Three Siblings With Familial Isolated Hypoparathyroidism: A Diagnostic Journey From to Novel Variant.

We report a patient who initially presented at 4 days old with hypocalcemia, hypoparathyroidism, and elevated phosphorous level. Treatment was initiated with calcitriol, calcium carbonate (CaCO), vitamin D, and low phosphorous formula. Family history was positive for an activating calcium sensing receptor () variant (R990G) identified previously in 2 older siblings who were treated with CaCO and calcitriol. However, genetic studies were negative for the variant in our patient. She maintained a large calcium requirement and was admitted for multiple episodes of hypocalcemia. Further investigation revealed that the variant identified in the older siblings was now considered a benign, nondisease-causing variant. Whole exome sequencing on our proband revealed a homozygous pathogenic variant in the gene (Gln392*) consistent with a molecular diagnosis of familial isolated hypoparathyroidism. Genetic studies revealed the 2 older siblings harbor the same genetic changes and parents are heterozygous carriers for this allele. Due to persistent hypocalcemia, we initiated teriparatide. She weaned off calcitriol and achieved normocalcemia on teriparatide, CaCO, and vitamin D. Siblings transitioned to the same treatment without complications. These findings demonstrate the importance of adequate diagnostic genetic testing and the role of variant reanalysis over time in promoting accurate diagnoses.