Revised diagnostic criteria for neurofibromatosis type 1 (NF1) enable early accurate differential diagnostic distinction from other RASopathies and facilitate the diagnosis

Abstract

Background: Neurofibromatosis type 1 (NF1) is one of the most common hereditary tumor predisposition syndromes and belongs to the RASopathies, a group of genetic disorders exhibiting overlapping clinical features. RASopathies are caused by defects in the RAS-mediated signal transduction pathway. The diagnostic criteria for NF1 were published in 1988 and have been used in the clinical practice since then; however, new clinical and genetic findings required a revision of these criteria. Furthermore, in early childhood the diagnostic criteria from 1988 may not enable an accurate diagnosis of NF1 and a differential diagnostic distinction from other RASopathies, such as Legius syndrome. Methods: A comprehensive analysis of the published data on genetics and clinical symptoms of NF1 was performed. The authors contributed to a modified Delphi method performed by an international board of experts in order to revise the diagnostic criteria for NF1 and compile the diagnostic criteria for Legius syndrome as well as mosaic forms of NF1 and Legius syndrome. Results: The diagnostic criteria were improved and specified. Newly identified clinical features such as choroidal anomalies as well as the detection of pathogenic NF1-gene variants were included in the revised diagnostic criteria for NF1. Discussion: The revised diagnostic criteria for NF1 as well as the newly compiled diagnostic criteria for Legius syndrome enable an early and accurate diagnosis of NF1 in young children with high specificity and sensitivity. Additionally, they facilitate a precise differential diagnostic distinction of NF1 from other disorders with overlapping clinical symptoms. This enables an early risk stratification and targeted medical care of patients.