From the Guidelines
Genetic testing for both NF1 and SPRED1 genes is crucial to differentiate between Legius syndrome and Neurofibromatosis type 1 (NF1) due to their overlapping clinical features but distinct genetic causes and prognoses. The latest update on pediatric cancer surveillance recommendations highlights the importance of accurate diagnosis in these conditions 1. For instance, NF1 has a higher incidence of cancer predisposition and requires specific tumor surveillance recommendations, whereas Legius syndrome has a more benign course.
Key Considerations for Genetic Testing
- Comprehensive genetic testing should include sequencing of both the NF1 gene and the SPRED1 gene to detect point mutations, deletions, and duplications in these genes.
- Next-generation sequencing methods are typically used, and blood samples are the most common tissue used for testing.
- Genetic counseling is essential to accompany testing, helping patients understand the implications of results, inheritance patterns, and management strategies based on the specific diagnosis.
Importance of Differentiation
- NF1 carries higher risks of complications, including tumors of the nervous system, whereas Legius syndrome generally does not have these serious complications.
- Both conditions share features like café-au-lait spots and freckling, making clinical diagnosis alone insufficient for distinguishing between them.
- The revised diagnostic criteria for NF1, as updated by Legius and colleagues in 2021, focus on differentiating NF1 from Legius syndrome and other RASopathies 1.
Clinical Implications
- Accurate diagnosis is vital for managing these conditions effectively and for providing appropriate genetic counseling to patients and their families.
- The genetic testing results can inform the development of personalized management plans, including surveillance strategies and preventive measures.
- As noted in the update on pediatric cancer surveillance recommendations, genotype–phenotype associations have been described, but for the majority of variants, the expressivity cannot be predicted on the basis of the specific variant 1.
From the Research
Genetic Testing for Legius Syndrome versus NF1
- Genetic testing is essential for differentiating between Legius syndrome and Neurofibromatosis type 1 (NF1) due to their overlapping phenotypic features, particularly in young patients with pigmentary findings 2.
- The revised diagnostic criteria for NF1 incorporate new clinical features and genetic testing, while the criteria for Legius syndrome were created to differentiate the two conditions 2.
- Mutations in the SPRED1 gene are associated with Legius syndrome, and genetic testing can help identify these mutations, which can modify the Spred1 surface and affect its binding to the Ras inactivator neurofibromin 3.
- Next-generation sequencing of target genes, combined with concurrent second-level tests, can help diagnose Legius syndrome and other neurocutaneous disorders in children presenting with pigmentary manifestations 4.
- Café-au-lait macules are often the first sign of NF1 in children, but a significant percentage of patients with multiple café-au-lait macules do not have NF1, and genetic testing can help guide their follow-up 5.
- SPRED1 mutations have been identified in patients with a mild NF1 phenotype, and screening for these mutations can help dissect the NF1 phenotype and provide useful genotype information for clinically useful diagnosis 6.