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

Abstract

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 FHH 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 FHH. PHPT patients are generally older and has a history of normal serum calcium with a new onset hypercalcemia. Endocrine society guideline suggests using 24h-CCCR (calcium-to-creatinine clearance ratio) to differentiate with 24h-CCCR <1% as an indicator for FHH and >2% as an indicator for PHPT. Case A 28 years-old African American lady with bipolar disorder is noted to have asymptomatic hypercalcemia in the range of 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). 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. 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. Plasma metanephrine was normal. Due to 24h-CCCR <1%, a genetic panel for FHH was performed. She has FHH1 with heterozygous mutation at CASR (c.1972C>T). Discussion FHH is an autosomal-dominant disease with a loss of function mutation at CASR (FHH1), GNA11 (FHH2) or AP2S1 (FHH3). FHH1 is the most common and constitutes 65-90% of FHH. It has a high degree of penetrance. Loss-of-function mutation in 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. Family history of hypercalcemia and 24h-CCCR <1% suggest FHH. However, the urinary calcium excretion in patients with PHPT and FHH can also be overlapped. In the study reported by Bertocchio et al, 2% of FHH had 24h-CCCR values over 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 FHH and PHPT or FHH 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 FHH is paramount to avoid unnecessary surgery in a patient with FHH. Clinical Lesson The biochemical picture of PHPT and FHH can be overlapped including 24h-CCCR value. Hence, genetic screening for FHH should be considered routinely in a patient with 24h-CCCR < 1% before considering a parathyroid surgery.