Testing for Genetic and Other Causes

Nonsurgical Hypoparathyroidism

Although most cases of hypoparathyroidism (hypoPT) are secondary to surgery, a significant proportion (20% to 25%) are due to other etiologies, including autoimmune and genetic causes.

Autoimmune polyendocrine syndrome type 1 (APS1) is an important cause of nonsurgical hypoPT. During the evaluation of the patient, a careful history is beneficial. It is important to consider other causes of nonsurgical hypoPT. These include genetic causes as well as infiltrative causes due to granulomatous disease, such as amyloidosis. Deposition of minerals, such as copper or iron, can also damage the parathyroid glands. Another (albeit rare) cause of hypoPT is metastatic disease. Radiation (both radioactive iodine and external beam radiation) has been reported to cause hypoPT. Magnesium deficiency is another potential cause of hypoPT, because magnesium is a cofactor for adenylate cyclase. Hypermagnesemia can also cause hypoPT, as magnesium binds to the calcium-sensing receptor and decreases the synthesis and secretion of parathyroid hormone (PTH). Lastly, severe burns or acute illness can also result in hypoPT.

A genetic cause should be suspected in young people, especially those with lifelong hypocalcemia. A family history may be present and should be carefully reviewed. Evaluation for syndromic features is helpful, as this will determine the gene panel to be completed in order to identify a molecular diagnosis for the hypoPT. The algorithm shown in Figure 2-2 can help identify a genetic cause of hypoPT.

There are many genetic testing modalities, most of which are now offered commercially, which can be used to confirm a genetic etiology of hypoPT. Some companies have developed hypoPT-specific panels, which include all known candidate genes and sequence the exons and exon-intron boundaries within those genes. Ultimately, the choice of test depends on the nature of the suspected mutation. For suspected syndromic causes of hypoPT, the locus or loci associated with the syndrome should be tested first, either by Sanger sequencing or next-generation sequencing. For non-syndromic hypoPT, testing should include sequencing of the CASR, GNA11, GCM2 and PTH genes. Chromosomal rearrangements and insertion/deletions, such as those that occur in the vicinity of the SOX3 locus, can be detected via chromosomal microarray, array comparative genomic hybridization , fluorescence in situ hybridization and similar techniques.

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