SUN-764 - Which Genes Promote Non-Surgical Biochemical Hypoparathyroidism Beyond Age 70?

A 70-year-old Asian female presented for osteoporosis with secondary osteoporosis workup showing biochemical hypoparathyroidism.

Clinical

Case: A 70-year-old Asian female with past medical history of hypertension, hyperlipidemia, and well-controlled type 2 diabetes mellitus presented for osteoporosis evaluation. She previously took weekly Fosamax inconsistently and supplements with calcium and vitamin D. She denied fractures, steroid use, kidney stones, family history of osteoporosis, or prior head/neck radiation or surgery. She is a non-smoker and non-drinker. Menopause occurred around age 50 without hormone replacement therapy. Last Dual-energy X-ray Absorptiometry (DEXA) showed osteoporosis of the lumbar spine (L1-L4, T-score -2.7), left femoral neck (T-score -2.8), right femoral neck (T-score -3.3), and right hip (T-score -2.5) with osteopenia of the left hip (T-score -2.1). Initial laboratory workup was significant for low parathyroid hormone (PTH) of 11 pg/mL (reference 16-77 pg/mL), serum calcium of 8.9 mg/dL (reference 8.7-10.3 mg/dL), serum phosphorus of 4.7 mg/dL (reference 2.1 - 4.3 mg/dL), serum magnesium of 2.2 mg/dL (reference 1.5-2.5 mg/dL), 25-hydroxyvitamin D of 59 ng/dl (reference > 30 ng/dL), bone specific alkaline phosphatase of 6.7 mcg/L (reference 5.6-29 mcg/L), and 24-hour urine calcium of 392 mg/g creat (reference 30-250 mg/g creat). Chlorthalidone 12.5 mg daily was started, with repeat urine calcium planned in four weeks. With consideration of an activating mutation in the calcium sensing receptor, repeat labs were completed and significant for low PTH of 10 pg/mL, serum phosphorous of 3.8, and estimated glomerular filtration rate of 97 (reference > 59 mL/min/1.73). The patient did not take biotin, which can lead to falsely low PTH levels, and had no known autoimmune conditions. Genetic testing of 18 hypoparathyroidism-associated genes (AIRE, CASR, CHD7, CYP24A1, FAM111A, GATA3, GCM2, GNA11, GNAS, HADHA, HADHB, PDE4D, PTH, PTH1R, SLC34A1, STX16, TBCE, TBX1) was negative. Activating antibodies to the calcium sensing receptor were considered.

This case highlights the incomplete understanding of the genetic basis of hypoparathyroidism, as even comprehensive multi-gene panel testing identifies causative mutations in only 27-35% of patients with non-surgical hypoparathyroidism, suggesting that additional undiscovered genes or regulatory mechanisms likely contribute to this disorder and warrant further investigation through whole exome or whole genome sequencing approaches.

References
Mannstadt M, Cianferotti L, Gafni RI, et al. Hypoparathyroidism: genetics and diagnosis. J Bone Miner Res. 2022
Gafni RI, Collins MT. Hypoparathyroidism. N Engl J Med. 2019
Kemp EH, et al. Activating autoantibodies against the calcium-sensing receptor detected in two patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2009

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