Lorida Llaci
Lorida Llaci
Lorida Llaci
Helios Scholar
School: Arizona State University
Hometown: Tempe, Arizona
Mentor: Isabelle Schrauwen, Ph.D.
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An unusual case of Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in NF1 (17q11.2), that affects 1 in 3000 individuals.  NF1 patients are prone to benign and malignant neurofibromas; the former are recently found to follow a two-hit hypothesis in the NF1 gene of neurofibromas, which is characterized by two mutations in the NF1 gene of neurofibromas. Patients need to have two or more of the following phenotypes to be diagnosed with NF1: six or more café-au-lait spots, two or more neurofibromas or one plexiform neurofibroma, optic glioma, two or more Lisch Nodules, freckling in the axillary or inguinal regions, a distinctive osseous lesion or a first-degree relative affected. Here we show an unusual case of Neurofibromatosis type 1, a 36-year old woman with multiple dermal and subcutaneous neurofibromas, three café-au-lait spots larger than 1.5 cm, a single freckle in the right axilla and no known first-degree relatives affected. A blood sample and three neurofibroma biopsies of this patient were studied by exome and Sanger sequencing. Surprisingly, we identified a germline missense variant (R68Q) in the CBL gene, and a double nucleotide polymorphism (DNPs) splice site mutation in NF1 (c.7189GG>AA) in her neurofibromas, both genes important in the RAS pathway and both involved in an umbrella of disorders called Rasopathies. This finding is the first description of a digenic two-hit hypothesis for the development of a neurofibroma associated with a germline mutation in the RAS pathway. In conclusion, we can diagnose this patient with a Rasopathy due to a germline CBL and somatic NF1 mutation, which is significant in providing (1) personalized treatment, and (2) screening of additional symptoms related to these genes.