Endocrine Abstracts

Hypoparathyroidism is a rare endocrine disorder characterized by inadequate production of parathyroid hormone to maintain normal blood calcium levels. Hypoparathyroidism is most frequently caused by damage to or removal of the parathyroid glands but can also be associated with genetic etiologies. Genetic forms of hypoparathyroidism can present as isolated or as part of a syndrome and include disorders of parathyroid gland formation, parathyroid hormone secretion, and damage to the parathyroid gland through autoimmunity. A sponsored genetic testing program in the United States was made available for patients with suspected genetic hypoparathyroidism who met program eligibility criteria and included those with an idiopathic diagnosis. The next-generation sequencing panel leveraging a whole exome backbone with copy number variant detection has evolved to include 26 genes known to be associated with hypoparathyroidism: ACADM, AIRE, ATP1A1, CASR, CHD7, CLDN16, CLDN19, CNNM2, DHCR7, EGF, FAM111A, FXYD2, GATA3, GCM2, GNA11, HADHA, HADHB, KCNA1, NEBL, PTH, SEMA3E, SLC12A3, SOX3, TBCE, TBX1 and TRPM6. A total of 169 samples over a 2-year period were tested from participants with a mean±D age of 23.4±20.4 (range 0-81). With the multi-gene panel, 77 variants were identified in 64 individuals (37.9%) which have been classified as pathogenic, likely pathogenic, and variants of uncertain significance. In order of frequency, the number of individuals with detected variants are as follows: CASR 56.3% (36/64), AIRE 12.5% (8/64), TBX1 9.38% (6/64), GATA3 7.8% (5/64), GNA11 6.25% (4/64), CHD7 3.13% (2/64), FAM111A 3.13% (2/64), PTH 3.13% (2/64), ACADM 1.6% (1/64), GCM2 1.6% (1/64), HADHB 1.6% (1/64) and TBCE 1.6% (1/64). Of note, 5 individuals had variants identified in more than 1 gene. Within this group of participants, the most frequent genetic form of hypoparathyroidism was found to be autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function mutations in the CASR gene (21.3%; 36/169). An ongoing global Phase 3 study is investigating an oral calcilytic that functions as a negative allosteric modulator of the calcium-sensing receptor, potentially the first targeted treatment for ADH1, which affected over half of individuals with identified variants. Genetic testing should be considered for all patients with non-surgical hypoparathyroidism as identified variants in known genes can inform medical management of patients. Genetic testing may uncover the underlying etiology of nonsurgical hypoparathyroidism and can help confirm clinical diagnosis, guide medical treatment, identify affected family members, and assist in determining eligibility for participation in clinical studies.