SUN-750 - Family Matters: A Case of Atypical Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a rare, autosomal dominant genetic disorder defined by lifelong asymptomatic hypercalcemia and inappropriately low urinary calcium excretion. These features are paradoxically accompanied by mildly elevated parathyroid hormone (PTH) levels. The disorder is most frequently caused by a heterozygous inactivating mutation in the calcium sensing receptor (CASR), but can also be caused by mutations in GNA11 (FHH type 2) and AP2S1 (FHH type 3). FHH has virtually a complete penetrance in people who inherit the pathogenic gene, and most individuals with a pathogenic mutation will show some biochemical features of the disease. Differentiating FHH from primary hyperparathyroidism is clinically important. FHH is benign and does not require surgical intervention, while primary hyperparathyroidism may necessitate parathyroidectomy.

A 55-year-old man with a past medical history significant for renal artery thrombosis, prediabetes, obstructive sleep apnea, benign prostatic hyperplasia, and hyperlipidemia presented to outpatient clinic for follow-up concerning intermittent hypercalcemia. On initial presentation, his serum calcium was mildly elevated to 10.4 mg/dL. He reported taking vitamin D supplementation (1000 IU daily) and mentioned his mother (age 94) had a lifelong history of hypercalcemia. He denied a personal history of nephrolithiasis, and a renal ultrasound (US) from years prior was negative for renal calculi. Initial laboratory workup showed vitamin D level of 31.5 ng/mL, PTH 31 pg/mL and slightly improved calcium of 10.1 mg/dL. However, on further follow up visits, calcium was again elevated to 10.6 mg/dL on basic metabolic panel. This prompted further evaluation. Results showed a urine calcium of 12.1 mg/dL and fractional excretion of calcium (FeCa) 0.011, serum phosphorus 3.1 mg/dL, PTH 23 pg/mL, serum calcium 10.2 mg/dL and ACE level 37 U/L, PTH-rP level < 2.0 pmol/L. Subsequently, the patient revealed his daughter was found to have elevated calcium levels, as well. Given his family history and lab findings suspicious for FHH, genetic testing was pursued. The assay found a deletion of one amino acid (isoleucine) in the calcium-sensing receptor (CASR) protein.

This case presents a patient with confirmed CASR gene mutation whose clinical picture did not fully align with the classic FHH lab findings. Although the patient had persistently elevated serum calcium levels and had a family history of hypercalcemia, his FeCa was borderline to slightly above the traditional diagnostic threshold for FHH ( < 0.01). These findings highlight the varied expression of FHH. The identified CASR mutation, single isoleucine deletion, has not previously been reported in literature. The significance of this deletion is not definitively known, however, it likely explains the patient’s history of mild hypercalcemia and his family history.

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