it maintains the plasma calcium level by reabsorbing calcium from the bones and kidney and promoting the production of active vitamin d1 ) .
after thyroid surgery is a common cause of hypoparathyroidism , a congenital disorder is the most common cause in childhood2 ) .
digeorge syndrome , which is associated with deletion of chromosome 22q12 , mutations in the glial cells missing homologue b ( gcmb ) gene , hdr syndrome ( hypoparathyroidism , sensorineural deafness , renal dysplasia ) caused by mutation of the gata3 gene , hrd syndrome ( hypoparathyroidism , retardation , dysmorphism ) caused by a defect in the tbce gene , familial x - linked recessive hypoparathyroidism , mutations of pth genes , and kearns - sayre syndrome resulting from mutations in mitochondrial dna are known causes of congenital hypoparathyroidism1,2 ) .
casr is a 1,078 amino acid g - protein - coupled receptor which consists of an extracellular domain of 612 amino acids , seven transmembrane domains of 250 amino acids and an intracellular domain of 216 amino acids .
although calcium is the endogenous ligand of casr , other cations such as mg , ba , and gd can also bind casr4 ) . the action of casr bound to ions other than ca is unknown3 ) .
casr is widely distributed , but the highest levels are found in the parathyroid gland and kidney tubular cells . its main function is to maintain calcium homeostasis5 ) . in the parathyroid gland ,
parathyroid cells detect small perturbations of the extracellular calcium concentration and modulate the secretion of pth in an inhibitory manner .
extracellular calcium concentration and pth secretion have an inverse sigmoidal relationship with each other5 ) . in the kidney ,
casr is highly expressed on the basolateral side of the cortical thick ascending limb of the loop of henle ( talh ) in rats6 ) .
a high peritubular calcium concentration activates casr and activated casr inhibits transporters in the talh , which subsequently reduces ca and mg reabsorption7 ) . inactivating and activating mutations of casr
inactivating mutations lead to resistance to extracellular calcium , which causes hypercalcemic disorders including familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism8 ) . activating mutations in the casr lead to hyperresponsiveness to extracellular calcium , which causes hypocalcemia with hypercalciuria , a disorder called autosomal dominant hypocalcemia ( adh)9 ) . activating mutations of casr
the association of adh with bartter syndrome ( bs ) has been previously described10,11 ) .
the present case report describes a patient with adh and type v bs due to an activating mutation in the transmembrane domain of casr .
the patient was followed at the seoul national university children 's hospital , inje university busan paik hospital and maryknoll medical center for hypocalcemia , hypokalemia , and hypomagnesemia .
she attended dong - a university hospital and laboratory results showed hypocalcemia , hypomagnesemia , and a low level of pth .
oral calcium , magnesium , and vitamin d supplements were prescribed and the seizures were controlled . however ,
1 ) . at 14 years of age , she suffered weight loss from 48 kg to 43 kg and a loss of appetite .
laboratory testing showed a serum calcium level of 16.9 mg / dl and serum phosphorus of 3.9 mg / dl . her serum creatinine was 1.4 mg / dl and her serum blood urea nitrogen 22.8 mg / dl ( table 1 ) .
she had been prescribed calcium carbonate 1,000 mg / day and alfacalcidol 1.5 g / day before admission ( table 2 ) .
medication was discontinued until serum calcium and phosphorus levels were below the normal range , after which the medications were restarted . at
17 years old , the patient visited hospital complaining of dizziness , nausea , and vomiting .
her serum calcium level was 19.6 mg / dl and her serum potassium 2.8 mg / dl .
calcification of the subcortical and basal ganglia of both frontal lobes was found on brain computed tomography ( fig .
her medication at admission was calcium acetate ( 4,000 mg / day ) , alfacalcidol ( 2.5 g / day ) , hydrochlorothiazide ( 75 mg / day ) , and amiloride ( 6.6 mg / day ) ( table 2 ) .
she had moved from maryknoll medical center to inje university busan paik hospital in busan a month before the second hypercalcemic episode and the dose of alfacalcidol had been increased from 1.25 g / day to 2.5 g / day at her initial visit to inje university busan paik hospital because her serum 25-hydroxy - vitamin d3 ( 25-ohvitd3 ) concentration was just above the lower limit of the normal range .
all medication was discontinued and her serum calcium and potassium concentrations gradually normalized , but because of persistent dizziness she was transferred to seoul national university children 's hospital . on the day after transfer , she complained of paresthesia of her hand and her serum calcium concentration was 8.2 mg / dl .
alfacalcidol and calcium carbonate were administered and the dose of medication was slowly increased to 2 g / day of alfacalcidol and 3,000 mg / day of calcium carbonate .
alfacalcidol was changed to calcitriol 1.0 g / day and she was discharged with 1.0 g / day of calcitriol , 3,000 mg / day of calcium carbonate , and 50 mg / day of thiazide . in the outpatient clinic 2 days after discharge , her calcium carbonate was reduced to 2,000 mg / day because her serum calcium level was elevated to 10.5 mg / dl .
ten days after her outpatient clinic visit , she was admitted again because of high calcium level .
she did not complain of muscle weakness , nausea , or vomiting and she did not appear anxious or depressive .
her height was 153.4 cm ( 5th-10th percentile ) and weight 50 kg ( 25th-50th percentile ) .
she was being treated with oral calcium carbonate ( 2,000 mg / day ) , calcitriol ( 1.0 g / day ) , and hydrochlorothiazide ( 50 mg / day ) ( table 2 ) .
her serum calcium concentration was 18.2 mg / dl ( normal range , 8.8 - 10.5 mg / dl ) , serum phosphorus 3.9 mg / dl ( normal range , 2.5 - 4.5 mg / dl ) , serum magnesium 1.7 meq / l ( normal range , 1.2 - 5 meq / l ) , and serum potassium was 2.8
her pth level was below 5 pg / ml ( normal range , 10 - 65 pg / ml ) ( table 1 ) . all medications were withheld and intravenous hydration was started .
medications were restarted when her calcium concentration reached 9.2 mg / dl and the calcium concentration was maintained at a stable level with 2,000 mg / day of calcium carbonate , 1.5 g / day of alfacalcidol , 12.5 mg / day of hydrochlorothiazide , and 1,800 mg of potassium chloride .
after informed consent was obtained , direct sequencing of all coding exons of casr revealed that the patient had a heterozygous substitution of adenine ( tat ) for guanine ( tgt ) at codon 829 , which would result in substitution of cysteine for tyrosine ( y829c ) in the protein ( fig .
this patient had adh with bs because of a y829c activating mutation of the casr gene .
bs is a genetically heterogeneous disorder with a unifying pathophysiology of decreased salt absorption by the talh . about 30% of sodium and chloride filtered in the glomeruli is reabsorbed in the talh .
defects in the function of proteins associated with sodium reabsorption in talh cause bs12 ) . however , reabsorption not only of sodium , but also of water and of other ions , including calcium , magnesium , and potassium , is influenced .
type 1 bs is caused by a loss - of - function mutation of the apical sodium - potassium - chloride cotransporter gene ( nkcc2 ) .
type 2 bs is caused by mutations in the apical renal outer medullary potassium channel gene ( romk ) .
type iv bs results from a loss - of - function mutation of bsnd , which encodes barttin , the  subunit of clc - k channels that is essential for their function .
casr expressed in the talh is activated by a high extracellular concentration of calcium ions , and activated casr inhibits the nkcc2 and romk in the apical membrane and the sodium potassium atpase in the basolateral membrane of the talh12 ) . in rat kidney ,
cytochrome p-450-dependent metabolites of arachidonic acid and cyclic amp are associated with the inhibitory effect of casr on romk13 ) .
calcium and magnesium in the talh are reabsorbed by a paracellular pathway driven by a positive luminal potential .
potassium excretion through romk is essential to generate this positive luminal voltage relative to the basolateral side , so inhibition of romk blocks the generation of the higher voltage on the luminal side and increases urinary calcium and magnesium excretion10,12 ) .
the clinical presentations and onset timing of bartter 's phenotype differ according to the type of mutation10 ) .
another case reported a patient with k29e mutation , who presented with hypocalcemia and mild hypokalemia without alkalosis , hyperreninemia , and hyperaldosteronemia . in this patient ,
hypokalemia occurred at 22 years old and was corrected with small doses of oral potassium11 ) .
patients with a843e or c131w mutations show the phenotype of bs including nephrocalcinosis , hypokalemia , hypomagnesemia , metabolic alkalosis , hyperreninemia , and hyperaldosteronemia as well as hypocalcemia . in patients with a843e mutation ,
the extracellular calcium concentration at which casr shows half of its maximal activity ( ec50 ) was 2.0 - 2.2
mmol / l ( 8.0 - 8.8 mg / dl ) for casr with k47n or p221l mutations , 1.45 mmol / l ( 5.8 mg / dl ) with the k29e mutation11 ) , and below 0.5
mmol / l ( 2.0 mg / dl ) for casr with a843e or c131w mutations .
the ec50 of the wild - type casr is 3.4 mmol / l ( 13.6 mg / dl ) .
this explains why patients with a843e or c131w mutations have the most severe symptoms of bs .
the onset timing of phenotype of bs also correlates with ec50 ; the lower the ec50 , the faster the onset of bartter 's phenotype10,11 ) . the characteristics of bs were expressed mildly in this patient .
serum potassium concentrations maintained in the normal range until hypokalemia appeared when the patient was about 17 years old . since then , the patient has been taking oral potassium .
this phenotype is similar to that of casr with the k29e mutation , so it could be assumed that the ec50 of casr with the y829c mutation is similar to that of casr with the k29e mutation .
however , this should be cautiously interpreted , as bs can differ between patients who have the same casr mutation11 ) .
the patient in this case had nephrocalcinosis and basal ganglia calcification . in one study of patients with casr mutation ,
basal ganglia calcification was found in 9 of 25 patients ( 36% ) and nephrocalcinosis was present in 3 of 25 patients ( 12%)14 ) . in another study ,
hypercalciuria was associated with nephrocalcinosis15 ) , but basal ganglia calcification and nephrocalcinosis were not related to the severity of hypocalcemia14 ) .
the first episode occurred when she was 14 years old and the others when she was 17 years old .
hypercalcemic episodes during the treatment of adh have been reported previously14,15 ) , and occurred in patients who had taken a high dose of alfacalcidol . during her first hypercalcemic episode , our patient suffered fever and severe weight loss . the volume loss and
the continuous medication might have caused the hypercalcemia . before the second event , her dose of alfacalcidol was increased because of low serum 25-ohvitd3 , although her serum calcium concentration remained in the normal range .
thus , an overdose of alfacalcidol might have induced the hypercalcemia . in the third hypercalcemic episode ,
the patient denied overdose of medication , infection , or over consumption of foods high in calcium .
but , considering the increase of serum calcium concentration from 7.6 mg / dl to 10.5 mg / dl 2 days after discharge , the doses of calcium and vitamin d3 supplementation were probably too high for the patient .
when symptoms disappear , medication doses should be adjusted to maintain serum calcium above the level that symptoms persisted . when increasing the doses of medications , special attention should be taken not to cause hypercalcemia . in conclusion , our paper reports a novel y829c mutation of casr .
the patient with this casr gene mutation had a mild phenotype of bs in addition to adh .
 the calcium sensing receptor ( casr ) plays an important role in calcium homeostasis . activating mutations of casr cause autosomal dominant hypocalcemia by affecting parathyroid hormone secretion in parathyroid gland and calcium resorption in kidney . 
 they can also cause a type 5 bartter syndrome by inhibiting the apical potassium channel in the thick ascending limb of the loop of henle in the kidney . 
 this study presents a patient who had autosomal dominant hypocalcemia with bartter syndrome due to an activating mutation y829c in the transmembrane domain of the casr . 
 symptoms of hypocalcemia occurred 12 days after birth and medication was started immediately . 
 medullary nephrocalcinosis and basal ganglia calcification were found at 7 years old and at 17 years old . 
 three hypercalcemic episodes occurred , one at 14 years old and two at 17 years old . 
 the bartter syndrome was not severe while the serum calcium concentration was controlled , but during hypercalcemic periods , the symptoms of bartter syndrome were aggravated . 
Introduction
Case report
Discussion