SAT-504 Role of Genetic Screening for FHH in a Patient with Hypercalcemia and Hyperparathyroidism

Background The estimated prevalence of primary hyperparathyroidism (PHPT) is one per 1000 whereas familial hypocalciuric hypercalcemia (FHH) is one per 78,000. Distinguishing between PHPT and&nbsp;FHH&nbsp;can be challenging due to the similarity in biochemical picture. PTH can be normal in 48% of patients with PHPT and 80% of patients with&nbsp;FHH.&nbsp; PHPT patients are generally older and has a history of normal serum calcium with a new onset hypercalcemia.&nbsp; Endocrine society guideline suggests using 24h-CCCR (calcium-to-creatinine clearance ratio) to differentiate with 24h-CCCR <1% as an indicator for&nbsp;FHH&nbsp;and >2% as an indicator for PHPT. &nbsp; Case A 28 years-old African American lady with bipolar disorder is noted to have asymptomatic hypercalcemia in the range of&nbsp;11.1 to 12.2 mg/dl (ref: 8.4-10.3) by routine lab since 2012 with PTH level of 14 to 155 pg/ml (ref: 12-88). She has never been treated with Lithium. Vitamin D was 25-32 ng/ml (ref: 30-100).&nbsp; Phosphorous was 2-2.4 mg/dl (ref: 2.4-4.5). Magnesium was normal. She has no history of fracture nor renal stone. She has no family history of hypercalcemia.&nbsp; She had a decline in creatine clearance from 96 ml/min to 67 ml/min over a year. 24h-CCCR was < 1% and remained low even after calcium supplementation. No parathyroid adenoma was localized on imaging.&nbsp; Plasma metanephrine was normal.&nbsp; Due to 24h-CCCR <1%, a genetic panel for&nbsp;FHH&nbsp;was performed. She has FHH1 with heterozygous mutation at CASR (c.1972C>T).&nbsp; &nbsp; Discussion FHH&nbsp;is an autosomal-dominant disease with a loss of function mutation at CASR (FHH1),&nbsp;GNA11 (FHH2) or AP2S1 (FHH3). FHH1 is the most common and constitutes 65-90% of&nbsp;FHH. It has a high degree of penetrance. Loss-of-function mutation in&nbsp;CASR causes reduced sensitivity of calcium sensing in parathyroid chief cells resulting in PTH secretion, increased reabsorption of calcium in renal tubule and increased serum calcium.&nbsp;Family history of hypercalcemia and 24h-CCCR <1% suggest FHH. However, the urinary calcium excretion in patients with PHPT and&nbsp;FHH&nbsp;can also be overlapped. In the study reported by Bertocchio et al, 2% of&nbsp;FHH&nbsp;had 24h-CCCR values&nbsp;over&nbsp;2% and 26% PHPT patients had 24h-CCCR <1%. Concomitant vitamin D deficiency and very low dietary calcium intake may lower 24h-CCCR. In addition, a patient may have coexisting&nbsp;FHH&nbsp;and PHPT or&nbsp;FHH&nbsp;and MEN. Genetic screening for FHH may not feasible or cost-effective in every case of hypercalcemia and hyperparathyroidism with 24h-CCCR <1%. Untreated PHPT increases the risk of renal stones, renal failure, osteoporosis and fracture. Surgical treatment of primary hyperparathyroidism is curative. However, differentiating PHPT from&nbsp;FHH is paramount to avoid unnecessary surgery in a patient with FHH. &nbsp; Clinical Lesson The biochemical picture of PHPT and&nbsp;FHH&nbsp;can be overlapped including 24h-CCCR value. Hence, genetic screening for&nbsp;FHH&nbsp;should be considered routinely in a patient with&nbsp;24h-CCCR < 1% before considering a parathyroid surgery.