Novel PTH gene mutations causing isolated hypoparathyroidism

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Hawkes, Colin P.
Al Jubeh, Jamal M.
Li, Dong
Tucker, Susan E.
Rajiyah, Tara
Levine, Michael A.
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Oxford University Press
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Context: PTH gene mutations represent a rare cause of familial isolated hypoparathyroidism (FIH). These defects can cause hypoparathyroidism with increased or decreased serum levels of PTH through 1) impaired PTH synthesis; 2) induction of parathyroid cell apoptosis; or 3) secretion of bioinactive PTH molecules. Eight pathogenic mutations of this gene have been described previously. Objective: Through describing two novel mutations of the PTH gene, we aim to extend the molecular basis for FIH and further refine the proposed mechanisms by which PTH mutations cause hypoparathyroidism. Design: Proband case reports with extended family analysis. Patients and Other Participants: The probands in both kindreds presented before 10-days-of-age with hypocalcemia and elevated phosphate levels. Proband A had low PTH levels, while these levels were elevated in Proband B. Proband B was initially diagnosed with pseudohypoparathyroidism. Interventions: Methylation analysis of CpG dinucleotides within three GNAS differentially methylated regions; Whole genome sequencing; and PTH infusion with analysis of nephrogenous cyclic AMP. Results: Proband A had a novel heterozygous sequence change in exon 2 of the PTH gene, c.46_47delinsAA (p.Ala16Lys) and Proband B had a novel homozygous nucleotide transition in PTH exon 3 (c.128G>A; p.G43E) that led to replacement of glycine by glutamic acid at position 12 of PTH 1-84. PTH 1-34 infusion demonstrated that renal responsiveness to PTH was intact and not antagonized by circulating bioinactive PTH. Conclusions: PTH gene mutations are uncommon causes of hypoparathyroidism, but can be misdiagnosed as disorders of gland development or receptor function if PTH levels are decreased or elevated, respectively. Genetic testing should be considered early in the diagnostic approach to these presentations.
Parathyroid , Hypoparathyroidism , Hypocalcemia , Genetic , Bioinactive , PTH
Hawkes, C. P., Al Jubeh, J. M., Li, D., Tucker, S. E., Rajiyah, T. and Levine, M. A. (2022) 'Novel PTH gene mutations causing isolated hypoparathyroidism', Journal of Clinical Endocrinology and Metabolism. doi: 10.1210/clinem/dgac086
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© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.