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.

Immobilization-induced hypercalcemia in a patient with renal failure.

SUMMARY: Immobilization-induced hypercalcemia is an uncommon cause of elevated calcium which is usually diagnosed following extensive systemic workup and exclusion of more common etiologies. Previously reported cases have largely described this phenomenon in adolescents and young adults a few weeks to months after the initial onset of immobilization. Metabolic workup tends to demonstrate hypercalcemia, hypercalciuria, and eventual osteoporosis. While the exact mechanism remains largely unclear, a dysregulation between bone resorption and formation is central to the pathogenesis of this disease. Decreased mechanical loading from prolonged bedrest tends to increase osteoclast induced bone resorption while promoting osteocytes to secrete proteins such as sclerostin to reduce osteoblast mediated bone formation. We describe the case of an 18-year-old male who was admitted following intraabdominal trauma. He underwent extensive abdominal surgery including nephrectomy resulting in initiation of dialysis. After 6 months of hospitalization, the patient gradually began developing uptrending calcium levels. Imaging and laboratory workup were unremarkable for any PTH-mediated process, malignancy, thyroid disorder, adrenal disorder, or infection. Workup did reveal significant elevated bone turnover markers which in combination with the clinical history led the physicians to arrive at the diagnosis of immobilization induced hypercalcemia. In order to prevent decreased rates of bone loss, the patient was administered denosumab for treatment. Hypocalcemia followed treatment expectedly and was repleted with supplementation via the patient's total parenteral nutrition. LEARNING POINTS: Immobilization-induced hypercalcemia should remain as a differential diagnosis of patients with prolonged hospitalizations with hypercalcemia. Extensive workup of common etiologies of hypercalcemia should be considered prior to arriving at this diagnosis. Denosumab, while off-label for this usage, offers an effective treatment option for immobilization-induced hypercalcemia though it carries a risk of hypocalcemia especially among patients with renal disease.

The role of parathyroidectomy in treating hypertension and other cardiac manifestations of primary hyperparathyroidism.

Among many recognized sequelae of primary hyperparathyroidism (PHPT), cardiovascular disease remains incompletely understood as a consequence of disordered calcium and parathyroid hormone (PTH) metabolism. While population studies have identified trends that associate PHPT with hypertension, metabolic syndrome, and vascular system calcifications, the fundamental pathophysiology, natural history, and opportunity to reverse or cure the cardiovascular effects with parathyroidectomy are not well established. This chapter reviews the current knowledge of this field of interest within PHPT and summarizes key findings from dedicated investigations that have addressed the impact of parathyroid surgery on the cardiovascular system.

Ultrasound and the Evaluation of Pediatric Thyroid Malignancy: Current Recommendations for Diagnosis and Follow-up.

Ultrasound (US) plays a critical role in the evaluation, treatment, screening, and surveillance of thyroid malignancy in pediatric patients. This review aims to summarize recent advances in this topic. Improvements in imaging technology have amplified the advantage of US and US-guided fine-needle aspiration biopsy for thyroid nodule evaluation, cancer diagnosis, and surgical planning. Ultrasound has a definitive screening role for early cancer detection in high-risk patients, including those with a history of radiation exposure from childhood treatments, environmental radiation disasters, or hereditary/familial cancer syndromes. Finally, US is a key component of lifelong surveillance for recurrence among pediatric thyroid cancer survivors.