Familial hypocalciuric hypercalcemia and related disorders

Abstract

Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit α11, or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-h urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH.

Genetic testing for hereditary hyperparathyroidism and familial hypocalciuric hypercalcaemia in a large UK cohort

“…PHPTH being one of the most common disorders seen in the endocrine clinic represents a significant health burden to the NHS. In 2014, the annual healthcare costs for patients with HPTH were estimated to be USD $37 000 and more than GBP £1000 for treatment 10,23 . Therefore, streamlining the treatment appropriately for a specific diagnosis is crucial to run a cost‐effective service.…”

“…FHH is most commonly caused by inactivating pathogenic variants in the calcium‐sensing receptor gene CASR (FHH1) or rarely by inactivating variants in the G‐protein subunit alpha 11 gene GNA11 (FHH2) and missense variants at the Arg15 residue of the adaptor protein 2 sigma subunit AP2S1 genes (FHH3) 8,9 . All forms of hereditary HPTH are inherited in an autosomal dominant fashion with FHH3 associated with the highest serum calcium levels 10 . Finally, bi‐allelic loss‐of‐function variants in the CASR gene can lead to neonatal severe primary hyperparathyroidism (NSHPT), 11 where severe PHPTH can lead to calcium levels of 4‐8 mmol/L associated with severe parathyroid hyperplasia which is often lethal without urgent total parathyroidectomy.…”

Control of PTH secretion by the TRPC1 ion channel

“…Global deletion of Trpc1 resulted in a phenotype that showed significant similarities to FHH (21,34). Statistically, as a group, patients with FHH exhibit mild but significant hypercalcemia, while a few of them show elevated PTH (5,35), similar to male Trpc1 -/mice. Hypocalciuria, a hallmark of FHH not typically seen in primary hyperparathyroidism (5,36), was also observed in our Trpc1 -/mice.…”

“…In primary hyperparathyroidism often resulting from PTG adenomas, abnormally high levels of PTH result in hypercalcemia, whereas in secondary hyperparathyroidism, frequently seen in renal failure, elevated PTH levels are actually associated with hypocalcemia. Patients with naturally occurring mutations in the gene encoding the Ca 2+ -sensing receptor (CaSR) (1,2), GNA11 encoding G protein subunit α 11 (Gα11) (3), or AP2S1 encoding the clathrin-associated adaptor protein-2 σ subunit 2 (AP2σ2) (4) develop familial hypocalciuric hypercalcemia (FHH), characterized by hypercalcemia and hypocalciuria and, in some cases, by inappropriately elevated levels (5). Proteins encoded by the FHH-associated genes function in a linear signaling pathway within the PTG to suppress production and secretion of PTH in response to hypercalcemia.…”

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

“…FHH is an autosomal dominant disorder characterized by elevated serum Ca 2+ concentrations in association with low Ca 2+ levels in urine. It can also be associated with slightly elevated circulating levels of parathyroid hormone (PTH) and mild hypermagnesemia [44]. FHH type 1 and 2 are usually asymptomatic.…”