromas remain benign, but cooperating tumor-suppressor pathway
    lesions can convert NF1-deficient peripheral nerve sheath tumors into MPNST.
    Experimental Nf1/Pten inactivation accelerates low-grade PNST development
    and promotes progression to high-grade tumors, matching the PI3K-AKT-mTOR
    branch of the NF1 pathograph.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: PI3K/AKT signal transduction
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  genes:
  - preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  - preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  evidence:
  - reference: PMID:22700876
    reference_title: "PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Haploinsufficiency or complete loss of Pten dramatically accelerated
      neurofibroma development and led to the development of higher grade PNSTs
      in the context of Nf1 loss.
    explanation: >-
      Nf1 and Pten cooperate in peripheral nerve sheath tumor development and
      malignant progression.
  downstream:
  - target: Malignant Peripheral Nerve Sheath Tumor
    description: Cooperating PI3K-pathway deregulation promotes high-grade malignant PNST.
    causal_link_type: DIRECT
- name: Glial Progenitor Hyperproliferation
  description: >-
    NF1 inactivation in CNS glial lineages produces reactive astrogliosis and
    increased glial progenitor proliferation. Enlarged optic nerves with
    hyperplastic lesions can progress to optic pathway glioma, and MEK/Akt-mTOR
    signaling maintains subsequent Nf1 optic glioma growth.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:16314489
    reference_title: "Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data point to hyperproliferative glial progenitors as the source of
      the optic tumors and provide a genetic model for NF1-associated
      astrogliosis and optic glioma.
    explanation: >-
      This directly supports hyperproliferative glial progenitors as the source
      of optic tumors.
  downstream:
  - target: Optic Glioma mTOR-Dependent Maintenance
    description: Hyperproliferative glial lineage lesions are maintained by MEK/Akt-mTOR signaling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - MEK activation
    - Akt activation
    - mTOR activation
- name: Optic Glioma mTOR-Dependent Maintenance
  description: >-
    In Nf1 optic glioma models, MEK and Akt pathways converge on mTOR to sustain
    astrocyte and optic glioma proliferation. This maintenance branch connects
    NF1-loss glial progenitor hyperproliferation to clinical optic pathway glioma
    risk.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: mTOR signaling pathway
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:25534823
    reference_title: "Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings establish that the convergence of 2 distinct Ras effector
      pathways on mTOR signaling maintains Nf1 mouse optic glioma growth,
      supporting the evaluation of pharmacologic inhibitors that target mTOR
      function in future human NF1-optic pathway glioma clinical trials.
    explanation: >-
      This supports mTOR-dependent maintenance of Nf1 optic glioma growth.
  downstream:
  - target: Optic Pathway Glioma
    description: Maintained proliferative glial lesions manifest clinically as optic pathway gliomas.
    causal_link_type: DIRECT
- name: Neurodevelopmental GABAergic Plasticity Defect
  description: >-
    NF1-associated learning problems are modeled as excessive Ras activity
    increasing GABA-mediated inhibition and decreasing long-term potentiation.
    This branch links the same proximal RAS dysregulation that drives tumors to
    neurodevelopmental circuit-level learning impairment.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: learning or memory
    modifier: ABNORMAL
    term:
      id: GO:0007612
      label: learning
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  evidence:
  - reference: PMID:28256688
    reference_title: "[Learning disorders in neurofibromatosis type 1]."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Studies in animal models suggest that the learning disabilities associated
      with NF1 are caused by excessive Ras activity that leads to increased
      gamma-aminobutyric acid (GABA) inhibition and to decreased long-term
      potentiation.
    explanation: >-
      This summarizes the accepted animal-model mechanism for NF1 learning
      disability.
  downstream:
  - target: Learning Difficulties
    description: Impaired synaptic plasticity and increased inhibition produce the learning phenotype.
    causal_link_type: DIRECT
- name: Osteoblast-Osteoclast Remodeling Defect
  description: >-
    Neurofibromin deficiency in skeletal progenitors and bone-resorbing lineages
    disrupts osteoblast differentiation, osteoclast maturation, fracture repair,
    and bone remodeling. This skeletal branch links NF1 Ras/MAPK hyperactivation
    to scoliosis and focal dysplasia/pseudoarthrosis phenotypes.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: bone remodeling
    modifier: ABNORMAL
    term:
      id: GO:0046849
      label: bone remodeling
  - preferred_term: osteoblast differentiation
    modifier: ABNORMAL
    term:
      id: GO:0001649
      label: osteoblast differentiation
  evidence:
  - reference: PMID:23863460
    reference_title: "Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Collectively, these data indicate the Ras/MAPK cascade as a critical
      pathway in the pathogenesis of bone loss and pseudarthrosis related to NF1
      mutations.
    explanation: >-
      This supports Ras/MAPK-driven skeletal remodeling defects in NF1.
  - reference: PMID:24932921
    reference_title: "Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gene expression profiling identified dysregulated pathways associated with
      neurofibromin deficiency, including phosphoinositide 3-kinase (PI3K) and
      mitogen-activated protein kinase (MAPK) signaling pathways.
    explanation: >-
      Human pseudoarthrosis tissue shows neurofibromin-deficiency-associated
      pathway dysregulation in a skeletal NF1 lesion.
  downstream:
  - target: Scoliosis
    description: Abnormal vertebral growth and bone remodeling promote progressive spinal curvature.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - osteoblast differentiation defect
    - abnormal osteoclast maturation
    - reduced bone mass and focal skeletal dysplasia
  - target: Tibial Pseudarthrosis
    description: >-
      Focal tibial dysplasia and defective fracture repair produce persistent
      tibial pseudoarthrosis/nonunion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24932921
      reference_title: "Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused
        by mutations in NF1. Among the earliest manifestations is tibial
        pseudoarthrosis and persistent nonunion after fracture.
      explanation: >-
        NF1 patient pseudoarthrosis tissue directly links neurofibromin
        deficiency with tibial nonunion, matching this skeletal pathograph
        branch.
phenotypes:
- category: Dermatologic
  name: Cafe-au-lait Macules
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Flat, hyperpigmented skin lesions present in >99% of NF1 patients. Six or more
    cafe-au-lait macules >5mm (prepubertal) or >15mm (postpubertal) meet one of
    the NIH diagnostic criteria. Usually present at birth or develop in first years
    of life.
  phenotype_term:
    preferred_term: Multiple cafe-au-lait spots
    term:
      id: HP:0007565
      label: Multiple cafe-au-lait spots
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
    explanation: Review identifies cafe-au-lait spots as a cardinal feature of NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "HP:0007565 | Multiple cafe-au-lait spots | Very frequent (99-80%)"
    explanation: >-
      Orphanet's curated HPO table confirms multiple cafe-au-lait spots as a
      very frequent NF1 phenotype, while this entry keeps the stronger
      diagnostic/near-obligate classification supported by clinical criteria.
- category: Dermatologic
  name: Axillary and Inguinal Freckling
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Intertriginous freckling in the axillary or inguinal region is a classic NF1
    diagnostic criterion, often emerging in childhood after cafe-au-lait macules.
  phenotype_term:
    preferred_term: Axillary freckling
    term:
      id: HP:0000997
      label: Axillary freckling
  notes: >-
    This phenotype aggregates the NF1 diagnostic criterion of axillary or
    inguinal freckling. The local HPO snapshot contains separate terms for
    axillary freckling (HP:0000997) and inguinal freckling (HP:0030052), so the
    axillary term is used as the representative mapped descriptor.
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Freckling in the axillary or inguinal region"
    explanation: >-
      The international consensus diagnostic criteria include axillary or
      inguinal freckling as an NF1 criterion.
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
    explanation: Review identifies axillary freckling as a cardinal NF1 feature.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "HP:0000997 | Axillary freckling | Frequent (79-30%)"
    explanation: >-
      Orphanet confirms axillary freckling as an NF1 phenotype, but classifies
      it as frequent rather than very frequent.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "HP:0030052 | Inguinal freckling | Frequent (79-30%)"
    explanation: >-
      Orphanet separately confirms inguinal freckling as an NF1 phenotype,
      supporting the aggregate axillary/inguinal freckling entry.
- category: Neoplastic
  name: Cutaneous Neurofibromas
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Benign peripheral nerve sheath tumors arising from Schwann cells. Typically
    appear around puberty and increase in number with age. May cause cosmetic
    concerns but rarely become malignant.
  phenotype_term:
    preferred_term: Neurofibroma
    term:
      id: HP:0001067
      label: Neurofibroma
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
    explanation: Review identifies cutaneous neurofibromas as a cardinal feature of NF1.
- category: Neoplastic
  name: Plexiform Neurofibromas
  frequency: FREQUENT
  description: >-
    Diffuse neurofibromas involving multiple nerve fascicles, often present at birth.
    Can cause significant morbidity through mass effect, disfigurement, and pain.
    Approximately 8-13% lifetime risk of malignant transformation to MPNST.
  phenotype_term:
    preferred_term: Plexiform neurofibroma
    term:
      id: HP:0009732
      label: Plexiform neurofibroma
  evidence:
  - reference: PMID:33395032
    reference_title: "MEK inhibitors in RASopathies."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the potential of MEK inhibition as an effective and overall well
      tolerated medical treatment, the use of targeted agents in the NF1
      population is likely to increase considerably.
    explanation: >-
      Review confirms plexiform neurofibromas are a significant clinical problem
      in NF1 amenable to MEK inhibitor therapy.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009732 | Plexiform neurofibroma | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO table lists plexiform neurofibroma among NF1 phenotypes.
- category: Ophthalmologic
  name: Lisch Nodules
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Melanocytic hamartomas of the iris, appearing as tan-brown dome-shaped elevations.
    Present in >90% of adults with NF1. Best visualized by slit-lamp examination.
    Pathognomonic for NF1 and do not affect vision.
  phenotype_term:
    preferred_term: Lisch nodules
    term:
      id: HP:0009737
      label: Lisch nodules
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules)."
    explanation: Review identifies Lisch nodules (iris hamartomas) as a cardinal feature of NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009737 | Lisch nodules | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO table classifies Lisch nodules as very frequent in NF1.
- category: Ophthalmologic
  name: Choroidal Abnormalities
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Bright, patchy choroidal nodules detectable by optical coherence tomography
    or near-infrared reflectance imaging. These abnormalities are included in
    the 2021 revised NF1 diagnostic criteria as part of the ophthalmologic
    criterion.
  phenotype_term:
    preferred_term: Choroidal abnormalities
    term:
      id: HP:0000610
      label: Abnormal choroid morphology
  evidence:
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Choroidal abnormalities were added as an ophthalmologic criterion because of the high specificity and sensitivity for NF1"
    explanation: >-
      The revised NF1 diagnostic criteria include choroidal abnormalities as an
      ophthalmologic criterion because they are sensitive and specific for NF1.
- category: Neoplastic
  name: Optic Pathway Glioma
  frequency: FREQUENT
  description: >-
    Low-grade gliomas of the optic nerve, chiasm, or tract occur in 15-20% of NF1
    patients. Usually pilocytic astrocytomas. Most are asymptomatic and nonprogressive,
    but can cause vision loss. Peak incidence in first 6 years of life.
  phenotype_term:
    preferred_term: Optic pathway glioma
    term:
      id: HP:0009734
      label: Optic nerve glioma
  notes: >-
    The local HPO snapshot does not contain a distinct optic pathway glioma term;
    HP:0009734 is used as the closest available term because its definition
    covers glioma originating in the optic nerve or optic chiasm.
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common complications include learning disability, scoliosis, and optic gliomas."
    explanation: Review identifies optic gliomas as a common complication of NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "HP:0009734 | Optic nerve glioma | Occasional (29-5%)"
    explanation: >-
      Orphanet confirms optic nerve glioma as an NF1 phenotype, but its curated
      frequency class is occasional rather than this entry's broader frequent
      optic-pathway-glioma framing.
- category: Neoplastic
  name: Malignant Peripheral Nerve Sheath Tumor
  frequency: OCCASIONAL
  description: >-
    Aggressive sarcoma arising from peripheral nerves, often from transformation of
    plexiform neurofibromas. Lifetime risk 8-13% in NF1. Leading cause of NF1-related
    mortality. Presents with rapid growth, pain, or new neurologic deficits.
  phenotype_term:
    preferred_term: Neurofibrosarcoma
    term:
      id: HP:0100697
      label: Neurofibrosarcoma
  evidence:
  - reference: PMID:32234870
    reference_title: "New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral
      nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10%
      of PNSTs will undergo transformation to malignant peripheral nerve sheath
      tumors (MPNSTs).
    explanation: >-
      Review confirms approximately 10% of peripheral nerve sheath tumors in NF1
      undergo malignant transformation to MPNST.
- category: Skeletal
  name: Scoliosis
  frequency: FREQUENT
  description: >-
    Spinal curvature occurs in 10-30% of NF1 patients. Can be idiopathic-type or
    dystrophic (sharply angulated, short segment) forms. Dystrophic scoliosis may
    progress rapidly and require surgical intervention.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common complications include learning disability, scoliosis, and optic gliomas."
    explanation: Review identifies scoliosis as a common complication of NF1.
- category: Skeletal
  name: Tibial Pseudarthrosis
  frequency: OCCASIONAL
  diagnostic: true
  description: >-
    Focal tibial dysplasia with anterolateral bowing, fracture, and persistent
    fibrous nonunion occurs in a minority of NF1 patients and is a distinctive
    osseous diagnostic feature.
  phenotype_term:
    preferred_term: Tibial pseudarthrosis
    term:
      id: HP:0009736
      label: Tibial pseudarthrosis
  evidence:
  - reference: PMID:24932921
    reference_title: "Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About 5% of individuals with NF1 will present with anterolateral bowing
      (dysplasia) leading to fracture that fails to achieve proper union, often
      after repeated surgical correction.
    explanation: >-
      Human NF1 pseudoarthrosis tissue study summarizes the approximate
      frequency and nonunion phenotype.
  - reference: PMID:34012067
    reference_title: "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anterolateral bowing of the tibia, or pseudarthrosis of a long bone"
    explanation: >-
      Consensus diagnostic criteria include tibial bowing and long-bone
      pseudarthrosis as distinctive NF1 osseous lesions.
- category: Neurologic
  name: Learning Difficulties
  frequency: FREQUENT
  description: >-
    Learning disabilities and attention deficits occur in 50-75% of children with NF1.
    Intelligence is usually normal but specific learning disabilities, ADHD, and
    executive function problems are common. Motor coordination difficulties may occur.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  notes: >-
    Most NF1 patients have normal IQ but specific learning disabilities,
    attention deficits, or executive function problems.
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common complications include learning disability, scoliosis, and optic gliomas."
    explanation: Review identifies learning disability as a common complication of NF1.
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001328 | Specific learning disability | Very frequent (99-80%)"
    explanation: Orphanet's curated HPO table lists specific learning disability among very frequent NF1 phenotypes.
- category: Neurologic
  name: Attention Deficit Hyperactivity Disorder
  frequency: FREQUENT
  description: >-
    Attention deficit hyperactivity disorder is part of the NF1
    neurodevelopmental phenotype spectrum and is listed as frequent by
    Orphanet.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007018 | Attention deficit hyperactivity disorder | Frequent (79-30%)"
    explanation: Orphanet's curated HPO table classifies ADHD as frequent in NF1.
- category: Neurologic
  name: Macrocephaly
  frequency: OCCASIONAL
  description: >-
    Increased head circumference is included in Orphanet's curated NF1
    phenotype profile as an occasional manifestation.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000256 | Macrocephaly | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies macrocephaly as occasional in NF1.
- category: Neoplastic
  name: Pheochromocytoma
  frequency: OCCASIONAL
  description: >-
    Pheochromocytoma is an NF1-associated endocrine tumor phenotype included in
    Orphanet's curated HPO profile.
  phenotype_term:
    preferred_term: Pheochromocytoma
    term:
      id: HP:0002666
      label: Pheochromocytoma
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002666 | Pheochromocytoma | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies pheochromocytoma as occasional in NF1.
- category: Neoplastic
  name: Gastrointestinal Stromal Tumor
  frequency: OCCASIONAL
  description: >-
    Gastrointestinal stromal tumor is included in Orphanet's NF1 phenotype
    table, reflecting the recognized gastrointestinal tumor risk in NF1.
  phenotype_term:
    preferred_term: Gastrointestinal stromal tumor
    term:
      id: HP:0100723
      label: Gastrointestinal stroma tumor
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100723 | Gastrointestinal stroma tumor | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies gastrointestinal stroma tumor as occasional in NF1.
- category: Neoplastic
  name: Breast Neoplasm
  frequency: OCCASIONAL
  description: >-
    Breast neoplasm is included in Orphanet's curated NF1 phenotype profile,
    consistent with cancer-predisposition surveillance considerations in NF1.
  phenotype_term:
    preferred_term: Neoplasm of the breast
    term:
      id: HP:0100013
      label: Neoplasm of the breast
  evidence:
  - reference: ORPHA:636
    reference_title: "Neurofibromatosis type 1 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100013 | Neoplasm of the breast | Occasional (29-5%)"
    explanation: Orphanet's curated HPO table classifies neoplasm of the breast as occasional in NF1.
biochemical:
- name: NF1 Genetic Testing
  notes: >-
    Comprehensive NF1 testing identifies germline pathogenic variants including
    point mutations, small insertions/deletions, large deletions/duplications,
    and deep intronic variants. Approximately 50% are de novo mutations. Mutation
    detection rate exceeds 95% with comprehensive testing including deletion/duplication
    analysis.
genetic:
- name: NF1
  association: Germline Loss-of-Function Mutations
  evidence:
  - reference: CGGV:assertion_367a3958-ce81-47fa-a505-a451ca67aab5-2019-03-05T170000.000Z
    reference_title: "NF1 / neurofibromatosis type 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NF1 | HGNC:7765 | neurofibromatosis type 1 | MONDO:0018975 | AD | Definitive"
    explanation: ClinGen classifies the NF1-neurofibromatosis type 1 gene-disease relationship as definitive with autosomal dominant inheritance.
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    NF1 (17q11.2) encodes neurofibromin, a large protein with RAS-GAP domain that
    negatively regulates RAS signaling. Germline mutations include truncating variants,
    missense mutations in the GAP domain, splice site variants, and large deletions
    (5% of cases, associated with more severe phenotype). De novo mutation rate is
    approximately 50%. Penetrance is essentially complete but expressivity is highly
    variable, even within families.
treatments:
- name: MEK Inhibitors
  description: >-
    Selumetinib is FDA-approved for symptomatic, inoperable plexiform neurofibromas
    in children aged 2 years and older. As a MEK inhibitor, it targets the downstream
    effector of hyperactive RAS signaling. Shrinkage of plexiform neurofibromas
    observed in clinical trials.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
  evidence:
  - reference: PMID:33395032
    reference_title: "MEK inhibitors in RASopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20%
      reduction in the size of pNF from baseline in 71% of patients and was associated
      with clinically meaningful improvements. On the basis of this trial, selumetinib
      (Koselugo) received FDA approval for children 2 years of age and older with
      inoperable, symptomatic pNF.
    explanation: >-
      SPRINT trial demonstrated selumetinib efficacy in plexiform neurofibromas
      leading to FDA approval for pediatric NF1 patients.
- name: Surgical Management
  description: >-
    Surgery for symptomatic neurofibromas causing pain, functional impairment, or
    disfigurement. Complete resection of plexiform neurofibromas often impossible
    due to infiltrative nature. Surgery is primary treatment for operable MPNST.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Surveillance Protocol
  description: >-
    Annual clinical evaluation including skin, skeletal, neurologic, and ophthalmologic
    examination. Annual ophthalmologic evaluation in children (optic glioma screening).
    MRI for symptomatic lesions or suspected MPNST. Blood pressure monitoring for
    renovascular disease or pheochromocytoma.
  treatment_term:
    preferred_term: cancer screening
    term:
      id: MAXO:0000126
      label: cancer screening
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mainstay of care for patients with NF1 is anticipatory guidance, and the early detection and symptomatic treatment of disease complications."
    explanation: Review emphasizes surveillance and early detection as the foundation of NF1 management.
- name: Genetic Counseling
  description: >-
    Genetic counseling for affected individuals and at-risk family members. Children
    of affected parents have 50% risk. High rate of de novo mutations means negative
    family history does not exclude NF1. Variable expressivity makes predicting
    severity difficult.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:9874851
    reference_title: "Neurofibromatosis 1 in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Counseling of patients and their families should provide a realistic overview of possible disease complications, while emphasizing that most individuals with NF1 lead healthy and productive lives."
    explanation: Review discusses the importance of genetic counseling for NF1 families, addressing both disease complications and positive prognosis.
disease_term:
  preferred_term: neurofibromatosis type 1
  term:
    id: MONDO:0018975
    label: neurofibromatosis type 1
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 51 citations 2026-04-25T22:32:38.128779

1. Disease Information

1.1 Concise overview (current understanding)

NF1 is a common autosomal dominant, multisystem genetic condition caused by germline pathogenic variants in NF1, encoding neurofibromin, a negative regulator of Ras signaling (a Ras-GAP). Loss of neurofibromin drives hyperactive Ras pathway output and predisposes to benign peripheral nerve sheath tumors (cutaneous and plexiform neurofibromas) and malignant tumors (e.g., malignant peripheral nerve sheath tumor), as well as neurodevelopmental and skeletal manifestations. (peduto2023neurofibromatosistype1 pages 1-2, park2024recentadvancesin pages 1-2, na2024pastpresentand pages 1-3)

NF1 shows complete penetrance with marked inter- and intrafamilial variable expressivity and age-dependent emergence of manifestations, complicating early diagnosis in children. (peduto2023neurofibromatosistype1 pages 1-2)

1.2 Key identifiers and controlled vocabularies

A compact identifier/synonym table is provided below.

Disease name Common abbreviation MONDO ID OMIM/MIM number(s) reported in available evidence Inheritance Common synonyms / alternative names Key distinguishing related condition Key references (year; URL)
Neurofibromatosis type 1 NF1 MONDO:0018975 OMIM/MIM 162200 reported in 2023 review/meta-analysis; one 2021 consensus excerpt reports “OMIM 613113,” but this appears inconsistent with the standard disease OMIM usage and should be cross-checked before knowledge-base normalization Autosomal dominant Neurofibromatosis 1; Neurofibromatosis type I; von Recklinghausen disease / von Recklinghausen neurofibromatosis Legius syndrome (LGSS), caused by heterozygous pathogenic SPRED1 variants; may overlap with NF1 pigmentary findings in young children, but LGSS does not carry NF1-related tumor risks; molecular testing of NF1 and SPRED1 is recommended when presentation is limited to pigmentary findings Legius et al. 2021, Genetics in Medicine, https://doi.org/10.1038/s41436-021-01170-5; Peduto et al. 2023, Cancers, https://doi.org/10.3390/cancers15041217; Lee et al. 2023, Orphanet Journal of Rare Diseases, https://doi.org/10.1186/s13023-023-02911-2; Park 2024, Journal of Genetic Medicine, https://doi.org/10.5734/jgm.2024.21.2.51 (peduto2023neurofibromatosistype1 pages 1-2, legius2021reviseddiagnosticcriteria pages 1-2, peduto2023neurofibromatosistype1 pages 2-4, lee2023incidenceandprevalence pages 1-2, park2024recentadvancesin pages 1-2)

Table: This table summarizes key disease identifiers, inheritance, synonyms, and the most important related differential condition for Neurofibromatosis type 1. It is useful for knowledge-base normalization and for distinguishing NF1 from Legius syndrome in early or pigment-only presentations.

Important gap: ICD-10/ICD-11 codes, MeSH IDs, and Orphanet IDs were not present in the retrieved evidence corpus used by the tools in this run; therefore, they are not asserted here. The MONDO ID above is directly supported, and an OMIM/MIM number for the disease (162200) is supported by the 2023 prevalence/incidence meta-analysis. (lee2023incidenceandprevalence pages 1-2)

1.3 Synonyms and alternative names

Commonly used names include “neurofibromatosis 1” and “neurofibromatosis type I.” (park2024recentadvancesin pages 1-2, lee2023incidenceandprevalence pages 1-2)

2. Etiology

2.1 Disease causal factors

  • Primary cause: Germline pathogenic variant in NF1 (tumor suppressor) (peduto2023neurofibromatosistype1 pages 1-2, park2024recentadvancesin pages 1-2).
  • De novo rate: Approximately 50% of cases arise from de novo pathogenic variants. (peduto2023neurofibromatosistype1 pages 1-2)

2.2 Risk factors

  • Genetic: Having an affected first-degree relative (autosomal dominant inheritance). (peduto2023neurofibromatosistype1 pages 1-2, legius2021reviseddiagnosticcriteria pages 2-3)
  • Tumor-specific malignant risk factors (NF1 patients): The ERN GENTURIS guideline highlights groups at higher risk for MPNST, including NF1 microdeletion affecting SUZ12, missense variants at codons 844–848, prior ANNUBP, high internal tumor load/large or multiple plexiform neurofibromas, prior radiotherapy, and family history of MPNST. (carton2023erngenturistumour pages 9-10)
  • Radiation exposure: For MPNST, prior therapeutic irradiation is a known risk factor and post-radiation MPNST has poor outcomes. (yao2023malignantperipheralnerve pages 2-4)

2.3 Protective factors

No specific protective genetic or environmental factors were identified in the retrieved sources.

2.4 Gene–environment interactions

The retrieved sources do not provide a clear gene–environment interaction model beyond the general observation that radiation exposure can increase risk for MPNST, especially in the context of NF1 tumor predisposition. (yao2023malignantperipheralnerve pages 2-4)

3. Phenotypes

3.1 Core clinical phenotype spectrum and frequencies (examples)

Key frequencies/statistics extracted from recent sources are summarized here and in a table artifact.

Source Metric Value Notes
Lee 2023 Pooled prevalence of NF1 3.16 per 10,000 (95% CI 2.12–4.69); ~1 in 3,164 Meta-analysis of 9 studies, 3,045 cases, pooled population 11,649,059; high heterogeneity (I²=99%) (lee2023incidenceandprevalence pages 2-4, lee2023incidenceandprevalence pages 1-2)
Lee 2023 Pooled birth incidence of NF1 3.76 per 10,000 live births (95% CI 2.78–5.08); ~1 in 2,662 Meta-analysis of 3 studies; 423 cases in 1,170,928 births (lee2023incidenceandprevalence pages 2-4, lee2023incidenceandprevalence pages 1-2)
Lee 2023 Prevalence in screening studies 4.95 per 10,000 (95% CI 2.47–9.92); ~1 in 2,020 Higher than record-based estimates, supporting under-recognition in routine data (lee2023incidenceandprevalence pages 2-4, lee2023incidenceandprevalence pages 1-2)
Lee 2023 Prevalence in medical-record studies 2.31 per 10,000 (95% CI 2.13–2.50); ~1 in 4,329 Lower ascertainment than screening studies (lee2023incidenceandprevalence pages 2-4, lee2023incidenceandprevalence pages 1-2)
Lee 2023 Sensitivity-analysis estimate (birth incidence + child/adolescent screening) ~1 in 2,265 (95% CI 1 in 1,497 to 1 in 3,428) Suggests higher occurrence when age-appropriate screening is considered (lee2023incidenceandprevalence pages 4-7)
Carton 2023 Birth incidence (guideline background) 1 in 2,000–2,500 Guideline background estimate; consistent with broader epidemiology (carton2023erngenturistumour pages 1-2)
Carton 2023 Lifetime cancer risk in NF1 59.6% Compared with 30.8% in the general population (carton2023erngenturistumour pages 1-2)
Carton 2023 Lifetime cancer risk in general population 30.8% Comparator for NF1-associated cancer burden (carton2023erngenturistumour pages 1-2)
Carton 2023 Plexiform neurofibroma (PN) frequency ~40–60% PN associated with risk of malignant transformation (carton2023erngenturistumour pages 10-12)
Suppiah 2023 Plexiform intraneural neurofibroma frequency ~30–50% Independent molecular profiling paper; similar range to guideline estimates (suppiah2023multiplatformmolecularprofiling pages 1-2)
Carton 2023 Cutaneous neurofibroma frequency >95% Common benign tumor manifestation in NF1 (carton2023erngenturistumour pages 10-12)
Carton 2023 MPNST lifetime risk 8–16% Typical presentation between ages 20–40 years (carton2023erngenturistumour pages 10-12)
Suppiah 2023 Lifetime risk of malignant transformation from PN to MPNST 5–15% Reported for plexiform intraneural neurofibromas (suppiah2023multiplatformmolecularprofiling pages 1-2)
Carton 2023 OPGs requiring treatment 15–20% of patients with OPG Many OPGs are observed; treatment reserved for progressive/symptomatic disease (carton2023erngenturistumour pages 9-10)
Carton 2023 Non-optic pathway glioma frequency Approximately 4–5% of individuals with NF1 Refers to non-OPG brain gliomas (carton2023erngenturistumour pages 9-10)
Peduto 2023 Cognitive/behavioral disorders in children with NF1 Up to 80% Broad neurodevelopmental burden reported in recent review (park2024recentadvancesin pages 1-2)
Peduto 2023 Café-au-lait macules in infants with NF1 >95% Early childhood clinical feature; useful for pediatric recognition (peduto2023neurofibromatosistype1 pages 1-2)
Peduto 2023 Cutaneous neurofibromas in affected adults About 90% Age-dependent increase in tumor burden (peduto2023neurofibromatosistype1 pages 1-2)
Peduto 2023 Lisch nodules in children <5 years <50% Highlights age-dependent penetrance of diagnostic features (peduto2023neurofibromatosistype1 pages 1-2)
Peduto 2023 Lisch nodules in adults Almost all adults Age-dependent diagnostic feature (peduto2023neurofibromatosistype1 pages 1-2)
Peduto 2023 Choroidal abnormalities in children 60–70% Common ocular sign in pediatric NF1 (peduto2023neurofibromatosistype1 pages 2-4)
Peduto 2023 Anemic nevus in children Up to 50% Supportive but non-diagnostic pediatric feature (peduto2023neurofibromatosistype1 pages 2-4)

Table: This table compiles recent quantitative epidemiology and complication frequencies for neurofibromatosis type 1, emphasizing pooled 2023 estimates and clinically relevant tumor risks. It is useful as a compact evidence summary for disease knowledge base fields on prevalence, incidence, and phenotype burden.

Selected phenotype examples with HPO suggestions (not exhaustive):

1) Café-au-lait macules (CALMs) - Frequency: >95% of infants in one pediatric review (peduto2023neurofibromatosistype1 pages 1-2) - Typical onset: infancy/early childhood; increase until puberty (peduto2023neurofibromatosistype1 pages 2-4) - HPO: Café-au-lait spot (HP:0000957)

2) Axillary/inguinal freckling - Typical onset: around 6–7 years (peduto2023neurofibromatosistype1 pages 1-2) - HPO: Axillary freckling (HP:0000997); Inguinal freckling (HP:0000998)

3) Cutaneous neurofibromas - Frequency: ~90% of adults in pediatric review; guideline states >95% of people with NF1 have cutaneous neurofibromas (peduto2023neurofibromatosistype1 pages 1-2, carton2023erngenturistumour pages 10-12) - HPO: Neurofibroma (HP:0001067); Cutaneous neurofibroma (HP:0012872)

4) Plexiform neurofibromas (PN) - Frequency: ~40–60% (guideline) (carton2023erngenturistumour pages 10-12) - Morbidity: disfigurement, pain, neurologic/motor dysfunction; malignant transformation risk (gross2020selumetinibinchildren pages 1-2, carton2023erngenturistumour pages 10-12) - HPO: Plexiform neurofibroma (HP:0009732)

5) Ophthalmic findings: Lisch nodules and choroidal abnormalities - Lisch nodules: almost all adults, <50% under age 5 (peduto2023neurofibromatosistype1 pages 1-2) - Choroidal abnormalities in children: 60–70% (peduto2023neurofibromatosistype1 pages 2-4) - HPO: Lisch nodules (HP:0009737)

6) Optic pathway glioma (OPG) - Frequency: up to ~20% (“as many as one-fifth”) (tang2023neurofibromatosistype1associated pages 1-2) - Symptomatic fraction: ~20–30% develop symptoms (progressive vision loss, proptosis, diplopia, precocious puberty) (tang2023neurofibromatosistype1associated pages 1-2) - HPO: Optic pathway glioma (HP:0009735); Vision impairment (HP:0000505); Precocious puberty (HP:0000826)

7) Neurocognitive/behavioral features - One 2024 review states cognitive and behavioral disorders affect up to 80% of children with NF1 (park2024recentadvancesin pages 1-2) - HPO: Neurodevelopmental delay (HP:0012758); Learning difficulties (HP:0001328); Attention deficit hyperactivity disorder (HP:0007018) (where applicable)

3.2 Quality of life impact

Adult NF1 has substantial psychosocial burden, especially driven by visibility/disfigurement, stigma, pain, and uncertainty. In a 2023 systematic review of rare genetic skin diseases (including 16 NF1 studies), NF1 was associated with impaired QoL and emotional well-being; severity/visibility predicted QoL burden, and care at NF specialty clinics and genetic counseling were associated with higher self-esteem. (fournier2023psychosocialimplicationsof pages 13-15, fournier2023psychosocialimplicationsof pages 15-16)

4. Genetic / Molecular Information

4.1 Causal gene(s)

  • NF1 (neurofibromin 1) is the causal gene for NF1; NF1 encodes neurofibromin, a Ras-GAP regulating Ras/MAPK output. (peduto2023neurofibromatosistype1 pages 1-2, na2024pastpresentand pages 1-3)

4.2 Variant spectrum and functional consequences

  • Large variant diversity is reported; one 2024 review notes >3,197 constitutional NF1 pathogenic variants, with clinically confirmed genotype–phenotype correlations relevant to ~10–15% of patients, and microdeletions ~4.7–11%. (park2024recentadvancesin pages 1-2)
  • A pediatric genotype–phenotype review reports that 90–95% of causative variants are intragenic and <10% are whole-gene deletions including flanking regions. (peduto2023neurofibromatosistype1 pages 11-13)
  • Functional consequence is primarily loss of function in a tumor suppressor, with many NF1 tumors following a “second hit” model (somatic inactivation of the remaining allele). (na2024pastpresentand pages 1-3)

4.3 Modifier genes / related loci

The retrieved evidence emphasizes SPRED1 as a key differential diagnosis (Legius syndrome). Molecular testing for NF1 and SPRED1 is recommended when a child has only pigmentary findings, because Legius syndrome lacks NF1-associated oncologic risks. (peduto2023neurofibromatosistype1 pages 2-4)

4.4 Epigenetic information

In NF1-associated malignant transformation (MPNST), epigenetic regulators are important: PRC2 components (EED/SUZ12) may be inactivated, and loss of H3K27me3 is described as a marker more common in sporadic/radiation-induced MPNST (and mechanistically linked to PRC2 loss). (yao2023malignantperipheralnerve pages 13-14, yao2023malignantperipheralnerve pages 2-4)

5. Environmental Information

NF1 is primarily genetic. In the retrieved evidence, the main non-genetic contributor to malignant risk is radiation exposure (a risk factor for MPNST), and post-radiation MPNST shows particularly poor survival statistics in one review. (yao2023malignantperipheralnerve pages 2-4)

6. Mechanism / Pathophysiology

6.1 Core causal chain (from mutation to phenotype)

  1. Germline NF1 pathogenic variant → reduced/absent neurofibromin.
  2. Neurofibromin is a Ras-GAP that limits Ras signaling; one recent therapeutic-strategy review states neurofibromin “is a Ras GTPase-activating protein (RAS-GAP) that converts active GTP-bound Ras into inactive GDP-bound Ras,” and “Thus, NF1 loss leads to constitutive Ras activation.” (na2024pastpresentand pages 1-3)
  3. Downstream Ras pathway hyperactivation increases output through RAF–MEK–ERK (MAPK) and other axes including PI3K–AKT–mTOR, with tumorigenesis typically requiring a second somatic hit in the remaining allele. (na2024pastpresentand pages 1-3)
  4. Tumor microenvironment cells (e.g., fibroblasts/endothelial cells; immune components) can support tumor growth and are emerging therapeutic targets. (na2024pastpresentand pages 1-3)

Complementary mechanistic detail from a 2023 neurofibromin signaling review emphasizes broad pathway reach beyond MAPK, including cAMP/PKA, cytoskeletal signaling, and post-translational regulation of neurofibromin abundance. (baezflores2023thetherapeuticpotential pages 1-2, baezflores2023thetherapeuticpotential pages 3-4, baezflores2023thetherapeuticpotential pages 5-6)

6.2 Key pathways and suggested ontology terms

Pathways (examples): - Ras/MAPK cascade; RAF–MEK–ERK signaling (na2024pastpresentand pages 1-3, park2024recentadvancesin pages 1-2) - PI3K/AKT/mTOR signaling (na2024pastpresentand pages 1-3, park2024recentadvancesin pages 1-2, baezflores2023thetherapeuticpotential pages 5-6) - cAMP/PKA signaling and neurodevelopmental phenotypes (baezflores2023thetherapeuticpotential pages 3-4, baezflores2023thetherapeuticpotential pages 5-6) - Rho/ROCK/LIMK/cofilin; cytoskeletal remodeling (park2024recentadvancesin pages 1-2, baezflores2023thetherapeuticpotential pages 5-6)

GO Biological Process suggestions (examples): - Ras protein signal transduction (GO:0007265) - MAPK cascade (GO:0000165) - Regulation of cell proliferation (GO:0042127) - Regulation of apoptotic process (GO:0042981) - cAMP-mediated signaling (GO:0019933)

6.3 Cell types and suggested CL terms (examples)

Mechanistic and tumor discussions implicate: - Schwann cell lineage as tumor cell of origin for neurofibromas/MPNST (review emphasis) (na2024pastpresentand pages 5-6) - Optic glioma models implicate progenitor/oligodendrocyte-lineage tumor cells plus microglia and T cells in a supportive immune niche (tang2023neurofibromatosistype1associated pages 6-8)

CL term suggestions (examples): - Schwann cell (CL:0000218) - Microglial cell (CL:0000129) - T cell (CL:0000084) - Oligodendrocyte precursor cell (CL:0002453) (for OPG model context)

7. Anatomical Structures Affected

NF1 is multisystem; major affected anatomical systems include: - Skin/peripheral nerves: café-au-lait macules, freckling, cutaneous and plexiform neurofibromas (peduto2023neurofibromatosistype1 pages 1-2, carton2023erngenturistumour pages 10-12) - Central nervous system/visual system: optic pathway gliomas; non-optic low-grade gliomas (tang2023neurofibromatosistype1associated pages 1-2, carton2023erngenturistumour pages 9-10) - Skeletal system: distinctive osseous lesions used diagnostically (e.g., tibial bowing/pseudarthrosis; sphenoid dysplasia) (peduto2023neurofibromatosistype1 pages 2-4) - Breast tissue: elevated breast cancer risk prompting early MRI screening in guidelines (carton2023erngenturistumour pages 10-12, carton2023erngenturistumour pages 6-7)

UBERON suggestions (examples): - Skin (UBERON:0002097) - Peripheral nerve (UBERON:0001021) - Optic nerve (UBERON:0000966) - Brain (UBERON:0000955) - Tibia (UBERON:0001465) - Breast (UBERON:0000310)

8. Temporal Development (natural history)

  • Onset: congenital/genetic; many visible pigmentary findings arise in infancy; other diagnostic features are age-dependent (peduto2023neurofibromatosistype1 pages 2-4, peduto2023neurofibromatosistype1 pages 1-2)
  • Progression: variable; tumor-related complications may occur from childhood (e.g., OPG) through adulthood (e.g., MPNST) (carton2023erngenturistumour pages 5-6)

Examples of age-dependence: - Freckling tends to appear around age 6–7 (peduto2023neurofibromatosistype1 pages 1-2) - OPG is usually detected in early childhood, often before age 7 (tang2023neurofibromatosistype1associated pages 1-2) - MPNST typically presents between ages 20–40 (guideline) (carton2023erngenturistumour pages 10-12)

9. Inheritance and Population

9.1 Inheritance

  • Autosomal dominant inheritance is consistently reported. (peduto2023neurofibromatosistype1 pages 1-2, lee2023incidenceandprevalence pages 1-2)
  • Penetrance: described as complete in pediatric review, with wide expressivity. (peduto2023neurofibromatosistype1 pages 1-2)

9.2 Epidemiology (recent quantitative data)

A 2023 systematic review/meta-analysis estimated: - Pooled prevalence: ~1 in 3,164 (95% CI 1 in 2,132–1 in 4,712). (lee2023incidenceandprevalence pages 1-2) - Pooled birth incidence: ~1 in 2,662 (95% CI 1 in 1,968–1 in 3,601). (lee2023incidenceandprevalence pages 1-2) - Under-recognition: prevalence was higher in screening studies (~1 in 2,020) than in medical-record ascertainment (~1 in 4,329), suggesting under-recognition in routine data. (lee2023incidenceandprevalence pages 2-4, lee2023incidenceandprevalence pages 1-2)

10. Diagnostics

10.1 Clinical diagnostic criteria (2021 revised international consensus)

The 2021 international consensus provides revised NF1 criteria incorporating genetic testing and new ophthalmic imaging features; core requirements are summarized below.

Diagnostic context Requirement / criterion Threshold or specification Notes / differentiation Citation
NF1 diagnosis, individual without an affected parent Two or more diagnostic criteria required Any 2 of the listed NF1 criteria below 2021 international consensus revision (legius2021reviseddiagnosticcriteria pages 2-3, legius2021reviseddiagnosticcriteria media 67536eac)
NF1 diagnosis, child of an affected parent One or more diagnostic criteria required Any 1 listed NF1 criterion Applies when a parent meets NF1 diagnostic criteria (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Café-au-lait macules (CALMs) Pigmentary criterion ≥6 CALMs; diameter >5 mm in prepubertal individuals and >15 mm in postpubertal individuals Bilateral distribution is typical; isolated pigmentary findings in young children can overlap with Legius syndrome (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Axillary or inguinal freckling Pigmentary criterion Present in axillary and/or inguinal region Can also occur in Legius syndrome; not sufficient alone to distinguish NF1 (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Neurofibromas / plexiform neurofibroma Tumor criterion ≥2 neurofibromas of any type or 1 plexiform neurofibroma Plexiform neurofibroma is highly supportive of NF1 and not a feature of Legius syndrome (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Optic pathway glioma Tumor criterion Presence of optic pathway glioma Included as a standalone diagnostic feature (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Iris Lisch nodules / choroidal abnormalities Ophthalmic criterion ≥2 iris Lisch nodules identified by slit lamp or ≥2 choroidal abnormalities detected by OCT/NIR imaging Choroidal abnormalities were added in the revised criteria (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Distinctive osseous lesion Skeletal criterion Sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone Revised wording emphasizes distinctive NF1-associated osseous lesions (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Molecular criterion Genetic criterion Heterozygous pathogenic NF1 variant with approximately 50% variant allele fraction in apparently normal tissue (e.g., blood) Allows diagnosis using molecular testing; especially useful in young children or atypical presentations (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)
Mosaic NF1 Special consideration Separate recommendations proposed Mosaic forms were specifically addressed by the consensus, but are not captured by the standard simplified rows above (legius2021reviseddiagnosticcriteria pages 1-2, legius2021reviseddiagnosticcriteria media 67536eac)
Legius syndrome differentiation Distinguishing related condition ≥6 bilateral CALMs and no other NF1 diagnostic criteria except possible freckling, or heterozygous pathogenic SPRED1 variant (~50% VAF) Legius syndrome can mimic early pigmentary NF1 but does not carry NF1-related oncologic risks (legius2021reviseddiagnosticcriteria pages 2-3, peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria media 67536eac)

Table: This table summarizes the 2021 international consensus diagnostic criteria for neurofibromatosis type 1, including the different threshold for individuals with and without an affected parent. It also briefly distinguishes Legius syndrome, an important overlapping condition in children with pigmentary findings.

Visual primary-source evidence: Table images of the revised diagnostic criteria were retrieved from the consensus publication (legius2021reviseddiagnosticcriteria media 67536eac, legius2021reviseddiagnosticcriteria media 57806d8a).

10.2 Genetic testing approach

The revised criteria explicitly allow diagnosis via identification of a heterozygous pathogenic NF1 variant (~50% variant allele fraction in normal tissue) as one diagnostic feature, supporting molecular diagnosis especially in young children or atypical cases. (peduto2023neurofibromatosistype1 pages 2-4, legius2021reviseddiagnosticcriteria pages 2-3)

10.3 Imaging / biomarkers

  • Plexiform neurofibroma trials use volumetric MRI and REiNS criteria to define response (≥20% volume reduction). (gross2023longtermsafetyand pages 1-2, gross2020selumetinibinchildren pages 1-2)
  • For OPG monitoring, OCT measures (RNFL/GCL) and VEP are discussed; VEP is reported to have ~90% sensitivity for detecting presence of an OPG (with specificity limitations), and OCT thinning can precede measurable vision loss. (tang2023neurofibromatosistype1associated pages 4-6)

10.4 Differential diagnosis

A critical differential in pigment-only presentations is Legius syndrome (SPRED1), which overlaps with café-au-lait macules ± freckling but lacks NF1 tumor risks; molecular analysis of NF1 and SPRED1 is recommended in such cases. (peduto2023neurofibromatosistype1 pages 2-4)

11. Outcome / Prognosis

11.1 Cancer burden

ERN GENTURIS reports markedly increased cancer burden: lifetime cancer risk 59.6% in NF1 vs 30.8% in the general population. (carton2023erngenturistumour pages 1-2)

11.2 MPNST prognosis

A 2023 MPNST clinical management review reports overall poor outcomes with a 5-year overall survival ~50–60% and median survival about 6 years, noting NF1-associated cases have worse survival than sporadic tumors. (yao2023malignantperipheralnerve pages 11-13)

11.3 Quality of life / psychosocial outcomes

A 2023 systematic review synthesizing adult NF1 studies (n≈1,180 across 16 studies) highlights stigma, anxiety/depression, and functional limitations. It reports that severity and visibility predict poorer QoL, and that self-esteem was higher in those receiving care at NF clinics or genetic counseling. (fournier2023psychosocialimplicationsof pages 13-15, fournier2023psychosocialimplicationsof pages 15-16)

12. Treatment

12.1 Pharmacotherapy and targeted therapy (plexiform neurofibromas)

The treatment landscape for symptomatic, inoperable NF1 plexiform neurofibromas has been transformed by MEK inhibition.

Publication / milestone Year Population Design / setting Response / efficacy Clinical outcomes / implementation notes Key adverse events / monitoring URL Citation
Gross et al., NEJM 2020 50 children with NF1 and symptomatic, inoperable plexiform neurofibromas; median age 10.2 years Open-label phase 2 trial; selumetinib 25 mg/m² twice daily continuously in 28-day cycles; volumetric MRI and patient-reported/functional outcomes assessed serially Confirmed partial response in 35/50 (70%); 28/35 responses durable for ≥1 year Mean child-reported tumor pain intensity decreased by 2 points after 1 year; clinically meaningful improvements in pain interference (child 38%, parent 50%), overall HRQoL (child 48%, parent 58%), strength (56%), and range of motion (38%); established selumetinib as first highly active systemic therapy for pediatric NF1-PN Most frequent toxicities: nausea/vomiting/diarrhea, asymptomatic creatine phosphokinase increase, acneiform rash, paronychia; 5 discontinued for toxicity; 6 had progression https://doi.org/10.1056/NEJMoa1912735 (gross2020selumetinibinchildren pages 1-2)
Gross et al., Neuro-Oncology long-term follow-up 2023 74 children (phase 1/2 cohort), median age 10.3 years, NF1 with inoperable symptomatic PN Long-term phase 1/2 follow-up of SPRINT (NCT01362803); continuous selumetinib; safety/efficacy through ~5 additional years Overall confirmed partial response 52/74 (70%); median treatment duration 57.5 cycles; 59% of responses lasted ≥12 cycles Durable improvement in tumor pain intensity (P=.015) and pain interference (P=.0059) through 48 cycles; supports long-term use in practice with sustained benefit and need for extended follow-up No new safety signals, but known AEs may first appear after several years; ongoing labs, echocardiograms, and ophthalmologic monitoring recommended https://doi.org/10.1093/neuonc/noad086 (gross2023longtermsafetyand pages 1-2)
Casey et al., FDA approval summary, Clin Cancer Res 2021 Pediatric patients ≥2 years with symptomatic, inoperable NF1-associated PN Regulatory review of single-arm multicenter trial data supporting approval Overall response rate 66% (95% CI 51–79); median duration of response not reached; 82% of responders had response duration ≥12 months FDA approved selumetinib (Koselugo) on April 10, 2020 for pediatric NF1 patients ≥2 years with symptomatic, inoperable PN; supported by radiographic response plus clinical outcome assessments Class MEK inhibitor toxicities emphasized: ocular, cardiac, musculoskeletal, gastrointestinal, dermatologic https://doi.org/10.1158/1078-0432.CCR-20-5032 (casey2021fdaapprovalsummary pages 1-1)
Armstrong et al., BMC Cancer review 2023 Children with NF1-related PN (clinical practice focus) Narrative clinical decision review on surgery, watchful waiting, and MEK inhibitor use Summarizes selumetinib activity as ~70% tumor volume reduction response in pivotal pediatric trial Selumetinib described as the only licensed medical therapy for pediatric symptomatic, inoperable NF1-PN at the time; treatment should be individualized by multidisciplinary teams based on tumor size/location, adjacent tissue effects, symptoms, and family preferences Review highlights need to balance benefits with MEK inhibitor toxicities and long treatment duration https://doi.org/10.1186/s12885-023-10996-y (gross2020selumetinibinchildren pages 1-2)
Azizi et al., Neuro-Oncology Practice AE consensus 2024 Pediatric NF1 patients with PN receiving selumetinib Modified Delphi expert consensus for prevention/management of selumetinib-associated adverse events in real-world care Not an efficacy trial; implementation-focused guidance based on accumulated trial and expanded-access experience Consensus agreement reached for 36 statements; supports practical toxicity management to keep patients on effective therapy when possible Reported AE frequencies include vomiting 86%, diarrhea 81%, dry skin 65%, elevated CPK 77%, decreased LVEF 28%, increased blood pressure 18%, blurred vision 15%; rare ocular events include central serous retinopathy 0.6% and retinal vein occlusion 0.3% https://doi.org/10.1093/nop/npae038 (azizi2024consensusrecommendationson pages 1-2)

Table: This table summarizes the pivotal selumetinib evidence base for NF1-associated plexiform neurofibromas, including the landmark pediatric trials, FDA approval, and 2024 adverse-event management guidance. It is useful for quickly linking efficacy, real-world implementation, and safety monitoring considerations.

Key primary-trial efficacy highlights: - In the pivotal pediatric phase 2 trial, confirmed partial response occurred in 70% (35/50) with many durable responses; pain and QoL improved meaningfully. (gross2020selumetinibinchildren pages 1-2) - Long-term follow-up (up to ~5 additional years) maintained 70% confirmed partial response in a larger cohort (52/74) with durable pain improvements and no new safety signals, but ongoing monitoring is required because known adverse events may appear later. (gross2023longtermsafetyand pages 1-2)

12.2 Treatment adverse events and real-world implementation guidance (2024)

A 2024 European expert panel (modified Delphi) produced consensus recommendations for prevention and management of selumetinib-associated adverse events and reported clinically relevant AE frequencies (e.g., vomiting 86%, diarrhea 81%, elevated CPK 77%, decreased LVEF 28%). (azizi2024consensusrecommendationson pages 1-2)

12.3 Surgical and interventional care

Surgery remains important for selected tumors/lesions (e.g., resectable ANNUBP, certain symptomatic gliomas), but is often limited by tumor location and morbidity. For MPNST, ERN GENTURIS states there is no place for watchful waiting and recommends urgent resection when feasible. (carton2023erngenturistumour pages 9-10, carton2023erngenturistumour pages 10-12)

12.4 Ongoing and recent clinical trials (real-world pipeline)

Examples of MEK inhibitor trials and post-authorization studies: - NCT01362803: Selumetinib (AZD6244) Phase I/II in children with NF1 PN; ACTIVE_NOT_RECRUITING. (NCT01362803 chunk 1) - NCT03962543 (ReNeu): Mirdametinib Phase 2b single-group in adults and children with inoperable symptomatic NF1 PN; ACTIVE_NOT_RECRUITING; primary completion 2023-09-20. (NCT03962543 chunk 1) - NCT05388370: Selumetinib post-authorisation safety study (PASS) prospective cohort; ACTIVE_NOT_RECRUITING; follow-up to 2028; monitoring includes LVEF reduction, physeal dysplasia, ocular toxicity, pubertal development. (NCT05388370 chunk 1) - NCT03231306: Binimetinib Phase II in children and adults with NF1 PN; COMPLETED with completion date 2024-04-17. (NCT03231306 chunk 1)

MAXO suggestions (examples): - MEK inhibitor therapy (MAXO term suggestion; no MAXO ID provided in retrieved evidence) - MRI surveillance (MAXO suggestion) - Genetic counseling (MAXO suggestion; supported as beneficial for self-esteem in adult NF1 systematic review) (fournier2023psychosocialimplicationsof pages 13-15)

13. Prevention

Primary prevention is not currently available for a germline genetic disorder, but secondary/tertiary prevention via surveillance is central.

ERN GENTURIS (2023) provides age-stratified surveillance recommendations, including: - Regular clinical assessments (at least annually in young children), - Ophthalmologic surveillance for OPG with OCT when feasible, - Imaging strategies for internal tumor burden at transition to adulthood (e.g., WB-MRI at least once), - Breast cancer screening: annual MRI starting as soon after age 30 as feasible until 50. (carton2023erngenturistumour pages 6-7, carton2023erngenturistumour pages 7-8)

14. Other Species / Natural Disease

The retrieved sources did not include naturally occurring NF1 disease descriptions in non-human species.

15. Model Organisms

NF1 optic pathway glioma research frequently uses genetically engineered mouse models. These models provide mechanistic insight into gliomagenesis, retinal ganglion cell injury, and the role of immune/microenvironmental cells (microglia and T cells) and neuronal activity factors in tumor initiation and progression. (tang2023neurofibromatosistype1associated pages 1-2, tang2023neurofibromatosistype1associated pages 6-8)

Recent developments and expert analysis (2023–2024 highlights)

  • Epidemiology refresh (2023): Updated pooled prevalence/incidence with evidence of under-recognition in routine medical records vs screening. (lee2023incidenceandprevalence pages 2-4, lee2023incidenceandprevalence pages 1-2)
  • Practice-changing implementation support (2024): Consensus adverse-event management for selumetinib in pediatric NF1 PN to facilitate safer long-term use outside trials. (azizi2024consensusrecommendationson pages 1-2)
  • Therapeutic strategy evolution (2024): Expert synthesis emphasizes that while MEK inhibition has succeeded for PNs and some low-grade gliomas, monotherapy is insufficient for aggressive tumors (e.g., MPNST), motivating combination and microenvironment-targeting approaches. (na2024pastpresentand pages 1-3)

Notes on PMID availability

Within the retrieved full-text excerpts, PMIDs were not consistently provided, so PMID-level indexing could not be verified for every citation in this tool run. All major claims are instead linked to specific retrieved documents via the provided context IDs and include DOIs/URLs and publication months/years as available.

References

  1. (lee2023incidenceandprevalence pages 1-2): Tin-Suet Joan Lee, Meera Chopra, Raymond H. Kim, Patricia C. Parkin, and Carolina Barnett-Tapia. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases, Sep 2023. URL: https://doi.org/10.1186/s13023-023-02911-2, doi:10.1186/s13023-023-02911-2. This article has 154 citations and is from a peer-reviewed journal.

  2. (peduto2023neurofibromatosistype1 pages 1-2): Cristina Peduto, Mariateresa Zanobio, Vincenzo Nigro, Silverio Perrotta, Giulio Piluso, and Claudia Santoro. Neurofibromatosis type 1: pediatric aspects and review of genotype–phenotype correlations. Cancers, 15:1217, Feb 2023. URL: https://doi.org/10.3390/cancers15041217, doi:10.3390/cancers15041217. This article has 80 citations.

  3. (park2024recentadvancesin pages 1-2): Su Jung Park. Recent advances in neurofibromatosis type 1 research: towards tailored therapeutics and treatment strategies. Journal of Genetic Medicine, 21:51-60, Dec 2024. URL: https://doi.org/10.5734/jgm.2024.21.2.51, doi:10.5734/jgm.2024.21.2.51. This article has 2 citations.

  4. (legius2021reviseddiagnosticcriteria pages 2-3): Eric Legius, Ludwine Messiaen, Pierre Wolkenstein, Patrice Pancza, Robert A. Avery, Yemima Berman, Jaishri Blakeley, Dusica Babovic-Vuksanovic, Karin Soares Cunha, Rosalie Ferner, Michael J. Fisher, Jan M. Friedman, David H. Gutmann, Hildegard Kehrer-Sawatzki, Bruce R. Korf, Victor-Felix Mautner, Sirkku Peltonen, Katherine A. Rauen, Vincent Riccardi, Elizabeth Schorry, Anat Stemmer-Rachamimov, David A. Stevenson, Gianluca Tadini, Nicole J. Ullrich, David Viskochil, Katharina Wimmer, Kaleb Yohay, Alicia Gomes, Justin T. Jordan, Victor Mautner, Vanessa L. Merker, Miriam J. Smith, David Stevenson, Monique Anten, Arthur Aylsworth, Diana Baralle, Sebastien Barbarot, Fred Barker, Shay Ben-Shachar, Amanda Bergner, Didier Bessis, Ignacio Blanco, Catherine Cassiman, Patricia Ciavarelli, Maurizio Clementi, Thierry Frébourg, Marco Giovannini, Dorothy Halliday, Chris Hammond, C.O. Hanemann, Helen Hanson, Arvid Heiberg, Pascal Joly, Michel Kalamarides, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Mia MacCollin, Conor Mallucci, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, Laura Papi, Allyson Parry, Juha Peltonen, Dominique Pichard, Bruce Poppe, Nilton Rezende, Luiz Oswaldo Rodrigues, Tena Rosser, Martino Ruggieri, Eduard Serra, Verena Steinke-Lange, Stavros Michael Stivaros, Amy Taylor, Jaan Toelen, James Tonsgard, Eva Trevisson, Meena Upadhyaya, Ali Varan, Meredith Wilson, Hao Wu, Gelareh Zadeh, Susan M. Huson, D. Gareth Evans, and Scott R. Plotkin. Revised diagnostic criteria for neurofibromatosis type 1 and legius syndrome: an international consensus recommendation. Genetics in Medicine, 23:1506-1513, Aug 2021. URL: https://doi.org/10.1038/s41436-021-01170-5, doi:10.1038/s41436-021-01170-5. This article has 888 citations and is from a highest quality peer-reviewed journal.

  5. (carton2023erngenturistumour pages 1-2): Charlotte Carton, D. Gareth Evans, Ignacio Blanco, Reinhard E. Friedrich, Rosalie E. Ferner, Said Farschtschi, Hector Salvador, Amedeo A. Azizi, Victor Mautner, Claas Röhl, Sirkku Peltonen, Stavros Stivaros, Eric Legius, Rianne Oostenbrink, Joan Brunet, Frank Van Calenbergh, Catherine Cassiman, Thomas Czech, María José Gavarrete de León, Henk Giele, Susie Henley, Conxi Lazaro, Vera Lipkovskaya, Eamonn R. Maher, Vanessa Martin, Irene Mathijssen, Enrico Opocher, Ana Elisabete Pires, Thomas Pletschko, Eirene Poupaki, Vita Ridola, Andre Rietman, Thorsten Rosenbaum, Alastair Santhouse, Astrid Sehested, Ian Simmons, Walter Taal, and Anja Wagner. Ern genturis tumour surveillance guidelines for individuals with neurofibromatosis type 1. eClinicalMedicine, 56:101818, Feb 2023. URL: https://doi.org/10.1016/j.eclinm.2022.101818, doi:10.1016/j.eclinm.2022.101818. This article has 129 citations and is from a peer-reviewed journal.

  6. (lee2023incidenceandprevalence pages 2-4): Tin-Suet Joan Lee, Meera Chopra, Raymond H. Kim, Patricia C. Parkin, and Carolina Barnett-Tapia. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases, Sep 2023. URL: https://doi.org/10.1186/s13023-023-02911-2, doi:10.1186/s13023-023-02911-2. This article has 154 citations and is from a peer-reviewed journal.

  7. (gross2020selumetinibinchildren pages 1-2): Andrea M. Gross, Pamela L. Wolters, Eva Dombi, Andrea Baldwin, Patricia Whitcomb, Michael J. Fisher, Brian Weiss, AeRang Kim, Miriam Bornhorst, Amish C. Shah, Staci Martin, Marie C. Roderick, Dominique C. Pichard, Amanda Carbonell, Scott M. Paul, Janet Therrien, Oxana Kapustina, Kara Heisey, D. Wade Clapp, Chi Zhang, Cody J. Peer, William D. Figg, Malcolm Smith, John Glod, Jaishri O. Blakeley, Seth M. Steinberg, David J. Venzon, L. Austin Doyle, and Brigitte C. Widemann. Selumetinib in children with inoperable plexiform neurofibromas. New England Journal of Medicine, 382:1430-1442, Apr 2020. URL: https://doi.org/10.1056/nejmoa1912735, doi:10.1056/nejmoa1912735. This article has 822 citations and is from a highest quality peer-reviewed journal.

  8. (tang2023neurofibromatosistype1associated pages 1-2): Yunshuo Tang and David H Gutmann. Neurofibromatosis type 1-associated optic pathway gliomas: current challenges and future prospects. Cancer Management and Research, 15:667-681, Jul 2023. URL: https://doi.org/10.2147/cmar.s362678, doi:10.2147/cmar.s362678. This article has 36 citations and is from a peer-reviewed journal.

  9. (na2024pastpresentand pages 1-3): Brian Na, Shilp R. Shah, and Harish N. Vasudevan. Past, present, and future therapeutic strategies for nf-1-associated tumors. Current Oncology Reports, 26:706-713, May 2024. URL: https://doi.org/10.1007/s11912-024-01527-4, doi:10.1007/s11912-024-01527-4. This article has 20 citations and is from a peer-reviewed journal.

  10. (legius2021reviseddiagnosticcriteria pages 1-2): Eric Legius, Ludwine Messiaen, Pierre Wolkenstein, Patrice Pancza, Robert A. Avery, Yemima Berman, Jaishri Blakeley, Dusica Babovic-Vuksanovic, Karin Soares Cunha, Rosalie Ferner, Michael J. Fisher, Jan M. Friedman, David H. Gutmann, Hildegard Kehrer-Sawatzki, Bruce R. Korf, Victor-Felix Mautner, Sirkku Peltonen, Katherine A. Rauen, Vincent Riccardi, Elizabeth Schorry, Anat Stemmer-Rachamimov, David A. Stevenson, Gianluca Tadini, Nicole J. Ullrich, David Viskochil, Katharina Wimmer, Kaleb Yohay, Alicia Gomes, Justin T. Jordan, Victor Mautner, Vanessa L. Merker, Miriam J. Smith, David Stevenson, Monique Anten, Arthur Aylsworth, Diana Baralle, Sebastien Barbarot, Fred Barker, Shay Ben-Shachar, Amanda Bergner, Didier Bessis, Ignacio Blanco, Catherine Cassiman, Patricia Ciavarelli, Maurizio Clementi, Thierry Frébourg, Marco Giovannini, Dorothy Halliday, Chris Hammond, C.O. Hanemann, Helen Hanson, Arvid Heiberg, Pascal Joly, Michel Kalamarides, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Mia MacCollin, Conor Mallucci, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, Laura Papi, Allyson Parry, Juha Peltonen, Dominique Pichard, Bruce Poppe, Nilton Rezende, Luiz Oswaldo Rodrigues, Tena Rosser, Martino Ruggieri, Eduard Serra, Verena Steinke-Lange, Stavros Michael Stivaros, Amy Taylor, Jaan Toelen, James Tonsgard, Eva Trevisson, Meena Upadhyaya, Ali Varan, Meredith Wilson, Hao Wu, Gelareh Zadeh, Susan M. Huson, D. Gareth Evans, and Scott R. Plotkin. Revised diagnostic criteria for neurofibromatosis type 1 and legius syndrome: an international consensus recommendation. Genetics in Medicine, 23:1506-1513, Aug 2021. URL: https://doi.org/10.1038/s41436-021-01170-5, doi:10.1038/s41436-021-01170-5. This article has 888 citations and is from a highest quality peer-reviewed journal.

  11. (peduto2023neurofibromatosistype1 pages 2-4): Cristina Peduto, Mariateresa Zanobio, Vincenzo Nigro, Silverio Perrotta, Giulio Piluso, and Claudia Santoro. Neurofibromatosis type 1: pediatric aspects and review of genotype–phenotype correlations. Cancers, 15:1217, Feb 2023. URL: https://doi.org/10.3390/cancers15041217, doi:10.3390/cancers15041217. This article has 80 citations.

  12. (carton2023erngenturistumour pages 9-10): Charlotte Carton, D. Gareth Evans, Ignacio Blanco, Reinhard E. Friedrich, Rosalie E. Ferner, Said Farschtschi, Hector Salvador, Amedeo A. Azizi, Victor Mautner, Claas Röhl, Sirkku Peltonen, Stavros Stivaros, Eric Legius, Rianne Oostenbrink, Joan Brunet, Frank Van Calenbergh, Catherine Cassiman, Thomas Czech, María José Gavarrete de León, Henk Giele, Susie Henley, Conxi Lazaro, Vera Lipkovskaya, Eamonn R. Maher, Vanessa Martin, Irene Mathijssen, Enrico Opocher, Ana Elisabete Pires, Thomas Pletschko, Eirene Poupaki, Vita Ridola, Andre Rietman, Thorsten Rosenbaum, Alastair Santhouse, Astrid Sehested, Ian Simmons, Walter Taal, and Anja Wagner. Ern genturis tumour surveillance guidelines for individuals with neurofibromatosis type 1. eClinicalMedicine, 56:101818, Feb 2023. URL: https://doi.org/10.1016/j.eclinm.2022.101818, doi:10.1016/j.eclinm.2022.101818. This article has 129 citations and is from a peer-reviewed journal.

  13. (yao2023malignantperipheralnerve pages 2-4): Chengjun Yao, Haiying Zhou, Yanzhao Dong, Ahmad Alhaskawi, Sohaib Hasan Abdullah Ezzi, Zewei Wang, Jingtian Lai, Vishnu Goutham Kota, Mohamed Hasan Abdulla Hasan Abdulla, and Hui Lu. Malignant peripheral nerve sheath tumors: latest concepts in disease pathogenesis and clinical management. Cancers, 15:1077, Feb 2023. URL: https://doi.org/10.3390/cancers15041077, doi:10.3390/cancers15041077. This article has 118 citations.

  14. (lee2023incidenceandprevalence pages 4-7): Tin-Suet Joan Lee, Meera Chopra, Raymond H. Kim, Patricia C. Parkin, and Carolina Barnett-Tapia. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. Orphanet Journal of Rare Diseases, Sep 2023. URL: https://doi.org/10.1186/s13023-023-02911-2, doi:10.1186/s13023-023-02911-2. This article has 154 citations and is from a peer-reviewed journal.

  15. (carton2023erngenturistumour pages 10-12): Charlotte Carton, D. Gareth Evans, Ignacio Blanco, Reinhard E. Friedrich, Rosalie E. Ferner, Said Farschtschi, Hector Salvador, Amedeo A. Azizi, Victor Mautner, Claas Röhl, Sirkku Peltonen, Stavros Stivaros, Eric Legius, Rianne Oostenbrink, Joan Brunet, Frank Van Calenbergh, Catherine Cassiman, Thomas Czech, María José Gavarrete de León, Henk Giele, Susie Henley, Conxi Lazaro, Vera Lipkovskaya, Eamonn R. Maher, Vanessa Martin, Irene Mathijssen, Enrico Opocher, Ana Elisabete Pires, Thomas Pletschko, Eirene Poupaki, Vita Ridola, Andre Rietman, Thorsten Rosenbaum, Alastair Santhouse, Astrid Sehested, Ian Simmons, Walter Taal, and Anja Wagner. Ern genturis tumour surveillance guidelines for individuals with neurofibromatosis type 1. eClinicalMedicine, 56:101818, Feb 2023. URL: https://doi.org/10.1016/j.eclinm.2022.101818, doi:10.1016/j.eclinm.2022.101818. This article has 129 citations and is from a peer-reviewed journal.

  16. (suppiah2023multiplatformmolecularprofiling pages 1-2): Suganth Suppiah, Sheila Mansouri, Yasin Mamatjan, Jeffrey C. Liu, Minu M. Bhunia, Vikas Patil, Prisni Rath, Bharati Mehani, Pardeep Heir, Severa Bunda, German L. Velez-Reyes, Olivia Singh, Nazanin Ijad, Neda Pirouzmand, Tatyana Dalcourt, Ying Meng, Shirin Karimi, Qingxia Wei, Farshad Nassiri, Trevor J. Pugh, Gary D. Bader, Kenneth D. Aldape, David A. Largaespada, and Gelareh Zadeh. Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities. Nature Communications, May 2023. URL: https://doi.org/10.1038/s41467-023-38432-6, doi:10.1038/s41467-023-38432-6. This article has 49 citations and is from a highest quality peer-reviewed journal.

  17. (fournier2023psychosocialimplicationsof pages 13-15): Hugo Fournier, Nicolas Calcagni, Fanny Morice-Picard, and Bruno Quintard. Psychosocial implications of rare genetic skin diseases affecting appearance on daily life experiences, emotional state, self-perception and quality of life in adults: a systematic review. Orphanet Journal of Rare Diseases, Feb 2023. URL: https://doi.org/10.1186/s13023-023-02629-1, doi:10.1186/s13023-023-02629-1. This article has 57 citations and is from a peer-reviewed journal.

  18. (fournier2023psychosocialimplicationsof pages 15-16): Hugo Fournier, Nicolas Calcagni, Fanny Morice-Picard, and Bruno Quintard. Psychosocial implications of rare genetic skin diseases affecting appearance on daily life experiences, emotional state, self-perception and quality of life in adults: a systematic review. Orphanet Journal of Rare Diseases, Feb 2023. URL: https://doi.org/10.1186/s13023-023-02629-1, doi:10.1186/s13023-023-02629-1. This article has 57 citations and is from a peer-reviewed journal.

  19. (peduto2023neurofibromatosistype1 pages 11-13): Cristina Peduto, Mariateresa Zanobio, Vincenzo Nigro, Silverio Perrotta, Giulio Piluso, and Claudia Santoro. Neurofibromatosis type 1: pediatric aspects and review of genotype–phenotype correlations. Cancers, 15:1217, Feb 2023. URL: https://doi.org/10.3390/cancers15041217, doi:10.3390/cancers15041217. This article has 80 citations.

  20. (yao2023malignantperipheralnerve pages 13-14): Chengjun Yao, Haiying Zhou, Yanzhao Dong, Ahmad Alhaskawi, Sohaib Hasan Abdullah Ezzi, Zewei Wang, Jingtian Lai, Vishnu Goutham Kota, Mohamed Hasan Abdulla Hasan Abdulla, and Hui Lu. Malignant peripheral nerve sheath tumors: latest concepts in disease pathogenesis and clinical management. Cancers, 15:1077, Feb 2023. URL: https://doi.org/10.3390/cancers15041077, doi:10.3390/cancers15041077. This article has 118 citations.

  21. (baezflores2023thetherapeuticpotential pages 1-2): Juan Báez-Flores, Mario Rodríguez-Martín, and Jesus Lacal. The therapeutic potential of neurofibromin signaling pathways and binding partners. Communications Biology, Apr 2023. URL: https://doi.org/10.1038/s42003-023-04815-0, doi:10.1038/s42003-023-04815-0. This article has 47 citations and is from a peer-reviewed journal.

  22. (baezflores2023thetherapeuticpotential pages 3-4): Juan Báez-Flores, Mario Rodríguez-Martín, and Jesus Lacal. The therapeutic potential of neurofibromin signaling pathways and binding partners. Communications Biology, Apr 2023. URL: https://doi.org/10.1038/s42003-023-04815-0, doi:10.1038/s42003-023-04815-0. This article has 47 citations and is from a peer-reviewed journal.

  23. (baezflores2023thetherapeuticpotential pages 5-6): Juan Báez-Flores, Mario Rodríguez-Martín, and Jesus Lacal. The therapeutic potential of neurofibromin signaling pathways and binding partners. Communications Biology, Apr 2023. URL: https://doi.org/10.1038/s42003-023-04815-0, doi:10.1038/s42003-023-04815-0. This article has 47 citations and is from a peer-reviewed journal.

  24. (na2024pastpresentand pages 5-6): Brian Na, Shilp R. Shah, and Harish N. Vasudevan. Past, present, and future therapeutic strategies for nf-1-associated tumors. Current Oncology Reports, 26:706-713, May 2024. URL: https://doi.org/10.1007/s11912-024-01527-4, doi:10.1007/s11912-024-01527-4. This article has 20 citations and is from a peer-reviewed journal.

  25. (tang2023neurofibromatosistype1associated pages 6-8): Yunshuo Tang and David H Gutmann. Neurofibromatosis type 1-associated optic pathway gliomas: current challenges and future prospects. Cancer Management and Research, 15:667-681, Jul 2023. URL: https://doi.org/10.2147/cmar.s362678, doi:10.2147/cmar.s362678. This article has 36 citations and is from a peer-reviewed journal.

  26. (carton2023erngenturistumour pages 6-7): Charlotte Carton, D. Gareth Evans, Ignacio Blanco, Reinhard E. Friedrich, Rosalie E. Ferner, Said Farschtschi, Hector Salvador, Amedeo A. Azizi, Victor Mautner, Claas Röhl, Sirkku Peltonen, Stavros Stivaros, Eric Legius, Rianne Oostenbrink, Joan Brunet, Frank Van Calenbergh, Catherine Cassiman, Thomas Czech, María José Gavarrete de León, Henk Giele, Susie Henley, Conxi Lazaro, Vera Lipkovskaya, Eamonn R. Maher, Vanessa Martin, Irene Mathijssen, Enrico Opocher, Ana Elisabete Pires, Thomas Pletschko, Eirene Poupaki, Vita Ridola, Andre Rietman, Thorsten Rosenbaum, Alastair Santhouse, Astrid Sehested, Ian Simmons, Walter Taal, and Anja Wagner. Ern genturis tumour surveillance guidelines for individuals with neurofibromatosis type 1. eClinicalMedicine, 56:101818, Feb 2023. URL: https://doi.org/10.1016/j.eclinm.2022.101818, doi:10.1016/j.eclinm.2022.101818. This article has 129 citations and is from a peer-reviewed journal.

  27. (carton2023erngenturistumour pages 5-6): Charlotte Carton, D. Gareth Evans, Ignacio Blanco, Reinhard E. Friedrich, Rosalie E. Ferner, Said Farschtschi, Hector Salvador, Amedeo A. Azizi, Victor Mautner, Claas Röhl, Sirkku Peltonen, Stavros Stivaros, Eric Legius, Rianne Oostenbrink, Joan Brunet, Frank Van Calenbergh, Catherine Cassiman, Thomas Czech, María José Gavarrete de León, Henk Giele, Susie Henley, Conxi Lazaro, Vera Lipkovskaya, Eamonn R. Maher, Vanessa Martin, Irene Mathijssen, Enrico Opocher, Ana Elisabete Pires, Thomas Pletschko, Eirene Poupaki, Vita Ridola, Andre Rietman, Thorsten Rosenbaum, Alastair Santhouse, Astrid Sehested, Ian Simmons, Walter Taal, and Anja Wagner. Ern genturis tumour surveillance guidelines for individuals with neurofibromatosis type 1. eClinicalMedicine, 56:101818, Feb 2023. URL: https://doi.org/10.1016/j.eclinm.2022.101818, doi:10.1016/j.eclinm.2022.101818. This article has 129 citations and is from a peer-reviewed journal.

  28. (legius2021reviseddiagnosticcriteria media 67536eac): Eric Legius, Ludwine Messiaen, Pierre Wolkenstein, Patrice Pancza, Robert A. Avery, Yemima Berman, Jaishri Blakeley, Dusica Babovic-Vuksanovic, Karin Soares Cunha, Rosalie Ferner, Michael J. Fisher, Jan M. Friedman, David H. Gutmann, Hildegard Kehrer-Sawatzki, Bruce R. Korf, Victor-Felix Mautner, Sirkku Peltonen, Katherine A. Rauen, Vincent Riccardi, Elizabeth Schorry, Anat Stemmer-Rachamimov, David A. Stevenson, Gianluca Tadini, Nicole J. Ullrich, David Viskochil, Katharina Wimmer, Kaleb Yohay, Alicia Gomes, Justin T. Jordan, Victor Mautner, Vanessa L. Merker, Miriam J. Smith, David Stevenson, Monique Anten, Arthur Aylsworth, Diana Baralle, Sebastien Barbarot, Fred Barker, Shay Ben-Shachar, Amanda Bergner, Didier Bessis, Ignacio Blanco, Catherine Cassiman, Patricia Ciavarelli, Maurizio Clementi, Thierry Frébourg, Marco Giovannini, Dorothy Halliday, Chris Hammond, C.O. Hanemann, Helen Hanson, Arvid Heiberg, Pascal Joly, Michel Kalamarides, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Mia MacCollin, Conor Mallucci, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, Laura Papi, Allyson Parry, Juha Peltonen, Dominique Pichard, Bruce Poppe, Nilton Rezende, Luiz Oswaldo Rodrigues, Tena Rosser, Martino Ruggieri, Eduard Serra, Verena Steinke-Lange, Stavros Michael Stivaros, Amy Taylor, Jaan Toelen, James Tonsgard, Eva Trevisson, Meena Upadhyaya, Ali Varan, Meredith Wilson, Hao Wu, Gelareh Zadeh, Susan M. Huson, D. Gareth Evans, and Scott R. Plotkin. Revised diagnostic criteria for neurofibromatosis type 1 and legius syndrome: an international consensus recommendation. Genetics in Medicine, 23:1506-1513, Aug 2021. URL: https://doi.org/10.1038/s41436-021-01170-5, doi:10.1038/s41436-021-01170-5. This article has 888 citations and is from a highest quality peer-reviewed journal.

  29. (legius2021reviseddiagnosticcriteria media 57806d8a): Eric Legius, Ludwine Messiaen, Pierre Wolkenstein, Patrice Pancza, Robert A. Avery, Yemima Berman, Jaishri Blakeley, Dusica Babovic-Vuksanovic, Karin Soares Cunha, Rosalie Ferner, Michael J. Fisher, Jan M. Friedman, David H. Gutmann, Hildegard Kehrer-Sawatzki, Bruce R. Korf, Victor-Felix Mautner, Sirkku Peltonen, Katherine A. Rauen, Vincent Riccardi, Elizabeth Schorry, Anat Stemmer-Rachamimov, David A. Stevenson, Gianluca Tadini, Nicole J. Ullrich, David Viskochil, Katharina Wimmer, Kaleb Yohay, Alicia Gomes, Justin T. Jordan, Victor Mautner, Vanessa L. Merker, Miriam J. Smith, David Stevenson, Monique Anten, Arthur Aylsworth, Diana Baralle, Sebastien Barbarot, Fred Barker, Shay Ben-Shachar, Amanda Bergner, Didier Bessis, Ignacio Blanco, Catherine Cassiman, Patricia Ciavarelli, Maurizio Clementi, Thierry Frébourg, Marco Giovannini, Dorothy Halliday, Chris Hammond, C.O. Hanemann, Helen Hanson, Arvid Heiberg, Pascal Joly, Michel Kalamarides, Matthias Karajannis, Daniela Kroshinsky, Margarita Larralde, Conxi Lázaro, Lu Le, Michael Link, Robert Listernick, Mia MacCollin, Conor Mallucci, Christopher Moertel, Amy Mueller, Joanne Ngeow, Rianne Oostenbrink, Roger Packer, Laura Papi, Allyson Parry, Juha Peltonen, Dominique Pichard, Bruce Poppe, Nilton Rezende, Luiz Oswaldo Rodrigues, Tena Rosser, Martino Ruggieri, Eduard Serra, Verena Steinke-Lange, Stavros Michael Stivaros, Amy Taylor, Jaan Toelen, James Tonsgard, Eva Trevisson, Meena Upadhyaya, Ali Varan, Meredith Wilson, Hao Wu, Gelareh Zadeh, Susan M. Huson, D. Gareth Evans, and Scott R. Plotkin. Revised diagnostic criteria for neurofibromatosis type 1 and legius syndrome: an international consensus recommendation. Genetics in Medicine, 23:1506-1513, Aug 2021. URL: https://doi.org/10.1038/s41436-021-01170-5, doi:10.1038/s41436-021-01170-5. This article has 888 citations and is from a highest quality peer-reviewed journal.

  30. (gross2023longtermsafetyand pages 1-2): Andrea M Gross, Eva Dombi, Pamela L Wolters, Andrea Baldwin, Anne Dufek, Kailey Herrera, Staci Martin, Joanne Derdak, Kara S Heisey, Patricia M Whitcomb, Seth M Steinberg, David J Venzon, Michael J Fisher, AeRang Kim, Miriam Bornhorst, Brian D Weiss, Jaishri O Blakeley, Malcolm A Smith, and Brigitte C Widemann. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro-oncology, 25:1883-1894, Apr 2023. URL: https://doi.org/10.1093/neuonc/noad086, doi:10.1093/neuonc/noad086. This article has 117 citations and is from a domain leading peer-reviewed journal.

  31. (tang2023neurofibromatosistype1associated pages 4-6): Yunshuo Tang and David H Gutmann. Neurofibromatosis type 1-associated optic pathway gliomas: current challenges and future prospects. Cancer Management and Research, 15:667-681, Jul 2023. URL: https://doi.org/10.2147/cmar.s362678, doi:10.2147/cmar.s362678. This article has 36 citations and is from a peer-reviewed journal.

  32. (yao2023malignantperipheralnerve pages 11-13): Chengjun Yao, Haiying Zhou, Yanzhao Dong, Ahmad Alhaskawi, Sohaib Hasan Abdullah Ezzi, Zewei Wang, Jingtian Lai, Vishnu Goutham Kota, Mohamed Hasan Abdulla Hasan Abdulla, and Hui Lu. Malignant peripheral nerve sheath tumors: latest concepts in disease pathogenesis and clinical management. Cancers, 15:1077, Feb 2023. URL: https://doi.org/10.3390/cancers15041077, doi:10.3390/cancers15041077. This article has 118 citations.

  33. (casey2021fdaapprovalsummary pages 1-1): Denise Casey, Suzanne Demko, Arup Sinha, Pallavi S. Mishra-Kalyani, Yuan-li Shen, Sachia Khasar, M. Anwar Goheer, Whitney S. Helms, Lili Pan, Yuan Xu, Jianghong Fan, Ruby Leong, Jiang Liu, Yuching Yang, Katherine Windsor, Mei Ou, Olen Stephens, Byeongtaek Oh, Gregory H. Reaman, Abhilasha Nair, Stacy S. Shord, Vishal Bhatnagar, Selena R. Daniels, Sharon Sickafuse, Kirsten B. Goldberg, Marc R. Theoret, Richard Pazdur, and Harpreet Singh. Fda approval summary: selumetinib for plexiform neurofibroma. Clinical Cancer Research, 27:4142-4146, Mar 2021. URL: https://doi.org/10.1158/1078-0432.ccr-20-5032, doi:10.1158/1078-0432.ccr-20-5032. This article has 122 citations and is from a highest quality peer-reviewed journal.

  34. (azizi2024consensusrecommendationson pages 1-2): Amedeo A Azizi, Darren Hargrave, João Passos, Pierre Wolkenstein, Thorsten Rosenbaum, Claudia Santoro, Verena Rosenmayr, Thomas Pletschko, Paolo A Ascierto, and Héctor Salvador Hernández. Consensus recommendations on management of selumetinib-associated adverse events in pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas. Neuro-Oncology Practice, 11:515-531, Apr 2024. URL: https://doi.org/10.1093/nop/npae038, doi:10.1093/nop/npae038. This article has 23 citations and is from a peer-reviewed journal.

  35. (NCT01362803 chunk 1): AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors. National Cancer Institute (NCI). 2011. ClinicalTrials.gov Identifier: NCT01362803

  36. (NCT03962543 chunk 1): MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas. SpringWorks Therapeutics, Inc.. 2019. ClinicalTrials.gov Identifier: NCT03962543

  37. (NCT05388370 chunk 1): PASS of Paediatric Patients Initiating Selumetinib. AstraZeneca. 2022. ClinicalTrials.gov Identifier: NCT05388370

  38. (NCT03231306 chunk 1): Bruce Korf, MD. Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas. University of Alabama at Birmingham. 2017. ClinicalTrials.gov Identifier: NCT03231306

  39. (carton2023erngenturistumour pages 7-8): Charlotte Carton, D. Gareth Evans, Ignacio Blanco, Reinhard E. Friedrich, Rosalie E. Ferner, Said Farschtschi, Hector Salvador, Amedeo A. Azizi, Victor Mautner, Claas Röhl, Sirkku Peltonen, Stavros Stivaros, Eric Legius, Rianne Oostenbrink, Joan Brunet, Frank Van Calenbergh, Catherine Cassiman, Thomas Czech, María José Gavarrete de León, Henk Giele, Susie Henley, Conxi Lazaro, Vera Lipkovskaya, Eamonn R. Maher, Vanessa Martin, Irene Mathijssen, Enrico Opocher, Ana Elisabete Pires, Thomas Pletschko, Eirene Poupaki, Vita Ridola, Andre Rietman, Thorsten Rosenbaum, Alastair Santhouse, Astrid Sehested, Ian Simmons, Walter Taal, and Anja Wagner. Ern genturis tumour surveillance guidelines for individuals with neurofibromatosis type 1. eClinicalMedicine, 56:101818, Feb 2023. URL: https://doi.org/10.1016/j.eclinm.2022.101818, doi:10.1016/j.eclinm.2022.101818. This article has 129 citations and is from a peer-reviewed journal.