Familial Syndromes of Primary Hyperparathyroidism

Abstract

Regulation of serum calcium in vertebrates is maintained by the actions of the parathyroid glands working in concert with vitamin D and critical target tissues that include the renal tubules, the small intestine, and bone cells. The parathyroid glands release parathyroid hormone (PTH) into the systemic circulation as is required in order to maintain the serum calcium concentration within a narrow physiologic range. Excessive secretion of PTH from one or more abnormal parathyroid glands however results in primary hyperparathyroidism (HPT), a metabolic disease typically associated with abnormally elevated serum calcium. Although HPT is typically a sporadic disease, it can represent a manifestation of an inherited syndrome. Many sporadic parathyroid tumors result from inactivating mutations in tumor suppressor genes that were first discovered by the analysis of genomic DNA from patients with HPT as part of an inherited syndrome. Somatic and inherited alterations in DNA encoding proto-oncogenes can also cause parathyroid neoplasia. Two promising future approaches for the discovery of novel genes pertinent to parathyroid tumor development are the analysis of acquired genetic alterations in DNA isolated from parathyroid tumors and the investigation of familial HPT in kindreds lacking germline mutation in the known genes predisposing to HPT.

A Case Report of Calcium- Sensing Receptor Gene Variant CASR (c.659G>A; p.R220Q) and Primary Hyperparathyroidism

“…Rather, we interpret the variant to be a genetic predisposition to both FHH and PHPT via a common mechanism that requires study, and modifier genes and environmental factors may contribute to the variable expressivity. Using the ACMG guidelines to assign classification [15], the following existing evidence suggests this variant likely contributes to the hypercalcemia in both our PHPT case and the FHH case: (1) This variant is present in only one individual in the Genome Aggregation Database (gnomAD v2.1.1), supporting that it is rare in unselected populations; (2) This variant affects an evolutionarily conserved extracellular domain residue. The extracellular domain is a mutational hotspot for loss-offunction variants; (3) Another missense variant impacting the same amino acid residue, p.R220W, is classified as pathogenic and causes FHH in the heterozygous state and neonatal hyperparathyroidism in the homozygous state, supporting the key role of this residue [13,14]; and (4) in-silico algorithms (SIFT, PolyPhen-2, Align-GVGD) have predicted that the c.659G>A; p.R220Q variant disrupts the structure and function of CaSR (Table 2).…”

“…This G q -protein coupled receptor is predominantly expressed in the parathyroid glands and the renal tubules [1]. In the parathyroid glands, the CaSR senses extracellular calcium concentrations, and beyond a threshold extracellular calcium concentration, it initiates the signaling pathway to decrease the release of parathyroid hormone (PTH) from the parathyroid glands and calcium reabsorption from the renal tubules [1][2][3]. Disorders of calcium metabolism can result from any disturbance in the regulators of calcium homeostasis, including CaSR-mediated signaling pathway defects and PTH-mediated hormonal signaling dysregulation [3].…”

“…The leading cause of hypercalcemia is primary hyperparathyroidism (PHPT), an endocrinopathy marked by autonomous activity of one or more parathyroid gland(s), most commonly due to parathyroid adenomas, followed by hyperplasia and rarely carcinomas [4]. While an estimated 90-95% of PHPT cases are sporadic, 5-10% are hereditary, comprising hereditary hyperparathyroidism (HHPT) [2], which includes syndromic and non-syndromic forms of hyperparathyroidism. Another disease entity considered in the differential diagnosis with PHPT is Familial hypocalciuric hypercalcemia (FHH), a rare autosomal dominantly inherited cause of mild hypercalcemia with clinical manifestations ranging from mostly asymptomatic to mimicking PHPT [5][6][7][8].…”