MON-761 Familial Hypocalciuric Hypercalcemia Across Three Generations: Exploring Coexistent Primary Hyperparathyroidism

Abstract Disclosure: L.I. Guerrero Arroyo: None. A.R. Gonciulea: None. S.K. Majumdar: None. Introduction: Familial Hypocalciuric Hypercalcemia (FHH) is an autosomal dominant condition characterized by hypercalcemia, relative hypocalciuria, and non-suppressed parathyroid hormone (PTH) levels, resulting from inactivating mutations in the CASR and associated genes. FHH usually follows a benign course and does not require surgical treatment but occasionally its features overlap with primary hyperparathyroidism (PHPT) making diagnosis and clinical management challenging. We describe three family members harboring a heterozygous variant in the CASR gene associated with FHH in whom calcium levels appear to increase with successive generations and two of whom have kidney stones and osteopenia. Case: Three women from successive generations of the same family were evaluated for hypercalcemia. They presented at ages 60, grandmother (G), 47, mother (M), and 17, daughter (D). Clinical follow up has been available for 10, 13, and 5 years, respectively for G, M, and D. The following laboratory results are notable during follow up (ranges for G, M, D): Calcium (mg/dL) 9.6-11.9, 8.8-12.4, and 11.4-12.5, Phosphorus (mg/dL) 2.5-2.6, 1.1-3.5, 2.4-2.8, Magnesium (mg/dL) 1.9-2.1, 1.5-2.4, 2.2-2.4, PTH (pg/mL) 88-122, 49-118, 34.8-102, 24h urine calcium (mg) 166, 60-248, 93-270, and calcium to creatinine clearance ratios of 0.009, 0.006, and 0.006. Bone density testing (Hologic) revealed a femoral neck (FN) T score of -2.1 at age 67 (G) and FN -1.3, spine -2.4 and distal radius -0.5 (T scores) in the daughter (age 49). G and M both have kidney stones documented on imaging studies and M had a 4D-CT of the neck with equivocal findings suggestive of 2 enlarged parathyroid glands. G had no imaging, and D had a negative parathyroid ultrasound. Genetic testing was performed to differentiate between FHH and PHPT which revealed a heterozygous pathogenic variant in the CASR gene in each patient: NM_000388:exon4:c.C658T:p. R220W (chr3:121980540) [hg19]. Discussion: PHPT and FHH are important to consider in the differential diagnosis of hypercalcemia with non-suppressed PTH since their management approaches differ, making it essential to differentiate between these conditions. We report a family with a R220W variant in the CASR gene in whom some members have features that overlap between PHPT and FHH. The variability in urine calcium, presence of kidney stones and low bone density, and successive generational increase in serum calcium may be features of the R220W variant. It is possible that our patients have independent genetic or sporadic risks for bone loss and kidney stones and the overall benefit of medical or surgical intervention remains uncertain. Presentation: Monday, July 14, 2025