Thyroidectomy Outcomes in Patients Identified With RET Pathogenic Variants Through a Population Genomic Screening Program.

Importance: Population-based genomic screening can facilitate early detection of medullary thyroid carcinoma (MTC) in patients with pathogenic/likely pathogenic (P/LP) RET variants. Objective: To evaluate the clinical treatment and patient outcomes after identification of P/LP RET proto-oncogene variants associated with the risk of MTC via a population genomic screening program. Design, Setting, Participants: This retrospective cross-sectional study was completed between June 1, 2016, and May 31, 2022, for a mean follow-up period of 22.4 months (range, 2-76 months). The study included patients who were identified as having P/LP RET variants through a population genomic screening program at a rural tertiary care center and who underwent thyroidectomy after results disclosure. Main Outcomes and Measures: The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging. Results: Seventy-five patients were identified as having P/LP RET variants exclusively through genomic screening. Twenty of these patients (27%; 11 women [55%] and 9 men [45%]; median age, 48 years [range, 22-73 years]) underwent total thyroidectomy; 13 of these patients (65%) also had a central neck dissection. No patients had clinically apparent disease at the time of surgery. Pathologic findings indicated MTC for 12 patients and papillary thyroid carcinoma in 2. Of patients with MTC, 10 had stage I disease, 1 had stage II disease, 1 had stage III disease, and none had stage IV disease. Based on postoperative surveillance imaging and laboratory results, no patient had evidence of recalcitrant disease. Conclusions and Relevance: In this cross-sectional study, all malignant neoplasms identified on surgical pathology were clinically occult, with surgical intervention based solely on the identification of the P/LP RET variant via population genomic screening. This finding suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes.

Observational study of population genomic screening for variants associated with endocrine tumor syndromes in a large, healthcare-based cohort.

BACKGROUND: In current care, patients' personal and self-reported family histories are primarily used to determine whether genetic testing for hereditary endocrine tumor syndromes (ETS) is indicated. Population genomic screening for other conditions has increased ascertainment of individuals with pathogenic/likely pathogenic (P/LP) variants, leading to improved management and earlier diagnoses. It is unknown whether such benefits occur when screening broader populations for P/LP ETS variants. This manuscript assesses clinical utility outcomes of a large, unselected, healthcare-based genomic screening program by describing personal and family history of syndrome-related features, risk management behaviors after result disclosure, and rates of relevant post-disclosure diagnoses in patient-participants with P/LP ETS variants. METHODS: Observational study of individuals informed of a P/LP variant in MEN1, RET, SDHAF2, SDHB, SDHC, SDHD, or VHL through Geisinger's MyCode Community Health Initiative between June 2016 and October 2019. Electronic health records (EHRs) of participants were evaluated for a report of pre-disclosure personal and self-reported family histories and post-disclosure risk management and diagnoses. RESULTS: P/LP variants in genes of interest were identified in 199 of 130,490 (1 in 656) adult Geisinger MyCode patient-participants, 80 of which were disclosed during the study period. Eighty-one percent (n = 65) did not have prior evidence of the result in their EHR and, because they were identified via MyCode, were included in further analyses. Five participants identified via MyCode (8%) had a personal history of syndrome-related features; 16 (25%) had a positive self-reported family history. Time from result disclosure to EHR review was a median of 0.7 years. Post-disclosure, 36 (55.4%) completed a recommended risk management behavior; 11 (17%) were diagnosed with a syndrome-related neoplasm after completing a risk management intervention. CONCLUSIONS: Broader screening for pathogenic/likely pathogenic variants associated with endocrine tumor syndromes enables detection of at-risk individuals, leads to the uptake of risk management, and facilitates relevant diagnoses. Further research will be necessary to continue to determine the clinical utility of screening diverse, unselected populations for such variants.

Recurrent Metatarsal Fractures in Postmenopausal Woman With Low Serum Alkaline Phosphatase: A Rare Diagnosis Not to Miss.

Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a loss-of-function mutation in the gene for tissue nonspecific isoenzyme of alkaline phosphatase (ALP) that results in low levels of ALP. The clinical presentation of HPP is variable and in adults can easily be misdiagnosed as other forms of osteomalacia. We present a case of a 53-year-old Caucasian female who was evaluated for recurrent metatarsal fractures. She reported her first metatarsal fracture at age 21, and since then had at least 8 more metatarsal fractures over her lifetime, most without injury other than weight bearing. She reported history of gait disturbance as a child and dental issues (spacing and loosening). Laboratory tests showed normal serum calcium, phosphorus, and parathyroid hormone, but low serum ALP <20 IU/L and elevated N-telopeptide. Foot X-ray showed several healed and nonhealed metatarsal fractures, and bone densitometry revealed osteopenia. She was treated with calcium and vitamin D. A year later she had a new metatarsal fracture and a nontraumatic pelvic fracture. Teriparatide therapy was attempted but not tolerated. Due to suspicion of HPP vitamin B6 levels were checked and found to be elevated at 263 µg/L. Given her clinical presentation and low ALP levels with elevated vitamin B6, the diagnosis of HPP was made. Clinicians should be attentive to a history of recurrent low trauma fractures, premature loss of deciduous teeth, and persistently low serum ALP to suspect this diagnosis. Early case detection with the availability of recent Food and Drug Administration-approved asfotase alfa may avoid years of undiagnosed morbidity.

Acute Pancreatitis Secondary to Severe Hypertriglyceridemia: Management of Severe Hypertriglyceridemia in Emergency Setting.

Hypertriglyceridemia (HTG) is the third most common cause of acute pancreatitis (AP). The incidence of AP is around 10-20% with levels > 2,000 mg/dL. We present here a case of a 44-year-old male with history of uncontrolled diabetes mellitus and HTG admitted with severe abdominal pain. Labs revealed elevated lipase and amylase. CT of abdomen with contrast showed AP. He was found to have a triglyceride (TG) level of 6,672 mg/dL. Besides conventional treatment for AP with intravenous (IV) hydration, he was started on IV regular insulin along with dextrose saline. He had marked improvement in his TG level the next day. He was continued on insulin and dextrose saline with hourly glucose monitoring until TG was < 500 mg/dL. He was discharged on statins and fenofibrate. The goal of management of AP secondary to severe HTG in emergency setting is to lower the TG levels to less than 500 as quickly as possible as lower levels are associated with good clinical outcomes. Apheresis and IV insulin are both helpful in lowering TG levels with no randomized controlled trials showing greater efficacy of one over other. Further episodes of AP can be prevented by lifestyle modification and lipid lowering drugs to keep TG levels below 500 mg/dL. Fibrates are first-line drugs to lower TG and used either alone or in conjunction with statins. Periodic plasmapheresis can also be considered in some non-compliant patients with recurrent episodes of pancreatitis.

Aspergillus thyroiditis: a complication of respiratory tract infection in an immunocompromised patient.

A 59-year-old male with past medical history significant for non-Hodgkin's lymphoma status after chemotherapy presented with acute onset of neck pain, odynophagia, and dysphagia associated with subjective fever, chills, and dyspnea. Physical findings included a temperature of 38.4°C, hypertension, and tachycardia. Patient was found to have anterior neck tenderness. Laboratory evaluation revealed neutropenia. The patient was started on empiric antibacterial and antiviral therapy and continued on home prophylactic antifungal treatment. Thyroid function tests revealed overt hyperthyroidism. A thyroid ultrasound showed heterogeneous echotexture without discrete nodules. Subacute thyroiditis was treated with methylprednisolone, metoprolol, and opiate analgesics. Patient's antibacterial, antifungal, and antiviral treatments were broadened. A fine needle aspiration was not conducted. The patient's condition deteriorated rapidly over his brief hospital course and he expired. Autopsy showed fungal thyroiditis secondary to disseminated invasive Aspergillus. This report describes the presentation of fungal thyroiditis secondary to disseminated invasive Aspergillus originating from the respiratory tract. The authors review the diagnostic challenges, pathophysiology, and treatment of this condition.