GTS5:Neurofibromatosis type 1 (NF1)
Primary Author(s)*
Ngonidzashe Faya, PhD
Madina Sukhanova, PhD, FACMG
Cancer Category/Type
Genetic Tumour Syndromes (GTS)
Cancer Sub-Classification / Subtype
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Definition / Description of Disease
Neurofibromatosis type 1(NF1) is an autosomal dominant disorder caused by a pathogenic NF1 variant, characterized by at least two of eight diagnostic criteria.
Essential and desirable diagnostic criteria
Essential:
A clinical diagnosis of NF1 requires the presence of at least two of the following features:
(1) Six or more café-au-lait macules (CALM) (> 5 mm diameter in children, > 15 mm in adults)
(2) Axillary/inguinal freckling
(3) Two or more neurofibromas of any type or one plexiform neurofibroma (PN)
(4) Optic pathway glioma (OPG)
(5) Two or more iris hamartomas (Lisch nodules) or two or more choroidal abnormalities
(6) Distinctive bony abnormality (anterolateral bowing of the tibia, pseudarthrosis of a long bone, sphenoid dysplasia)
(7) Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue
(8) Parent with NF1 (by the above criteria).
These criteria were revised in 2021[1]. Of note, there are other conditions with features that overlap with NF1, including Legius syndrome (OMIM 611431), Noonan syndrome[2], and constitutive mismatch repair deficiency[3].
Synonyms / Terminology
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Epidemiology / Prevalence
NF1 is a common autosomal dominant disorder with a birth incidence of 1 per 3000 [4]
Clinical Features
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| Signs and Symptoms | EXAMPLE Asymptomatic (incidental finding on complete blood counts)
EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon) |
| Laboratory Findings | EXAMPLE Cytopenias
EXAMPLE Lymphocytosis (low level) |
Sites of Involvement
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Morphologic Features
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Immunophenotype
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| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE CD1 |
| Positive (subset) | EXAMPLE CD2 |
| Negative (universal) | EXAMPLE CD3 |
| Negative (subset) | EXAMPLE CD4 |
Chromosomal Rearrangements (Gene Fusions)
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| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE t(9;22)(q34;q11.2) | EXAMPLE 3'ABL1 / 5'BCR | EXAMPLE der(22) | EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference) |
Yes | No | Yes | EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
Individual Region Genomic Gain/Loss/LOH
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| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE
7 |
EXAMPLE Loss | EXAMPLE
chr7:1- 159,335,973 [hg38] |
EXAMPLE
chr7 |
Yes | Yes | No | EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE
8 |
EXAMPLE Gain | EXAMPLE
chr8:1-145,138,636 [hg38] |
EXAMPLE
chr8 |
No | No | No | EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference). |
Characteristic Chromosomal Patterns
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| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
Gene Mutations (SNV/INDEL)
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| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
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Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
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Familial Forms
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Additional Information
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Links
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References
- ↑ Legius, Eric; et al. (2021-08). "Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation". Genetics in Medicine: Official Journal of the American College of Medical Genetics. 23 (8): 1506–1513. doi:10.1038/s41436-021-01170-5. ISSN 1530-0366. PMC 8354850 Check
|pmc=value (help). PMID 34012067 Check|pmid=value (help). Check date values in:|date=(help) - ↑ Conboy, Erin; et al. (2016-02). "Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines". Journal of Medical Genetics. 53 (2): 123–126. doi:10.1136/jmedgenet-2015-103177. ISSN 1468-6244. PMID 26337637. Check date values in:
|date=(help) - ↑ M, Suerink; et al. (2019 Feb). "Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy". Journal of medical genetics. 56 (2). doi:10.1136/jmedgenet-2018-105664. ISSN 1468-6244. PMID 30415209. Check date values in:
|date=(help) - ↑ Uusitalo, Elina; et al. (2015-03). "Incidence and mortality of neurofibromatosis: a total population study in Finland". The Journal of Investigative Dermatology. 135 (3): 904–906. doi:10.1038/jid.2014.465. ISSN 1523-1747. PMID 25354145. Check date values in:
|date=(help)
(use "Cite" icon at top of page)
EXAMPLE Book
- Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
Notes
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