Case Report: A Diagnostic Challenge in Adult‐Onset Hypophosphatasia With Persistent Polyarthralgia

An 18-year-old woman had been experiencing polyarthralgia for 3 years. Her main complaints were bilateral knee joint pain, bilateral hip joint pain, and bilateral Achilles tendon enthesitis. There was no apparent joint swelling or associated skin lesions. Her height was 160 cm, and her weight was 53.0 kg. Laboratory findings showed a C-reactive protein (CRP) level of 0.01 mg/dL and an erythrocyte sedimentation rate (ESR) of 9 mm/h. Both rheumatoid factor and anti-cyclic citrullinated peptide antibody were negative. Alkaline phosphatase (ALP) was low at 31 U/L (normal range: 38–113 U/L). The ALP value was consistently low in multiple tests. Calcium was 9.3 mg/dL (reference range: 8.3–10.1 mg/dL), and phosphorus was 3.7 mg/dL (reference range: 2.7–4.6 mg/dL), both within the normal range. No other significant abnormalities were detected. Radiographs did not reveal joint deformities or evidence of healed fractures. Calcified lesions in the knee joint, hip joint, or Achilles tendon were not observed. There were also no findings of nephrocalcinosis. Bone scintigraphy showed no accumulation suggestive of arthritis, osteomyelitis, or microfractures was observed (Figure 1). Bone densitometry was conducted to investigate the potential reduction in bone mineral density (BMD) associated with osteomalacia or abnormalities in bone mineralization. Bone densitometry revealed a BMD of 1.004 g/cm2 with a T-score of −0.3 in the lumbar spine and 0.825 g/cm2 with a T-score of −0.6 in the femoral neck. The reference values for BMD in healthy young Japanese women are 0.989 ± 0.112 g/cm2 for the lumbar spine and 0.806 ± 0.088 g/cm2 for the femoral neck, with a T-score of −1.0 or higher considered normal [1]. The BMD in this case was within the normal range. Laboratory tests revealed a low ALP level; although her mother was asymptomatic, she also exhibited low ALP levels. Considering the possibility of adult-onset hypophosphatasia (HPP) despite the absence of a history of apparent fractures or tooth loss, genetic testing for mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase, was performed. Genetic testing revealed a heterozygous variant of the c.613G>A (p.Ala205Thr) in the ALPL gene. Based on the findings from the low level of ALP and ALPL gene analysis, a suspected diagnosis of adult-onset HPP was made. In the diagnosis of adult-onset HPP, it is necessary to meet either two major criteria or one major criterion along with two minor criteria. The major criteria include (a) the presence of a pathogenic or likely pathogenic ALPL gene variant, (b) elevated levels of natural substrates, (c) atypical femoral fractures (pseudofractures), and (d) recurrent metatarsal fractures. The minor criteria consist of (a) poorly healing fractures, (b) chronic musculoskeletal pain, (c) early atraumatic loss of teeth, (d) chondrocalcinosis, and (e) nephrocalcinosis [2]. However, this case fulfills only one major criterion of low ALP levels and the presence of an ALPL gene variant, in addition to one minor criterion of musculoskeletal pain. Therefore, the diagnostic criteria for adult-onset HPP are not satisfied in this case. Enzyme replacement therapy with asfotase alfa (AA) is under consideration as a potential treatment strategy. Enzyme replacement therapy using AA has been approved in numerous countries, including the United States, the European Union, Canada, and Japan. A Japanese clinical trial demonstrated the efficacy of AA in treating patients with HPP [3]. In Japan, AA is covered by health insurance, and the establishment of treatment guidelines facilitates its accessibility and availability for healthcare professionals and patients. This contrasts with countries lacking insurance coverage or regulatory approval for this therapy in adult-onset HPP [4]. There are several challenges in diagnosing adult-onset HPP. First, the severity and symptoms of adult HPP vary widely, making the diagnosis difficult [5]. Additionally, adult HPP often remains undiagnosed for an average of approximately 10 years after symptom onset [6]. Many patients are initially misdiagnosed with other conditions, such as osteoporosis or fibromyalgia, which can lead to inappropriate treatments [5]. In cases such as this, where chronic musculoskeletal pain is present without evidence of fractures or joint calcification, establishing a diagnosis becomes particularly challenging. The diagnosis of HPP cannot be confirmed without the identification of an ALPL gene variant through genetic testing. Adult-onset HPP, if left untreated, has been reported to result in persistent chronic musculoskeletal pain (52.5%), dental abnormalities (42.6%), fatigue (23.4%), recurrent fractures (22.0%), and generalized pain (22.0%) [7]. These findings underscore the critical importance of early diagnosis and timely initiation of appropriate treatment. To confirm a diagnosis of adult-onset HPP, clinicians must consider a combination of clinical findings, consistently low ALP levels, and genetic testing for the ALPL gene variant. R.K. designed the report. R.K., Y.M., H.H., M.C., N.M., and T.A. contributed to the manuscript writing. R.K. and Y.M. handled data collection responsibilities. R.K., Y.M., H.H., M.C., N.M., and T.A. reviewed and approved the final manuscript. The authors have nothing to report. Informed consent was obtained from the patient for the publication of this report and the accompanying images. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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