What is the difference between Neurofibromatosis type 1 (NF1) and Legius syndrome genetic testing?

From the Guidelines

Genetic testing for NF1 should be prioritized over Legius syndrome testing due to its higher prevalence and more severe complications, including neurofibromas, optic gliomas, and skeletal abnormalities, as noted in the 2024 study by 1. When clinical features overlap between NF1 and Legius syndrome, genetic testing is essential for a definitive diagnosis. The key difference between the two conditions is the gene being tested, with NF1 examining the NF1 gene on chromosome 17 and Legius syndrome testing looking for mutations in the SPRED1 gene on chromosome 15. Some key points to consider when deciding between NF1 and Legius genetic testing include:

• NF1 is more common, with a birth prevalence of 1/2,000 to 1/3,000 persons, as stated in the study by 1.
• NF1 has more severe complications, which are absent in Legius syndrome, making it a priority for testing, as mentioned in the study by 1.
• Testing methods include next-generation sequencing, MLPA (Multiplex Ligation-dependent Probe Amplification), and comprehensive panels that examine both genes simultaneously.
• A definitive genetic diagnosis is crucial for proper management, as NF1 requires more intensive surveillance for complications, as noted in the study by 1. If clinical suspicion for NF1 exists but initial genetic testing is negative, testing for Legius syndrome should be considered as the next step, especially in patients with café-au-lait spots but without neurofibromas or other NF1-specific features, as suggested by the study by 1.

From the Research

NF1 vs Legius Syndrome Genetic Test

• The genetic test for NF1 and Legius syndrome involves analyzing the NF1 and SPRED1 genes, respectively 2, 3, 4, 5, 6.
• Legius syndrome is caused by germline loss-of-function SPRED1 mutations, resulting in overactivation of the RAS-MAPK signal transduction cascade 4.
• The NF1 gene is mutated in approximately 73.3% of cases, while the SPRED1 gene is mutated in approximately 2.8% of cases 6.
• Molecular analysis of the NF1 and SPRED1 genes is usually needed to differentiate between NF1 and Legius syndrome, especially in young children with multiple café-au-lait macules and no other manifestations of NF1 5.
• Next-generation sequencing of target genes, combined with concurrent second-level tests such as multiplex ligation-dependent probe amplification and RNA analysis, can be used for the differential molecular diagnosis of these pathologies 6.

Key Differences between NF1 and Legius Syndrome

• NF1 is characterized by multiple café-au-lait macules, skinfold freckling, iris Lisch nodules, and benign or malignant peripheral nerve sheath tumors 5.
• Legius syndrome is characterized by multiple café-au-lait macules and skinfold freckling, but without an increased risk of tumors 4, 5.
• The presence of Lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors can help differentiate NF1 from Legius syndrome 2, 5.

Diagnostic Criteria

• 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.
• The diagnostic criteria for NF1 and Legius syndrome include minimal clinical and genetic criteria, as well as criteria for the mosaic forms of these conditions 2.