Endocrine Abstracts

Introduction: Patients with “mixed” phenotypes are common among patients with multiple endocrine and non-endocrine neoplasias. Their diagnoses do not fit a given pattern making ge netic counseling difficult and testing impossible to guide. Most of these patients end up getting genome-wide studies for the identification of any predisposing genetic defect. We present a rare case of a 57 year old female who presented clinically with medullary thyroid cancer (MTC), mesothelioma and meningioma. As part of our diagnostic work-up for this category of patients, we performed a SNP microarray (comparative genomic hybridization; CGH) and whole exome sequencing (WES). CGH did not reveal any abnormalities; WES revealed two variants of unknown significance (VUS) in two separate genes, namely APC and RASAL1.

Case presentation: The patient, a 57 year old female patient, was diagnosed with AML at 41y old, peritoneal mesothelioma at 43y old, meningioma at 53y old and medullary thyroid cancer with lymph node metastasis at 53y old. She also suffers from autoimmune atrophic gastritis, alopecia universalis and relapsing perichondritis of the ear.

Results: WES was performed by DNA extracted from blood and revealed two specific VUS, in the APC gene: p.R1103W, c.3307 A>T and in the RASAL1 gene: p.R538H, c.1613 G>A. The APC gene (OMIM #17500) is a tumor suppressor gene involved in Wnt / β catenin signaling pathway; mutations have been reported in Familial Adenomatous Polyposis (FAP), brain tumors and Turcot syndrome. Mutations in the RASAL1 gene (OMIM#604118) have been found in thyroid cancer (both papillary and medullary) and Cowden syndrome. The above two variants found in this patient have not been reported previously as pathogenic. The mutations in the APC and RASAL1 genes are probably involved in thyroid cancer development. In addition, the mesothelioma and meningioma are likely related to mutations in the APC gene. This unique clinical presentation has not been reported before and is being proven by additional immunostaining and molecular studies.

Conclusion: Patients with unique phenotypes may present with a list of clinical manife stations that do not fit any given diagnosis. These patients deserve genome-wide testing that is often rewarding but also complex. In our patient with MTC, mesothelioma and meningioma two new gene defects were identified that are probable responsible for the phenotype.