Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that stems from a pathogenic variant in the NF1 gene, which regulates the production of the tumor-suppressing neurofibromin protein. NF1 disorder is characterized by pigmentation changes (e.g., café au lait spots; see image), 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. Almost half of the casesde novo
As a susceptibility biomarker, NF1 predicts risk of malignancy. Individuals with NF1 variants have a:
- 60% risk for developing a malignant nerve sheath tumor
- 20%–40% risk for developing female breast cancer
- Increased risk for developing a gastrointestinal stromal or central nervous system tumor
Penetrance and Diagnosis
- Six or more café au lait spots (see image) larger than 5 mm in prepubertal individuals and six or more that are greater than 15 mm for postpubertal individuals, which occurs in 99% of children
- Two or more cutaneous neurofibromas (see image), which occurs in 99% of adolescents and adults
- Plexiform neurofibromas, which occurs in 30% of infants
- Two or more lisch nodules (iris hamartomas; see image), which occurs in 95% of children
- Freckling in the axillary or inguinal region, which occurs in 85% of children
- Optic glioma, which occurs in 20% of children younger than 6 years
- Vertebral or tibia dysplasia, which occurs in less than 2% of infants
- A first-degree relative who meets NF1 disorder clinical criteria or has a known NF1 pathogenic variant
Germline Biomarker Testing
Individuals meeting the clinical criteria typically obtain testing at age 5 years or earlier, depending on their symptoms and family history. Detecting pathogenic variants is challenging 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.
NF1 is associated with an 8- to 15-year reduction in life expectancy, so lifetime screening and appropriate treatment guided by a team familiar with the disorder is necessary. Screening recommendations include:
- Annual ophthalmologic examination starting age 2
- Regular developmental screening questionnaire assessment and observation in children
- Regular blood pressure monitoring starting at age 5
- Annual physical examination for neurofibromas or new or changing plexiform neurofibromas starting in infancy; consider whole-body magnetic resonance imaging (MRI).
- Annual neurologic assessment for seizures, neurologic deficits, headaches, or pain beginning at age 2–3; follow-up with brain MRI for seizures or headaches.
- Annual assessment for skeletal asymmetry and scoliosis until growth is complete; osteoporosis assessment with vitamin D levels 10–20 years earlier than recommended for the general population
- Annual mammography starting at age 30; consider breast MRI alternating every six months with mammography from age 30–50.
- Clinical breast exam every 6–12 months starting at age 25 with education about symptoms that require prompt evaluation
Malignant nerve sheath tumors are aggressive and implicated in early mortality 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 around age 25.
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. 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 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 in affected individuals. Oncology nurses can assess for psychosocial distress and refer patients for counseling if indicated.