Hager, Megan M.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy characterized by renal loss of calcium and magnesium leading to progressive renal failure. The disorder is caused by variants to the tight junction proteins claudin-16 and -19. While rare, this disorder causes a significant burden to patients based on its clinical manifestations of various electrolyte abnormalities, nephrocalcinosis, and early progression to renal failure. In this report we describe the diagnosis of a novel variant of CLDN16 which clinically presented with severe hypomagnesemia, hypocalcemia, nephrocalcinosis, and renal failure.

AbstractNoonan syndrome (NS) is an autosomal dominant condition with variable expressivity most commonly due to a germline pathogenic variant in PTPN11, which encodes the protein tyrosine phosphatase SHP‐2. Gain‐of‐function variants in PTPN11 are known to promote oncogenic behavior in affected tissues. We report the clinical description of a young adult male presenting with relapsing ganglioneuromas, dysmorphic features, cardiac abnormalities, and multiple lentigines, strongly suspicious for NS. Solid tumor testing identified the recurrent pathogenic c.922G>A (p.Asn308Asp) in PTPN11. Proband and parental blood sampling testing confirmed c.922G>A as a de novo germline alteration. Comprehensive literature review of solid tumors specifically associated to PTPN11, indicates that this is the first documentation of ganglioneuroma and its clinical recurrence after resection in conjunction with a genetically confirmed NS diagnosis. The findings in our patient further extend the list of neuroblastic and neural crest‐derived neoplasms associated with this condition.

Abstract Background: Hereditary factors play a key role in the risk of developing breast cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and testing for family members. Aim: To determine the prevalence of pathogenic or likely pathogenic germline mutations (P/LP) using a “universal” testing approach and uptake of no-cost cascade family testing in patients with breast cancer. Methods: We undertook a prospective multi-site study of germline genetic alterations among breast cancer patients receiving care at Mayo Clinic cancer centers in Rochester, MN; Eau Claire, WI; Jacksonville, FL and Phoenix, AZ between April 1, 2018 and March 31, 2020. Patients with a new or active breast cancer diagnosis (all stages) irrespective of cancer family history were tested with a >80-gene next generation sequencing panel.Results: Of 390 patients, the median age was 58 years (SD 12.3), 1% were male, 85% were white and 28% had advanced (stage 3-4) disease. P/LP were found in 12.1% (n=47) of patients, including 29 in moderate and high penetrance cancer susceptibility genes. 13 (3.3%) patients had mutations in BRCA1 or 2, while 33 (8.4%) had mutations in BRCAness (ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C, RAD51D, WRN) associated genes. Of the P/LP findings the most frequent aberrations were in BRCA2 (13.5%), BRCA1 (11.5%), CHEK2 (11.5%), MUTYH (11.5%), and WRN (9.6%). Variants of uncertain significance were found in 209 (53.6%) including 26 (6.6%) with concurrent P/LP and VUS. 37 (9.4%) patients had mutations associated with published management recommendations, precision therapies and/or clinical trial eligibility. 10 (2.6%) patients had P/LP that would not have met current screening guidelines, including 4 with moderate or high penetrance mutations. Patients with younger age of diagnosis were less likely than patients with older age of diagnosis to have a P/LP mutation (OR= 0.47, 95%CI: 0.25-0.90 p = 0.020). Only 10 (21%) patients with P/LP had family members undergo familial site- specific testing at no cost.Conclusions: In this prospective multi-center study of unselected breast cancer patients, universal multi-gene panel testing found that 1 in 8 patients harbor P/LP germline variants. Current guidelines were able to identify the majority of patients with P/LP mutations. Familial site specific testing is greatly under-utilized even when cost is not a barrier. Multigene panels impact cancer patient care by identifying precision medicine treatment interventions, and guiding long-term medical management and preventive surveillance. Citation Format: Brenda Ernst, Natalie Ertz-Archambault, Deborah J Rhodes, Donald W Northfelt, Myra Wick, Douglas L Riegert-Johnson, Scott Okuno, Katie Kunze, Michael Golafshar, Cindy M Azevedo, PLS Uson Junior, ED Esplin, Robert Nussbaum, Margaret Klint, Sarah Mantia, Megan Hager, Keith Stewart, Niloy Jewel Samadder. Universal genetic testing in breast cancer patients: A multi-center prospective study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-05.