Birt Hogg Dube Syndrome and Thyroid Cancer - Is There an Association?

A 71-year-old man presented for evaluation of thyroid nodules. Past medical history includes auricular trichodiscoma/fibrofolliculomas and colon cancer at age 39. He underwent genetic testing revealing mutations of the CHEK2 and FLCN gene, conferring a diagnosis of Birt-Hogg-Dube syndrome (BHD). Subsequently, several family members were diagnosed with this syndrome. He was initially seen for evaluation of chronic cough. A neck ultrasound showed suspicious thyroid nodules and fine needle aspiration revealed suspicion for papillary thyroid cancer. He had molecular testing by AFIRMA and was GSC negative. He underwent right hemithyroidectomy and then completion with findings of a right lobe follicular thyroid carcinoma. Given underlying history of BHD, genetic testing was performed to assess for additional mutations that could predispose to thyroid cancer. This may help to raise awareness of screening for the presence of thyroid nodules and possibly thyroid carcinoma in individuals with BHD. Birt-Hogg-Dube (BHD) syndrome is a rare, autosomal dominant syndrome caused by a germline mutation in the FLCN gene, and is characterized by the presence of fibrofolliculomas, pneumothorax, and renal tumors. Thyroid nodules have been associated with BHD, present in 65% of individuals and 90% of families with this syndrome, however connection between BHD and thyroid cancer has not been established. For our patient, the most significant finding after a 170-gene panel analysis was an NRAS Q61R mutation. Mutations in RAS genes may be found in 15-20% of papillary thyroid cancers, 40-50% of follicular cancers, and 20-40% in follicular adenomas, and indicate poor prognosis. A CHEK2 mutation was also identified, which has been associated with an increased risk of multiple cancers, including thyroid. In addition, he had coding variants in the ATR gene on chromosome 3, as well as the IDH2 gene on chromosome 13. IDH2 may have a role in the development of thyroid cancer, however the contribution of these variants to tumor development or progression is currently unknown. For our patient, there is no published data to our knowledge regarding the findings of his coding variants and their possible association to BHD syndrome. More research needs to be done to assess for additional mutational variations present in those with BHD syndrome that may predispose to the development of thyroid cancer. Hara, H et al. “N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma.” Surgery vol. 116,6 (1994): 1010-6.