SAT-730 - A Case of Familial Hypocalciuric Hypercalcemia Type 3 Presenting with Chronic Polyuria and A Misleading 24-Hour Urinary Calcium

Introduction:
Familial hypocalciuric hypercalcemia type 3 (FHH3) accounts for 20% of FHH cases and is caused by mutations in AP2S1, leading to decreased calcium-sensing receptor (CaSR) internalization and signaling. FHH3 is the most severe subtype, with higher calcium and PTH levels compared with FHH1/2. More than 20% of patients are symptomatic; neurocognitive deficits, low bone mineral density, cardiac arrythmias and pancreatitis have been reported. Because of biochemical overlap with primary hyperparathyroidism (PHPT), FHH3 is frequently misdiagnosed. We present a case of FHH3 initially misdiagnosed as PHPT. Our patient had persistent polyuria despite mild hypercalcemia, raising the possibility of a CaSR-mediated mechanism including AVP-resistance.
Clinical

Case:
A 36-year-old man was found to have hypercalcemia on routine laboratory testing in late 2009. Symptoms over preceding months included fatigue, one syncopal episode, chronic polyuria, and polydipsia. His maternal grandmother had kidney stones. Neither his mother nor his five siblings were known to have hypercalcemia. His father’s history was unknown. He had no prior fractures or nephrolithiasis. Initial laboratory evaluation showed serum calcium 10.9 mg/dL, ionized calcium 6.5 mg/dL, inappropriately normal PTH 76 pg/mL, vitamin D 12 ng/mL. 24-hour urine calcium was 266 mg, but urine creatinine and volume were unavailable, and hence calculation of the fractional excretion of calcium (FeCa) was not possible. DXA showed normal bone density. Parathyroid SPECT and neck ultrasound were non-localizing. He underwent four-gland parathyroid exploration in November 2010. All glands showed mild hyperplasia, and half a gland was reimplanted into the right pectoralis muscle. Intraoperative PTH decreased from 143 to 53 pg/mL, and postoperative calcium normalized but later increased to 10.6 mg/dL with non-suppressed PTH on follow up three months later. Fourteen years later, he re-presented with persistent hypercalcemia of 11.2 mg/dL, PTH 31 pg/mL, vitamin D 27 ng/mL, FeCa 0.53%, and ongoing polyuria (3L/24h). Genetic testing identified a heterozygous pathogenic variant in the AP2S1 gene consistent with FHH3.

Discussion:
Familial forms of hypercalcemia including FHH should be considered in young patients presenting with PTH-dependent hypercalcemia, even without family history, as de novo cases have been reported. A 24-hour urine calcium excretion in the absence of concurrent urinary creatinine measurement can be misleading, as demonstrated in our polyuric patient, and may obscure the diagnosis of FHH, even in the setting of vitamin D deficiency. While polyuria has not been reported in FHH, severe CaSR signaling defects in FHH3 could theoretically contribute. Cinacalcet may restore CaSR signaling, though its role in FHH remains unproven. Patient declined further polyuria evaluation due to minimal symptoms.

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