Scientific Background
Legius syndrome, historically known as Neurofibromatosis type 1-like syndrome (NFLS), is characterized by multiple café-au-lait spots with or without additional freckle-like spots in the axilla or groin. In addition, macrocephaly, learning difficulties, and developmental delay may be present. Thus, the diagnostic criteria of the NIH Consensus Development Conference Statement are overlapping with the diagnosis of neurofibromatosis type 1, and no clinical differentiation from NF1 is possible. A distinctive difference from NF1 in patients with Legius syndrome is the absence of other clinical NIH criteria such as Lisch nodules of the iris, neurofibromas, optic gliomas, typical bone changes, and possibly nodule-like changes of the choroid. In contrast, Legius syndrome involves subcutaneous lipomas occurring in adulthood.
Legius syndrome can be confirmed by detection of a pathogenic variant in the SPRED1 gene. SPRED1 (Sprouty-Related EVH1 Domain Containing 1) is a member of the so-called Sprouty (SPRY) family of proteins that function as negative regulators within mitogen-activated protein kinase (MAPK) signal transduction. Approximately 90% of variants are small nucleotide changes in the SPRED1 gene, with larger genomic deletions or duplications present in 10% of patients. Most pathogenic variants result in premature translational stop in protein biosynthesis and loss of protein function upon inhibition of Raf1 kinase activation. In classical neurofibromatosis type 1, pathogenic variants in the NF1 gene can be detected in up to 95% patients if more than two clinical NIH criteria are met. In contrast, the detection rate of pathogenic variants in the SPRED1 gene is about 2% in sporadic patients with NF1-like phenotype or Legius syndrome, and up to 19% in patients with a positive family history including the presence of café-au-lait spots and freckling without other clinical criteria for NF1.
References
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