CASR Related Disorders - The calcium sensing receptor (CASR) is a plasma membrane G-protein receptor.  Ligand binding results in the activation of signaling cascades causing a decrease in parathyroid hormone(PTH)  secretion from parathyroid chief cells and a reduction of renal tubular calcium absorption. Several disorders have been linked to mutations in the CASR gene.  CASR inactivating or loss of function mutations have been described in hyperparathyroidism, neonatal severe (NSHPT; MIM 239200) and hypocalciuric hypercalcemia, familial, type 1 (HHC1; MIM 145980) and its variant hypercalciuric hypercalcemia.  CASR activating or gain of function mutations have been linked to hypocalcemia, autosomal dominant 1 (HYPOC1; MIM 601198) and its variant hypocalcemia, autosomal dominant 1, with Bartter Syndrome (MIM 601198).  Additionally, CASR mutations have been described in epilepsy, idiopathic generalized susceptibility to, 8 (EIG8; MIM 612899).

Hyperparathyroidism, neonatal severe (NSHPT)

NSHPT is caused by loss of function mutations in CASR.  Homozygous or compound heterozygous mutations are typical but heterozygous mutations have been described.  NSHPT manifests early in life with severe hypercalcemia and bone demineralization. Findings may include failure to thrive, multiple fractures, metaphyseal irregularities, narrow chest, polydipsia, constipation, hepatomegaly and splenomegaly.  The endocrine picture is that of primary hyperparathyroidism with hypophosphatemia, hypercalciuria, hyperphosphaturia, elevated PTH, chief cell hyperplasia and aminoaciduria. NSHPT has been clinically confused with osteogenesis imperfecta and the narrow thorax is reminiscent of Jeune asphyxiating thoracic dystrophy. If untreated, NSHPT may be lethal.

Hypocalciuric hypercalcemia, familial, type 1 (HHC1)

HHC1 is an autosomal dominant disorder caused by loss of function mutations in CASR.  CASR mutations in HHC1 have a high degree of penetrance. HHC1, also known as familial benign hypercalcemia, is characterized by elevated serum calcium and inappropriately low urine calcium with a normal or mildly elevated PTH.  Patients are often asymptomatic but pancreatitis and chondrocalcinosis are known complications.  Hypercalciuric hypercalcemia is considered a variant of HHC1.  In at least one family, a specific CASR mutation when heterozygous is associated with HHC1 but when homozygous causes NSHPT.

Hypocalcemia, autosomal dominant 1 (HYPOC1) and hypocalcemia, autosomal dominant 1, with Bartter syndrome

HYPOC1, also known as hypercalciuric hypocalcemia or hypocalcemia, familial and the related disorder, hypocalcemia, autosomal dominant 1, with Bartter syndrome are caused by gain of function mutations in CASR.  HYPOC1 patients have hypocalcemia with low or normal serum PTH.  About 50% of these individuals are asymptomatic, while the remaining patients have seizures, paresthesias, muscle spasms/tetany and about 10% have hypercalciuria, nephrocalcinosis and renal impairment.  Some patients have been described with calcifications of the basal ganglia or calcifications in other regions of the brain.  Hypocalcemia, autosomal dominant 1, with Bartter syndrome has similar findings to HYPOC1 with the addition of hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia and hyperaldosteronemia. It should be noted that treatment of these patients with vitamin D to correct hypocalcemia can result in hypercalciuria resulting in nephrocalcinosis and kidney failure. Because of this, these patients need to be distinguished from those with other causes of hypoparathyroidism.