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: 10–65 pg/mL) while her serum ALP, calcium, and inorganic phosphate levels were normal (527 U/L, normal range: 395–1289 U/L; 9.5 mg/dL, normal range: 8.8–10.6 mg/dL; 5.9 mg/dL, normal range: 3.8–6.2 mg/dL, respectively). Her percentage of tubular reabsorption of phosphate (%TRP) was elevated (96.9%, normal range: 80–95%). Her urine calcium/creatinine level was reduced (0.019, normal range: 0.035–0.80), and her urine cross-linked N-telopeptide of type I collagen (NTX) level was 1340 nmol BCE/mmol creatinine (normal range: 369–2385 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 (). 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: 20–100 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 ().
Lower-limb radiograph. The epiphyses were calcified. 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 μg/dL, normal range: 64–118 μg/dL). Mild elevation of the urine phosphoethanolamine (PEA) level (279.1 μmol/g creatinine, normal range: 83–222 μmol/g creatinine) suggested hypophosphatasia (4
Therefore, we analyzed the ALPL gene for a diagnosis of hypophosphatasia. 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. Primer sequences and PCR conditions are available on request.
An ALPL heterozygous mutation, c.1559delT, was detected in the patient and her father (), but no mutation was detected in her mother. The serum ALP level of her father was mildly reduced (84 U/L, normal range: 96–284 U/L) and that of her mother was normal (180 U/L). Therefore, the patient and her father were diagnosed as carriers of hypophosphatasia. Her father had no history of bone fracture or abnormal skeletal findings. It was unknown whether he had presented genu varum during childhood.
ALPL analysis in the patient’s family. Black dots indicate heterozygous ALPL carriers (c.1559delT).