elevated serum alkaline phosphatase ( alp ) level is an essential marker for the diagnosis of vitamin d deficiency ( 1 ) .
some cases of vitamin d deficiency are diagnosed accidentally on the basis of elevated alp levels .
therefore , cases without high alp may be excluded from a diagnosis of vitamin d deficiency .
hypophosphatasia is a congenital skeletal disease caused by mutation of the alpl gene , which encodes the alp isozyme , tissue - nonspecific alkaline phosphatase ( tnsalp ) ( 2 ) .
hypophosphatasia is characterized by severe reduction of alp as well as various skeletal abnormalities such as rickets . since most cases are transmitted as an autosomal recessive trait , those heterozygous for alpl mutation are carriers who exhibit a low or normal alp level ( 3 ) .
here , we describe a case of vitamin d deficiency without an elevated alp level in a patient that proved to be a heterozygous carrier of hypophosphatasia .
a 1-year - old japanese girl was referred to our hospital for the evaluation of genu varum . she had no history of bone fractures . at her initial visit , her serum intact pth level was elevated ( 273 pg / ml , normal range : 1065 pg / ml ) while her serum alp , calcium , and inorganic phosphate levels were normal ( 527 u / l , normal range : 3951289
u / l ; 9.5 mg / dl , normal range : 8.810.6 mg / dl ; 5.9 mg / dl , normal range : 3.86.2 mg / dl , respectively ) . her percentage of tubular reabsorption of phosphate ( % trp ) was elevated ( 96.9% , normal range : 8095% ) .
her urine calcium / creatinine level was reduced ( 0.019 , normal range : 0.0350.80 ) , and her urine cross - linked n - telopeptide of type i collagen ( ntx ) level was 1340 nmol bce / mmol creatinine ( normal range : 3692385 nmol bce / mmol creatinine ) .
additional measurement of serum 25-hydoxyvitamin d ( 25-ohd ) was not performed , because of normal serum alp levels . on limb radiography ,
calcification of epiphyses was detected , and both flaring and fraying of metaphyses were also detected slightly ( fig .
therefore , the patient was initially diagnosed with spontaneously half - healed vitamin d deficiency rickets and was followed closely without treatment . however , 3 months later , her serum intact pth level remained elevated and serum 25-ohd level was reduced ( 6 ng / ml , normal range : 20100 ng / ml ) . the patient was subsequently diagnosed with vitamin d deficiency .
the serum intact pth level improved immediately after initiation of alfacalcidol administration and has not been elevated since the end of treatment .
in addition , her serum alp level decreased gradually ( table 1table 1 laboratory data ) .
the metaphyses were flared and frayed slightly . although these courses of treatment support the diagnosis of vitamin d deficiency , the relatively low alp level was atypical . low serum zinc level , which is one of the causes of reduced alp level , was not identified ( 71 g / dl , normal range : 64118 g / dl ) .
mild elevation of the urine phosphoethanolamine ( pea ) level ( 279.1 mol / g creatinine , normal range : 83222 mol / g creatinine ) suggested hypophosphatasia ( 4 ) .
genomic dna was extracted from peripheral blood leukocytes of the patient and her parents after obtaining written informed consent .
all coding exons and flanking introns of alpl were analyzed using the pcr direct sequencing method .
an alpl heterozygous mutation , c.1559delt , was detected in the patient and her father ( fig .
black dots indicate heterozygous alpl carriers ( c.1559delt ) . ) , but no mutation was detected in her mother . the serum alp level of her father was mildly reduced ( 84 u / l , normal range : 96284
u / l ) and that of her mother was normal ( 180 u / l ) .
this is the first report of vitamin d deficiency without an elevated serum alp level in a carrier of hypophosphatasia .
vitamin d deficiency is reemerging worldwide ( 5 ) , and elevated serum alp is a hallmark of this disease ( 1 ) .
vitamin d deficiency may fail to be diagnosed if serum alp is not elevated . however , simultaneous measurement of the serum intact pth level is helpful for diagnosis .
measurement of urine pea was useful for the diagnosis of hypophosphatasia in the present case .
while severe elevation of the urine pea level ( approximately > 1000 mol / g creatinine in childhood ) is detected in patients with hypophosphatasia , mild elevation suggests carrier status of this disease ( 3 ) .
the alpl mutation c.1559delt is the most common mutation in japanese patients with hypophosphatasia ( 6 ) .
a homozygous c.1559delt mutation is involved in the perinatal lethal form of hypophosphatasia with a severe reduction in serum alp ( 6 ) .
the heterozygous mutation is found in carriers who present various levels ( either low or normal ) of serum alp without skeletal abnormality ( 3 ) .
furthermore , urine pea levels also range from normal to high in such individuals ( 3 ) .
the frequency of carriers is predicted to be high ( 1/480 ) ( 3 ) .
since vitamin d deficiency is reemerging , the present case should be kept in mind , as the possibility of such conditions occurring more frequently is high .
vitamin d deficiency rickets was reported to be associated with the infantile form of hypophosphatasia in a 9-month - old boy ( 7 ) . in that report , although the serum alp level increased from 66 u / l at baseline to 400 u / l at diagnosis , it decreased soon after treatment .
on the other hand , the present case was considered to be mild vitamin d deficiency because of the mild elevation of serum alp level and lack of clinical findings of active rickets . in conclusion ,
an alpl heterozygous mutation was detected in a patient with vitamin d deficiency without an elevated serum alp level .
measurement of serum intact pth and urine pea levels is helpful for diagnosing vitamin d deficiency and identifying carriers of hypophosphatasia , respectively .
   elevated serum alkaline phosphatase ( alp ) is a screening marker for the diagnosis of vitamin d deficiency , which may fail to be diagnosed if serum alp is not elevated . here 
 , we describe a case of vitamin d deficiency without elevation of serum alp . 
 a 1-year - old japanese girl was referred to our hospital for the evaluation of genu varum . 
 her serum intact pth level was elevated , while her serum alp level was normal . 
 furthermore , her serum 25-hydroxyvitamin d level was reduced , and her urine phosphoethanolamine ( pea ) level was mildly elevated . 
 alpl gene analysis revealed she was a heterozygous carrier of hypophosphatasia ( c.1559delt ) . 
 serum intact pth and urine pea evaluations were helpful for diagnosing vitamin d deficiency and hypophosphatasia carrier status , respectively . 
 therefore , the possibility of vitamin d deficiency without elevation of serum alp should be considered . 
Introduction
Case Report
Discussion