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Highly Variable Phenotype of LZTR1 Schwannomatosis Includes Neurofibromas
Justus L Groen, MD PhD1; Liesbeth Spruijt, MD PhD2; Yvette van Ierland, MD1; Martijn J.A. Malessy, MD, PhD1; Saskia A Lesnik Oberstein, MD PhD1
1Leiden University Medical Center, Leiden, Netherlands, 2Radboud University Medical Center, Nijmegen, Netherlands
Introduction: Schwannomatosis is a hereditary disorder defined by the presence of 2 or more peripheral or cranial (non vestibular) nerve schwannomas. Schwannomatosis is genetically heterogeneous; two known causative genes are SMARCB1 and the more recently identified LZTR1. The LZTR1 schwannomatosis phenotype has been expanded to include unilateral vestibular schwannoma (UVS). To date, neurofibromas have never been described in patients with schwannomatosis. Herein we describe a family with schwannomatosis due to a LZTR1 gene mutation, in which one family member has a severe early-onset phenotype encompassing both schwannomas and pathologically confirmed neurofibromas.
Materials & Methods: Whole exome sequencing was performed in the proband. Mutation and cosegregation was confirmed using Sanger sequencing.
Results: A 55 year old male (proband) suffered a severe phenotype including multiple cutaneous schwannomas, unilateral trigeminal schwannoma and pathologically confirmed subcutaneous and multiple intraneural neurofibromas. Age of disease onset was 16yo. His sister showed a mild phenotype with late onset schwannomas. Both parents were not available for examination or testing. Whole exome sequencing identified a mutation in the LZTR1 gene (c.2324dup, p.Ile776fs) in both proband, also present in affected sister. Exome sequencing did not show any mutations in SMARCB1, NF1 en NF2.
Conclusions: We describe the presence of neurofibromas as a part of the LZTR1 phenotype, implying loss of LZTR1 function could predispose to the development of neurofibromas, as well as schwannomas and UVS. This finding suggests a role of LZTR1 in Ras/MAPK pathway, in parallel with NF1, a GTPase activating protein that is a negative regulator of Ras.
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