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Case Reports
. 2011 Jan;32(1):E1985-98.
doi: 10.1002/humu.21404.

Legius syndrome in fourteen families

Ellen Denayer  1 , Magdalena Chmara, Hilde Brems, Anneke Maat Kievit, Yolande van Bever, Ans M W Van den Ouweland, Rick Van Minkelen, Arja de Goede-Bolder, Rianne Oostenbrink, Phillis Lakeman, Eline Beert, Takuma Ishizaki, Tomoaki Mori, Kathelijn Keymolen, Jenneke Van den Ende, Elisabeth Mangold, Sirkku Peltonen, Glen Brice, Julia Rankin, Karin Y Van Spaendonck-Zwarts, Akihiko Yoshimura, Eric Legius
Affiliations
Free PMC article
Case Reports

Legius syndrome in fourteen families

Ellen Denayer et al. Hum Mutat. 2011 Jan.
Free PMC article

Abstract

Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome.

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Figures

Figure 1
Figure 1
Elk-1 quantitative luciferase assay for Erk activation. Empty vector or vector carrying wild-type (WT; as a control) or mutant SPRED1 (Trp31Cys, W31C; Thr102Arg, T102R; Ile81del, I81 del) were transfected into HEK293T cells along with Elk-1 reporter plasmids. Elk-1 activation is measured as an increase in luciferase activity after stimulation with EGF. Three different amounts of plasmids were transfected: 0.05μg, 0.1 μg and 0.2 μg. The bars represent the average increase in luciferase activity of 3 replicates and error bars represent the standard deviation. Wild-type SPRED1 vector efficiently suppresses EGF induced Elk-1 activation in comparison to empty vector. Similar to the known pathogenic Thr102Arg and Ile81del mutations, Trp31Cys is unable to downregulate the increase in luciferase activity after EGF stimulation.
Figure 2
Figure 2
T2 weighed sagittal secion of brain MRI of patient I1 family 11: T2 hyperintense spot is present in the frontal white matter (arrow).
See this image and copyright information in PMC

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