Pigmentary findings in neurofibromatosis type 1-like syndrome (Legius syndrome): potential diagnostic dilemmas.

THE STUDY BY MESSIAEN AND COLLEAGUES 1 IN THIS issue of JAMA provides a significant advance in understanding the clinical presentation and genetic spectrum of individuals with SPRED1 mutations that alter sprouty-related EVH1 domain– containing protein 1 function. It is clearly a vanguard report for understanding neurofibromatosis type 1 (NF1)–like syndrome, recently designated Legius syndrome. Legius syndrome is deemed a more appropriate term to avoid confusion in counseling families regarding anticipatory guidance. The term NF1-like syndrome implies overlap with myriad medical complications associated with NF1, which this report demonstrates is not the case. The few reports of individuals with loss-offunction SPRED1 mutations have shown that the primary phenotype of Legius syndrome is café au lait macules, sometimes associated with axillary freckling, inguinal freckling, or both. Messiaen et al provide supportive information on the phenotype of Legius syndrome with an increased number of individuals, document the lack of a specific genotype-phenotype correlation, and clarify the clinical overlap with NF1. Based on current knowledge, the clinical practice guidelines for an individual with Legius syndrome should primarily be focused on developmental delays, learning disabilities, and attention-deficit/hyperactivity disorder, but future studies will be needed to assess the appropriate clinical management regimen. For example, Messiaen et al described some individuals with abnormal angiogenesis, leading to the question of whether individuals with mutations in SPRED1 are at risk of vascular malformations, cardiovascular defects, and hypertension as observed in NF1. Isolated cases of malignancies have also been reported in Legius syndrome, and the potential for malignant predisposition must be considered given the role of the RAS–mitogenactivated protein kinase (MAPK) signal transduction pathway in cellular growth and differentiation. Pasmant et al theorized that individuals with Legius syndrome are predisposed to leukemia in childhood. However, the relatively large number of individuals reported by Messiaen et al suggests that tumorigenesis is not associated with Legius syndrome, as no systematic occurrence of a malignant tumor type was observed. Still, approximately 100 individuals have been reported to date, even fewer with a detailed phenotype, and it will be important to further characterize the phenotypic spectrum of Legius syndrome, especially to identify potential rare manifestations. Messiaen et al provide important insights into a clinical description of this syndrome and a better understanding of the phenotypic variability of disorders of the RAS-MAPK pathway. Specifically, 35 of 42 patients had more than 5 café au lait spots, of which almost half also had freckling of the axillae, inguinal area, or both. These data raise the question of sole reliance on pigmentary manifestations to establish the diagnosis of NF1, especially in younger individuals. As the authors point out, “ . . . a correct diagnosis has important implications . . . ” and they advocate molecular genetic testing to distinguish Legius syndrome from NF1. Their findings also challenge the specificity of the National Institutes of Health consensus diagnostic criteria for NF1. Neurofibromatosis type 1 is a common autosomal dominant condition due to mutations in the NF1 gene, and like SPRED1, its protein product, neurofibromin, interacts directly with RAS. Clinical diagnostic criteria were developed several decades ago and since that time have been the mainstay for the diagnosis of NF1. The diagnostic criteria state that the clinical diagnosis of NF1 is made if 2 or more of the following are found: (1) 6 or more café au lait macules larger than 5 mm in diameter in prepubertal individuals and larger than 15 mm in greatest diameter in postpubertal individuals; (2) 2 or