Disorders of the Calcium Sensing Signaling Pathway: From Familial Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy

Abstract

Familial hypocalciuric hypercalcemia (FHH) is a mostly benign condition of elevated calcium and PTH levels based on a hyposensitive calcium sensing receptor (CaSR) in FHH 1 or its downstream regulatory pathway in FHH2 and FHH3. In children, adolescents and young adults with FHH the main challenge is to distinguish the condition from primary hyperparathyroidism and thereby to avoid unnecessary treatments including parathyroidectomy. However, inheritance of FHH may result in neonatal hyperparathyroidism (NHPT) or neonatal severe hyperparathyroidism (NSHPT), conditions with high morbidity, and in the latter even high mortality. This review focuses on the genetic and pathophysiological framework that leads to the severe neonatal form, gives recommendations for counselling and summarizes treatment options.

Keywords: calcium sensing receptor (CaSR); cinacalcet; familial hypocalciuric hypercalcemia (FHH); neonatal hyperparathyroidism (NHPT); neonatal severe hyperparathyroidism (NSHPT).

Figure 1

The intracellular cascade following ligand (calcium-) binding to the calcium-sensing receptor. Abbreviations: Ca²⁺, calcium; CaSR, calcium sensing receptor; AP2S1, adaptor-related protein complex 2 subunit 2; G_i, inhibitory G-protein; cAMP, cyclic adenosine monophosphate; PLC, phospholipase C; PIP3, phosphatidylinositol-3,4,5-triphosphate; DAG, diacylglycerol; PKC, protein kinase C.

Figure 2

Pathophysiological effects of hypo- and hypercalcemia at the parathyroid glands, the kidneys and the skeleton. Abbreviations: Ca²⁺, calcium; PTH, parathyroid hormone; PTHR1, parathyroid hormone receptor 1; cAMP, cyclic adenosine monophosphate; SLC1A1, solute carrier 1A1; Na⁺, sodium; Cl⁻, chloride; K⁺, potassium.

Figure 3

Change of the set point of the calcium concentration for half maximal PTH secretion in FHH. Abbreviations: FHH, familial hypocalciuric hypercalcemia.

Figure 4

Impact of the in-utero environment on fetal calcium homeostasis in calcium-hyposensitivity disorders. If the fetus is affected by heterozygous CaSR mutations, fetal and maternal calcium needs are concordant (left panel). If the maternal environment is normocalcemic (middle panel) but the fetus affected by a paternally derived or de-novo mutation in CaSR, the maternal environment is perceived as hypocalcemic by the fetus and PTH stimulation arises resulting in NHPT. If both parents are affected by FHH (right panel), the fetus may inherit both mutations and a most severe stimulation of PTH and hypercalcemia arises, a NSHPT. Abbreviations: FHH, familial hypocalciuric hypercalcemia; WT, wild type; NHPT, neonatal hyperparathyroidism; NSHPT, neonatal severe primary hyperparathyroidism.