ODP118 PTH (1-34) Replacement Therapy for Hypoparathyroidism due to Sporadic Calcium Sensing Receptor Gain-of-Function Point Mutation
Authors: Basina Marina , Bhalla Vivek , Shah Nandi 
Published: November 2022

Abstract

Background
The calcium sensing receptor (CASR) regulates parathyroid hormone secretion in response to extracellular calcium concentration. A gain-of-function mutation of the CASR lowers the set point for extracellular calcium sensing, resulting in both reduced parathyroid hormone secretion and increased urinary calcium excretion compared to other causes of hypoparathyroidism.

Clinical Case
After presenting with hypocalcemia-associated seizures at the age of two years, our patient had an undetectable serum parathyroid hormone level. He was started on calcitriol and calcium supplementation, however continued to have recurrent seizures throughout childhood. On ultrasound at age four, he exhibited nephrocalcinosis. DNA sequence analysis revealed a heterozygous T383G mutation nucleotide substitution on exon 3, resulting in the replacement of phenylalanine with cysteine at amino acid position 128. Our patient's base substitution likely represents a de novo mutation as we have confirmed that he has no family history of hypocalcemia. Notably, a different missense mutation at the same codon (F128L) co-segregated with autosomal dominant hypocalcemia in a large family, and functional studies confirm that mutation of this phenylalanine provides gain-of-function to the CASR. After enrolling in a clinical trial for continuous recombinant parathyroid hormone infusion at age seven, his symptoms of hypocalcemia abated. His seizures stopped, and anti-epileptic drugs were discontinued at age eight. After the clinical trial concluded, he was switched to teriparatide 10 micrograms three times daily, and serum calcium was maintained between 7.5 and 8.5 mg/dL. With the goal to minimize hypercalciuria and reduce the frequency of injections, teriparatide was discontinued, and recombinant parathyroid hormone (Natpara) 50 micrograms daily was started. This led to symptomatic hypocalcemia with muscle cramping and cognitive changes, and he was thus restarted on teriparatide with calcium carbonate supplementation. Despite maintenance of 24-hour urine calcium excretion ranging 325-388 mg, he developed bilateral flank pain. Computed tomography images revealed worsening nephrocalcinosis and bilateral nephrolithiasis. To reduce hypercalciuria and risk of stone formation, he was started on chlorthalidone, switched to calcium citrate, and encouraged to reduce dietary sodium intake.

Conclusion
This patient has a novel T383G activating mutation in CASR gene resulting in hypoparathyroidism and type 5 Bartter syndrome that has not been previously published in the literature. His hypocalcemia has remained stable on teriparatide for over 18 years, which to our knowledge, is the longest treatment duration using recombinant human parathyroid hormone for this purpose. We demonstrate a unique clinical challenge to balance treatment of hypoparathyroidism and hypocalcemia with teriparatide and supplemental calcium, while minimizing hypercalciuria and associated nephrocalcinosis.
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