A 14-year-old boy is brought to the emergency department after accidental ingestion of a chicken bone that lodged in his esophagus. Upper endoscopy is performed and the bone is successfully removed. However, the patient is incidentally found to have mild hypercalcemia on laboratory testing. On follow-up with his primary care provider 2 weeks later, he has no symptoms and clinical examination is unremarkable. Further questioning reveals that several of his family members also have mild hypercalcemia. Subsequent laboratory studies show a borderline high parathyroid hormone concentration, very low urinary calcium level, and normal 25-hydroxyvitamin D level. A mutation in which of the following receptors is most likely responsible for this patient's laboratory abnormalities?

Question

A 14-year-old boy is brought to the emergency department after accidental ingestion of a chicken bone that lodged in his esophagus.  Upper endoscopy is performed and the bone is successfully removed.  However, the patient is incidentally found to have mild hypercalcemia on laboratory testing.  On follow-up with his primary care provider 2 weeks later, he has no symptoms and clinical examination is unremarkable.  Further questioning reveals that several of his family members also have mild hypercalcemia.  Subsequent laboratory studies show a borderline high parathyroid hormone concentration, very low urinary calcium level, and normal 25-hydroxyvitamin D level.  A mutation in which of the following receptors is most likely responsible for this patient's laboratory abnormalities?

Quizplus · Accepted Answer

11ec160b_36b0_2f31_9249_eb5826e612dd_MD0001_00 Calcium-sensing receptors (CaSRs) are transmembrane G_q protein-coupled (metabotropic) receptors that regulate the secretion of parathyroid hormone (PTH) in response to changes in circulating calcium levels. Binding of calcium to CaSRs leads to the inhibition of PTH release, whereas low calcium levels allow increased PTH release. Familial hypocalciuric hypercalcemia (FHH) is a benign autosomal dominant disorder caused by defective CaSRs in the parathyroid gland and kidneys. In FHH, higher serum calcium levels are required to suppress the secretion of PTH. This raises the set point of calcium-induced regulation of PTH secretion. Patients with FHH have mild asymptomatic hypercalcemia, reduced urinary excretion of calcium, and high normal or mildly elevated PTH. (Choice A) Steroid hormones, thyroid hormone, and vitamin D act by binding to intracellular receptors with DNA-binding domains that interact with the regulatory DNA sequences of target genes. (Choice C) Transmembrane ligand-gated ion channels (ionotropic receptors) allow a regulated flux of calcium, sodium, potassium, and chloride ions across the cell membrane. Neurotransmitters that work via ion channel-linked receptors include acetylcholine, serotonin, N-methyl-D-aspartate, and gamma-aminobutyric acid. (Choice D) Insulin and insulin-like growth factor work by stimulating transmembrane receptors with intrinsic tyrosine kinase activity in the intracellular domain, initiating a downstream phosphorylation cascade. (Choice E) Janus kinase (JAK) is a cytoplasmic protein activated by ligand binding to transmembrane receptors. JAKs activate cytoplasmic transcription factors called signal transducers and activators of transcription (STAT), which enter the nucleus to promote gene transcription. Examples of hormones using a JAK/STAT messenger system include erythropoietin, growth hormone, and prolactin. Educational objective: Calcium-sensing receptors are G protein-coupled receptors that regulate the secretion of parathyroid hormone in response to changes in circulating calcium levels. Familial hypocalciuric hypercalcemia is a benign autosomal dominant disorder caused by defective calcium-sensing receptors in the parathyroid gland and kidneys. __________ References: Familial hypocalciuric hypercalcaemia: a review. (http://www.ncbi.nlm.nih.gov/pubmed/21986511)

A 14-Year-Old Boy Is Brought to the Emergency Department After