MON-775 - PTH Driven Hypercalcemia - Thinking Beyond Primary Hyperparathyroidism

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant condition most commonly caused by a pathogenic variant in the calcium-sensing receptor (CASR) gene. FHH results in lifelong, typically asymptomatic, hypercalcemia. The hallmark of FHH is a relatively low urine calcium excretion, which helps distinguish the diagnosis from primary hyperparathyroidism (pHPT). Retrospective chart review at a single tertiary care referral center revealed 29 patients (20F, 9M) with a rare variant in CASR (8 pathogenic, 7 likely pathogenic, and 12 variants of unknown significance) or adaptor protein-2 sigma subunit (AP2S1) (1 pathogenic). Mean age of diagnosis was 38 years. Taking an average of the first three calcium levels following presentation, the mean calcium was 10.8 mg/dL (reference range 8.6-10.3 mg/dL). Sixteen (55%) had a maximum parathyroid hormone level at least 20 units higher than the upper limit of normal (65 pg/mL). Nine patients (31%) did not undergo a complete 24H-urinary calcium/creatinine collection, two of whom had surgical procedures. Of the 20 patients in which a Ca/Cr ratio could be calculated, two (10%) were too low for detection, 11 (55%) were below the common FHH threshold ( < 0.01), and seven (35%) were >0.01. There was a pertinent family history in the majority of patients (18, 62%), with six (32%) having at least one first/second degree relative who underwent a parathyroidectomy. Nineteen patients were referred to surgery via endocrinology (14, 74%) or primary care (5, 26%). During their surgical consult, seven (37%) patients were sent for genetic evaluation, which resulted in appropriately cancelled procedures. Forty-one percent (12) of patients underwent parathyroidectomy – ten (83%) prior to genetic evaluation and two (17%) following a genetic diagnosis under the assumption of concomitant pHPT. Following surgery, two (17%) patients had resolution of hypercalcemia. There were no incidences of postoperative hypoparathyroidism. While rare, FHH must be considered in the evaluation of hypercalcemia. Endocrinologists should obtain detailed family history and the appropriate biochemical evaluation, including 24-hour urinary calcium and creatinine in all patients, prior to surgical referral, to avoid potentially unnecessary procedures with associated morbidity.

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