Patients with benign familial hypocalciuric hypercalcemia (FHH) possess inactivating mutations of the CaSR gene, specifically in a heterozygous manner. As a result, there is either complete or partial loss of function of one CaSR allele. This genetic alteration leads to an elevated setpoint for parathyroid hormone (PTH) secretion, requiring higher levels of calcium (Ca++) to suppress PTH release. Furthermore, the CaSR is normally expressed in the thick ascending limb of the renal tubule, where it inhibits Ca++ reabsorption in response to increased blood Ca++ levels. In individuals with FHH, the reduced ability of the CaSR in the kidney to sense and respond to elevated blood Ca++ levels results in hypocalciuria despite hypercalcemia.

Parathyroid hormone–related peptide (PTHrP) is a peptide hormone that acts as a paracrine factor and is produced by various adult tissues including the skin, hair, and breast. It plays a role in regulating proliferation and differentiation in these tissues. PTHrP also contributes to the relaxation of smooth muscle in response to stretching in blood vessels, uterus, and bladder. During lactation, PTHrP promotes bone resorption in the mother and facilitates the transport of calcium into breast milk. In the context of development, PTHrP regulates calcium transport across the placenta and is a key regulator of chondrocyte proliferation and differentiation in the growth plate of long bones. Notably, the N-terminus of PTHrP shares significant structural homology with parathyroid hormone (PTH). While PTHrP is not regulated by circulating Ca++ and does not typically play a role in calcium and phosphate homeostasis in adults, certain tumors can secrete excessive amounts of PTHrP, leading to hypercalcemia of malignancy and symptoms resembling hyperparathyroidism.

The active form of vitamin D, known as 1,25-(OH)2D3, is involved in the hormonal regulation of calcium and phosphate metabolism. It facilitates the absorption of calcium and phosphate in the small intestine and also plays a role in bone remodeling and renal reabsorption of calcium and phosphate.

Vitamin D3, or cholecalciferol, is synthesized from 7-dehydrocholesterol through the action of ultraviolet B (UV-B) light. This conversion occurs primarily in the basal layers of the skin. Chemically, vitamin D3 is classified as a secosteroid, as it involves the opening of one of the cholesterol rings. Once synthesized, vitamin D3 undergoes further transformations in the liver and kidneys to produce the biologically active form, 1,25-dihydroxyvitamin D. This active metabolite exerts its effects on various tissues including the gut, bone, and kidney.
Patientswithbenign familial hypocalciuric hypercalcemia (FHH) areheterozygousforinactivatingmutationsoftheCaSR.Inthesepatients,becauseofcompleteorpartiallossofoneCaSRallele,higherlevelsof[Ca++]arerequiredtosuppressPTHsecretion.Thisresultsinanelevated[Ca++]setpointforPTHsecretion,accountingforthehypercalcemia.TheCaSRisalsoexpressedinthethickascendinglimboftherenaltubule,whereitnormallyinhibitsCa++ reabsorptionwhenbloodCa++ rises.ThehypocalciuriainthefaceofhypercalcemiainFHHisduetothereducedabilityoftheCaSRinthekidneytosenseandrespondtoelevatedblood[Ca++]byincreasingCaexcretion.
Parathyroid hormone–related peptide (PTHrP) isapeptideparacrinehormoneproducedbyseveraladulttissues(skin,hair,breast),whereitmayregulateproliferationanddifferentiation.Italsoplaysaroleinrelaxationofsmoothmuscleinresponsetostretchinbloodvessels,uterus,andbladder.Duringlactation,PTHrPpromotesmaternalboneresorptionandthetransportofcalciumintomilk.Duringdevelopment,PTHrPregulatescalciumtransportacrosstheplacentaandisakeyregulatorofchondrocyteproliferationanddifferentiationinthegrowthplateoflongbones.The30aminoacidsattheN-terminusofPTHrPhavesignificantstructuralhomologywithPTH.PTHrPisnotregulatedbycirculatingCa++ andnormallydoesnotplayaroleinCa/Pihomeostasisinadults.However,certaintumorssecretehighlevelsofPTHrP,whichcauseshypercalcemia of malignancy andsymptomsthatresemblehyperparathyroidism.
Hormonal Regulation of Calcium and Phosphate Metabolism 1,25-(OH)2D3 24,25-(OH)2D3 •Fig. 40.5 Biosynthesisof1,25-dihydroxyvitaminD.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.) and to a lesser extent Pi absorption by the small intestine. It also regulates bone remodeling and renal reabsorption of Ca and Pi.
Structure, Synthesis, and Transport of Active Vitamin D Metabolites
Vitamin D3 (also called cholecalciferol) is synthesized via conversion of 7-dehydrocholesterol by ultraviolet B •Fig. 40.6 VitaminDmetabolism.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)7-Dehydrocholesterol Vit D-DBP and Vit D-chylomicron 25(OH) Vit D-DBP Vit D-chylomicron Lymphatic Vit D-DBP 1,25-Dihydroxyvitamin D Portal blood Caval blood Peripheral blood Vitamin D3 Enterocyte Dietary vitamin D3 and vitamin D2 Vit D UV-B Hepatocyte Vit D 25-Hydroxyvitamin D 25-Hydroxylase 24-Hydroxylase 24-Hydroxylase25-Hydroxyvitamin D 24,25-Dihydroxyvitamin D 1, 25-Dihydroxyvitamin D 1,24,25-Trihydroxyvitamin D Biological effects at gut, bone, kidney, etc. 1˜-Hydroxylase (UVB) light in the more basal layers of the skin (Fig. 40.6 ). Chemically, vitamin D3 is a secosteroid in which one of the cholesterol rings is opened (see