A Novel Missense CASR Gene Sequence Variation Resulting in Familial Hypocalciuric Hypercalcemia.

Background/Objective: Familial hypocalciuric hypercalcemia (FHH) is an uncommon cause of hypercalcemia; however, it is important to consider and rule out in patients with suspected primary hyperparathyroidism (PHPT), ideally, before proceeding with surgery. Herein, we present a patient where this process identified a calcium-sensing receptor gene (CASR) sequence variant currently labeled as a variant of unknown significance (VUS), yet the patient's family pedigree suggests that it is in fact a pathogenic CASR sequence variant. Case Report: A 35-year-old woman was referred to the Endocrine Surgery clinic for evaluation of "recurrent PHPT" and need for reoperative parathyroidectomy. Before referral, she was treated with subtotal parathyroidectomy for the presumed diagnosis of PHPT-related symptomatic hypercalcemia. Postoperatively, she had persistent symptoms. Upon referral, additional relevant information was elicited that suspected FHH instead of PHPT, including a family history of hypercalcemia with CASR VUS in multiple family members and hypocalciuria in the patient. She underwent genetic testing revealing a missense CASR VUS in exon 3 c.392C>A (p.Ala110Asp), the same as in her mother. Medical management instead of reoperation was advised for the diagnosis of FHH. Discussion: To our knowledge, this CASR sequence variation has not been previously reported in the literature. Reporting newly discovered sequence variations with the context of a family's medical history is important because it allows for the recognition of new pathogenic variants. This expands the registry of already known sequence variations and their associated clinical pathology for future patients undergoing genetic testing. Conclusion: This CASR variant represents a novel pathogenic sequence variation causing FHH.

Personalized Breast Cancer Risk Assessment: Incorporation of Genetic and High-Risk Factorson Breast Cancer Risk and Management.

Breast cancer remains the second most diagnosed cancer in women worldwide and the number one cause of cancer in women in the United States. It is unfortunately the primary cause of cancerrelated deaths among women, with 14% of all cancer deaths attributed to it. Over the past decade, screening methods have matured, and imaging modalities are continuously improving. Screening mammograms remain the only modality that have been shown to improve breast cancer survival, however, more modalities like MRI, abbreviated MRI, and CT mammography are gaining in momentum. Now more than ever, providers need to identify the patient population that is at an elevated risk for breast cancer to offer them a personalized screening approach specific to their empiric risk. In this paper we shed light on risk factors of breast cancer and summarize risk assessment tools that have been recently incorporated in assessing a woman's risk of breast cancer. We also summarize new genetic testing strategies and their implications in prevention of breast cancer. And finally, we offer a personalized approach to management of women with agenetic predisposition as well as to women at elevated risk but without a genetic mutation. The hope is to identify women at increased risk and perfect a "personalized screening approach" for breast cancer.