Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Legius Syndrome, Neurofibromatosis Type 1-like Syndrome (NFLS) [Q85.9]

OMIM numbers: 611431, 609291 (SPRED1)

Dr. rer. nat. Karin Mayer

Scientific Background

In 2007, patients with clinical signs and symptoms similar to neurofibromatosis type 1 (NF1), such as café-au-lait spots, freckle-like spots in the armpits and the groin area, macrocephaly and, in some cases, an appearance typical for Noonan syndrome, were first described. However, instead of the NF1 gene, a mutation was identified in the SPRED1 gene; a gene which had been unknown to this point. In 2009, this clinical picture was named Legius syndrome after Eric Legius, who had first described it. Patients with Legius syndrome fulfill the diagnostic criteria of the NIH Consensus Development Conference Statement of NF1; in children with additional learning difficulties and macrocephaly or in regard to the skin manifestations, it is not possible to differentiate the Legius syndrome from NF1. A characteristic difference to NF1 is the absence of Lisch nodules of the iris, neurofibromas, optic gliomas or bone changes as well as the presence of subcutaneous lipomas in adults with Legius syndrome.

Just like NF1, the Legius syndrome follows an autosomal dominant pattern; however, it is caused by mutations in the SPRED1 gene. SPRED1 (Sprouty-Related EVH1 Domain Containing 1) belongs to what is known as the Sprouty (SPRY) family of proteins, which act as negative regulators within the mitogen-activated protein kinase (MAPK) signal transduction. The SPRED1 gene consists of 7 coding exons. So far, 200 patients have been clinically described and more than 40 different SPRED1 mutations most of which cause a premature translation stop have been identified. The proportion of genomic deletions/duplications is estimated to be 10%. While in the case of classic NF1, mutations in the NF1 gene can be detected in up to 95% of all patients, the detection rate for mutations in the SPRED1 gene is < 2% in regard to all patients clinically diagnosed with NF1 and up to 25% in patients with an NF1-like phenotype or Legius syndrome without a mutation in NF1.