Genetic Disorder Reference Sheet: Neurofibromatosis Type 1

August 29, 2023 by Suzanne M. Mahon DNS, RN, AOCN®, AGN-BC, FAAN

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that stems from a pathogenic variant in the NF1 gene, which regulates the production (https://www.ncbi.nlm.nih.gov/books/NBK1109/) of the tumor-suppressing neurofibromin protein. NF1 disorder is characterized by pigmentation changes (e.g., café au lait spots; see image (https://www.ncbi.nlm.nih.gov/books/NBK1109/figure/nf1.F1/)), cutaneous neurofibromas, malignant nerve sheath tumors, gastrointestinal stromal tumors (GISTs), and intellectual disorders. Signs and symptoms vary widely, but NF1 disorders occur in 1 in about 3,000–4,000 people (https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/#frequency). Almost half of the cases (https://www.ncbi.nlm.nih.gov/books/NBK1109/) are de novo (https://www.ons.org/genomics-taxonomy/variant#denovovariant).

Cancer Risks

As a susceptibility biomarker (https://www.ons.org/genomics-taxonomy/biomarkers), NF1 predicts risk of malignancy. Individuals with NF1 variants have a:

NF1 is also a prognostic biomarker (https://www.ons.org/genomics-taxonomy/biomarkers) in that the five-year survival rates for female breast cancer with a pathogenic NF1 variant are 67.9% compared to 87.8% (https://doi.org/10.1200/jco.2015.65.3576) in women without.

Penetrance and Diagnosis

Penetrance (https://www.ons.org/genomics-taxonomy/genome-foundations#penetrance) is nearly complete by the end of childhood. Suspect NF1 disorder in individuals who have two or more of the following (https://www.ncbi.nlm.nih.gov/books/NBK1109/):

Germline Biomarker Testing

Individuals meeting the clinical criteria typically obtain testing at age 5 years or earlier (https://www.ncbi.nlm.nih.gov/books/NBK1109/), depending on their symptoms and family history. Detecting pathogenic variants is challenging (https://link.springer.com/article/10.1007/s00439-021-02410-z) because NF1 is a large gene with long stretches of intronic DNA and many large deletions and insertions.

Testing might include RNA analysis of the intron/exon boundaries, DNA sequencing with duplication and deletion analysis, copy number analysis of NF1 exons and whole gene deletions. The NF1 gene is also a component of many germline breast cancer panels. Referral to a genetics professional can help individuals select the best test and interpret the findings.

Screening

NF1 is associated with an 8- to 15-year reduction in life expectancy (https://www.gimjournal.org/article/S1098-3600(21)01831-1/fulltext), so lifetime screening and appropriate treatment guided by a team familiar with the disorder is necessary. Screening recommendations include (https://www.ncbi.nlm.nih.gov/books/NBK1109/):

Surgical Interventions

Malignant nerve sheath tumors are aggressive and implicated in early mortality (https://www.gimjournal.org/article/S1098-3600(21)01831-1/fulltext) for individuals with NF1 disorder. Because effective systemic anticancer treatments are limited, early detection facilitates surgical removal.

Females with a significant fam­ily history may consider risk-reducing mastectomies. Ideally, those with NF1 disorder will establish care with a breast surgeon in a high-risk clinic (https://www.gimjournal.org/article/S1098-3600(21)01831-1/fulltext) around age 25.

Nursing Implications

Promptly identifying families with inherited NF1 variants and referring them to a genetics professional and center with experience managing NF1 disorder can help reduce morbidity and mortality (https://www.gimjournal.org/article/S1098-3600(21)01831-1/fulltext). Nurses should also be aware of the disorder’s implications on other anticancer treatments, such an increased risk of developing malignant peripheral nerve sheath tumors (https://www.gimjournal.org/article/S1098-3600(21)01831-1/fulltext) in a radiation treatment field.

NF1 disorder’s cutaneous manifestations often increase over time, and the accumulated cosmetic burden may contribute to distress and depression (https://www.gimjournal.org/article/S1098-3600(21)01831-1/fulltext) in affected individuals. Oncology nurses can assess for psychosocial distress (https://www.apna.org/resources/apna-assessment-and-monitoring-toolkit/) and refer patients for counseling if indicated.


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