idiopathic hypoparathyroidism is an unusual endocrine deficiency characterized by 
 hypocalcemia with a decreased level of serum pth . familial hypoparathyroidism may occur as either 
 isolated endocrinopathies with autosomal dominant , autosomal recessive , or x - linked 
 recessive transmission , or as part of complex congenital anomalies such as the digeorge ( mim 
 no.188400 ) , kenny - caffey ( mim no.244460 ) and hypoparathyroidism - deafness - renal dysplasia 
 ( hdr ) ( mim no.146255 ) syndromes ( 1,2,3 ) . the mechanisms 
 underlying at least some of the recessively inherited forms have been characterized as 
 mutations in the pth gene ( 4 , 5 ) . on the other hand , activating mutations of the calcium - sensing 
 receptor ( casr ) gene have been identified in some cases of autosomal dominant 
 hypoparathyroidism or autosomal dominant hypocalcemia ( adh ; mim no.146200 ) ( 6,7,8,9,10,11 ) . hdr 
 syndrome , which is caused by mutations of the dual zinc finger transcription factor ( gata3 ) 
 gene , is also an autosomal dominant disorder ( 3 ) . recently , we experienced a female neonatal case of familial hypoparathyroidism with an 
 autosomal dominant pattern of transmission . early diagnosis and treatment were required 
 because the patient had severe hypocalcemia on the fifth day after birth . we report here the 
 clinical course of our patient and describe the molecular analysis of the casr gene in both 
 the patient and her mother . the patient was a female neonate , delivered by cesarean section at 37 wk and 6 d of 
 gestation because of breech presentation . the patient s mother had been 
 diagnosed with idiopathic hypoparathyroidism at the age of 9 yr , and had been receiving 
 vitamin d treatment since then . her serum calcium concentration was maintained between 7.2 
 and 8.5 mg / dl by oral administration of 6.0 g / day of 1(oh)d3 and 4.0 mg / day of 
 trichlormethiazide before and during pregnancy . her serum phosphorus levels , serum magnesium 
 levels , serum intact pth levels , and urinary calcium / creatinine ( ca / cr ) ratio were 5.15.9 
 mg / dl , 1.61.8 mg / dl , 313 pg / ml and 0.1040.305 mg / mg , respectively . furthermore , there is no history of hearing impairment or renal disease on 
 the mother s side . at birth , the patient s serum calcium concentration was 8.4 mg / dl , but it 
 fell to 4.0 mg / dl on the fifth day after birth . , 
 she had a body temperature of 37.1c , a heart rate of 165 /min , and a respiratory rate of 50 
 /min . small fistulas were found in front of both ears . there were no abnormal findings on 
 the chest or abdomen . laboratory findings showed a low serum calcium level of 4.0 mg / dl ( normal range : 8.610.2 
 mg / dl ) , an elevated serum phosphorus level of 9.6 mg / dl ( normal range : 4.07.0 mg / dl ) , and a 
 low serum magnesium level of 1.4 mg / dl ( normal range : 1.82.6 mg / dl ) ( table 1table 1 . laboratory findings on admission ) . additionally , the patient s urinary ca / cr ratio was 0.3 mg / mg . on 
 endocrinological investigation , serum concentrations of intact pth and 1,25(oh)2d were 21 
 pg / ml ( normal range : 1065 pg / ml ) and 81.8 pg / ml ( normal range : 2070 pg / ml ) , respectively 
 ( table 1 ) . based on these findings , the patient was 
 diagnosed with familial hypoparathyroidism . as shown in fig . 1 . clinical course of the present case after admission to the pediatric ward . , oral administration of 1(oh)d3 ( 0.1 g / kg / day ) and continuous intravenous infusion 
 of 8.5% calcium gluconate were immediately initiated after admission . magnesium sulphate 
 ( 0.5 m , 0.5 ml / kg ) was intravenously administered twice for hypomagnesemia . on day 9 , 
 1(oh)d3 was increased to a dose of 0.2 g / kg / day . furthermore , trichlormethiazide ( 0.1 
 mg / kg / day ) was orally administered because the patient s urinary ca / cr ratio was elevated to 
 0.7 mg / mg . the patient s serum calcium concentration improved thereafter and was normalized 
 on day 25 . the patient was discharged on day 31 , and since then has been followed up at our outpatient 
 clinic with oral medication of 1(oh)d3 ( 0.2 g / kg / day ) and trichlormethiazide ( 0.1 
 mg / kg / day ) . abdominal ct and auditory brainstem responses ( abr ) have revealed no 
 abnormalities since discharge . recent laboratory findings have shown a serum calcium level 
 of 10.1 mg / dl , a serum phosphorus level of 5.9 mg / dl , a serum magnesium level of 1.8 mg / dl , 
 a serum intact pth level of 5 pg / ml and a urinary ca / cr ratio of 0.19 mg / mg . at present ( age 
 of 5 yr ) , the patient s growth and psychomotor development are normal . in our patient , adh due to an activating mutation in the casr gene was suspected because of 
 autosomal dominant hypoparathyroidism with hypomagnesemia and relative hypercalciuria . on 
 the other hand , hdr syndrome is unlikely since the patient has neither hearing impairment 
 nor kidney anomaly . this study was approved by the local ethics committee of jikei university school of 
 medicine . first , genomic dna was extracted from the patient s and her mother s white blood 
 cells by standard procedures after informed consent was obtained from the patient s parents . polymerase chain reaction ( pcr ) was then carried out using specific primers to amplify exons 
 27 of the casr gene , encompassing the entire coding sequence ( table 2table 2 . primers designed for the amplification and sequencing of the dna fragments of 
 the casr gene ) . sequencing analysis was performed by the dideoxy method using a terminator 
 cycle sequencing kit ( applied biosystems , foster city , ca ) . in the present study , the 
 sequences of all six exons of the casr gene were investigated , but no mutation was found in 
 either the patient or her mother . familial dominant hypoparathyroidism is an uncommon condition that can come to clinical 
 attention at any point in life . in 1994 , pollak et al . first reported that an activating 
 mutation in the casr gene can be a cause of adh ( 6 ) . the casr is a g protein - coupled receptor that plays key roles in mineral ion , fluid and 
 electrolyte homeostasis ( 12 ) . the binding of calcium 
 ion to casr on parathyroid cells decreases pth secretion ; thus , casr determines the 
 set - point of pth secretion by acting as a calcium sensor . patients with activating mutations 
 in the casr gene exhibit hypocalcemia , hyperphosphatemia , hypomagnesemia , and abnormally low 
 pth levels ( 6 , 8,9,10 , 13,14,15 ) . however , the clinical presentation 
 is variable , ranging from asymptomatic forms to severe neonatal seizures ( 11 ) . hyperphosphatemia , 
 hypomagnesemia , and a serum intact pth level too low to maintain normocalcemia were also 
 found . it 
 is reported that vitamin d therapy in patients with activating casr mutations often results 
 in disproportionate hypercalciuria ( 7 , 13 , 16 ) , and 
 thiazide diuretics are therefore administered to reduce urinary ca excretion at any level of 
 serum ca ( 17 ) . actually , in this case subsequent 
 therapy with 1(oh)d3 and trichlormethiazide was effective for hypocalcemia and 
 hypercalciuria . moreover , a recent report suggested that screening of the casr mutation 
 should be considered in hypoparathyroidism patients with relative hypercalciuria or with a 
 family history of hypocalcemia ( 18 ) . in view of these 
 findings , adh due to the activating mutation in the casr gene was clinically suspected for 
 our patient and her mother , but molecular analysis found no mutation in either individual . this result leads us to speculate that the patient s hypoparathyroidism may have been caused 
 by an abnormality in a gene other than casr . however , the gata3 mutation causing hdr 
 syndrome is unlikely in our case because of isolated hypoparathyroidism without hearing 
 impairment or kidney anomaly . to clarify the molecular basis of familial hypoparathyroidism 
 such as we report here , further investigation is required . in summary , we have described a neonatal case of autosomal dominant hypoparathyroidism 
 without mutation of the casr gene . regular measurement of serum calcium , phosphorus , pth 
 concentrations and urinary ca / cr ratio after birth is necessary for neonatal patients who 
 have a parent with idiopathic hypoparathyroidism .
we experienced a case of familial hypoparathyroidism with an autosomal dominant 
 pattern of transmission and performed molecular analysis of the calcium - sensing receptor 
 ( casr ) gene . 
 the patient was a female neonate , born by cesarean section at term because of 
 breech presentation . 
 her mother had been diagnosed with idiopathic hypoparathyroidism at 
 the age of 9 yr and had been receiving vitamin d treatment since then . at birth , 
 the 
 patient s serum calcium concentration was 8.4 mg / dl , but it fell to 4.0 mg / dl on the fifth 
 day after birth . furthermore , her serum intact pth level was inappropriately low , while 
 hyperphosphatemia and hypomagnesemia were found . 
 she was diagnosed with familial 
 hypoparathyroidism , and was immediately started on oral administration of 1(oh)d3 ( 0.1 
 g / kg / day ) and continuous intravenous infusion of 8.5% calcium gluconate . additionally , 
 trichlormethiazide was administered because of elevated urinary calcium / creatinine ( ca / cr ) 
 ratio . 
 her serum calcium concentration gradually improved thereafter . in this case , 
 autosomal dominant hypocalcemia ( adh ) due to abnormality in the casr gene was clinically 
 suspected , but dna sequencing analysis revealed no mutation of the casr gene in either the 
 patient or her mother . 
 this result suggests that the patient s hypoparathyroidism may have 
 been caused by abnormality in a gene other than casr .