Adult hypophosphatasia presenting with recurrent acute joint pain

in Endocrinology, Diabetes & Metabolism Case Reports
Authors:
Hayao Yoshida Department of Diabetes and Endocrinology, Shiga General Hospital, Moriyama, Japan
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan

Search for other papers by Hayao Yoshida in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0009-0005-0155-9177
,
Takaaki Murakami Department of Diabetes and Endocrinology, Shiga General Hospital, Moriyama, Japan
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan

Search for other papers by Takaaki Murakami in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0003-3844-1138
,
Atsubumi Ogawa Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

Search for other papers by Atsubumi Ogawa in
Current site
Google Scholar
PubMed
Close
,
Takashi Sunouchi Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan

Search for other papers by Takashi Sunouchi in
Current site
Google Scholar
PubMed
Close
,
Naoko Hidaka Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan

Search for other papers by Naoko Hidaka in
Current site
Google Scholar
PubMed
Close
,
Nobuaki Ito Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan
Division of Therapeutic Development for Intractable Bone Diseases, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

Search for other papers by Nobuaki Ito in
Current site
Google Scholar
PubMed
Close
,
Hiromi Murakami Department of Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

Search for other papers by Hiromi Murakami in
Current site
Google Scholar
PubMed
Close
,
Hidenori Kawasaki Department of Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

Search for other papers by Hidenori Kawasaki in
Current site
Google Scholar
PubMed
Close
,
Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Search for other papers by Tomoyuki Akiyama in
Current site
Google Scholar
PubMed
Close
,
Katsumi Nakajima Department of Diabetes and Endocrinology, Shiga General Hospital, Moriyama, Japan

Search for other papers by Katsumi Nakajima in
Current site
Google Scholar
PubMed
Close
,
Daisuke Yabe Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan

Search for other papers by Daisuke Yabe in
Current site
Google Scholar
PubMed
Close
, and
Taizo Yamamoto Department of Diabetes and Endocrinology, Shiga General Hospital, Moriyama, Japan

Search for other papers by Taizo Yamamoto in
Current site
Google Scholar
PubMed
Close

Correspondence should be addressed to T Murakami: tmurakam@kuhp.kyoto-u.ac.jp
Open access

Summary

Hypophosphatasia (HPP) is a genetic disorder due to pathological variants in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP is typically associated with bone-related symptoms, such as bone deformity, fractures and bone pain in children, but can appear in adults with symptoms resembling arthritis. A 22-year-old male experienced repeated and severe sudden attacks of joint pain in the elbows and knees. Magnetic resonance imaging and joint ultrasonography showed joint effusions indicating chronic inflammation. Blood biochemical tests revealed a remarkably low serum ALP level, and repeated examination confirmed a sustained low ALP level; urine phosphoethanolamine, plasma inorganic pyrophosphate and plasma pyridoxal-5′-phosphate levels were elevated, raising concern for HPP. While the patient had no history of premature loss of primary teeth, fragility fractures, muscle weakness or abnormalities in growth, genetic testing revealed a likely pathogenic and a pathogenic heterozygous variant in the ALPL gene, i.e., c.979T>C (p.Phe327Leu) and c.1559del (p.Leu520Argfs), confirming HPP. Additional genetic testing of his parents showed a heterozygous c.1559del variant in his father and a heterozygous c.979T>C variant in his mother. A diagnosis of adult HPP due to compound heterozygous mutations was therefore confirmed. Enzyme replacement therapy with asfotase alfa was then introduced; no attacks of arthralgia occurred in the 1-year period since then. This case highlights the possibility of HPP in adults who present clinically with repeated joint symptoms and low serum ALP levels but without bone-related symptoms.

Learning points

  • A diagnosis of adult HPP without bone-related symptoms can be challenging.

  • A reduction in tissue-nonspecific ALP activity leads to an accumulation of pyrophosphate in the joints, which can cause arthralgia.

  • Some cases of adult HPP have arthralgia as the only presenting symptom.

  • At one-year follow-up, enzyme replacement therapy with asfotase alfa might lead to a reduction in arthralgia attacks due to HPP.

Abstract

Summary

Hypophosphatasia (HPP) is a genetic disorder due to pathological variants in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP is typically associated with bone-related symptoms, such as bone deformity, fractures and bone pain in children, but can appear in adults with symptoms resembling arthritis. A 22-year-old male experienced repeated and severe sudden attacks of joint pain in the elbows and knees. Magnetic resonance imaging and joint ultrasonography showed joint effusions indicating chronic inflammation. Blood biochemical tests revealed a remarkably low serum ALP level, and repeated examination confirmed a sustained low ALP level; urine phosphoethanolamine, plasma inorganic pyrophosphate and plasma pyridoxal-5′-phosphate levels were elevated, raising concern for HPP. While the patient had no history of premature loss of primary teeth, fragility fractures, muscle weakness or abnormalities in growth, genetic testing revealed a likely pathogenic and a pathogenic heterozygous variant in the ALPL gene, i.e., c.979T>C (p.Phe327Leu) and c.1559del (p.Leu520Argfs), confirming HPP. Additional genetic testing of his parents showed a heterozygous c.1559del variant in his father and a heterozygous c.979T>C variant in his mother. A diagnosis of adult HPP due to compound heterozygous mutations was therefore confirmed. Enzyme replacement therapy with asfotase alfa was then introduced; no attacks of arthralgia occurred in the 1-year period since then. This case highlights the possibility of HPP in adults who present clinically with repeated joint symptoms and low serum ALP levels but without bone-related symptoms.

Learning points

  • A diagnosis of adult HPP without bone-related symptoms can be challenging.

  • A reduction in tissue-nonspecific ALP activity leads to an accumulation of pyrophosphate in the joints, which can cause arthralgia.

  • Some cases of adult HPP have arthralgia as the only presenting symptom.

  • At one-year follow-up, enzyme replacement therapy with asfotase alfa might lead to a reduction in arthralgia attacks due to HPP.

Background

Hypophosphatasia (HPP) is a rare metabolic disorder characterized by a reduced serum alkaline phosphatase (ALP) activity due to variants in ALPL, which encodes a tissue-nonspecific isozyme of ALP. While most HPP patients have bi-allelic or compound heterozygous variants, some with mild forms of HPP carry monoallelic heterozygous variants that exert dominant-negative effects (1). The frequency of recognized genetic variants varies by region, with c.1559del being the most common in Japan, with a carrier rate of 1/480 (2). As the number of Japanese HPP patients with a confirmed diagnosis is currently between 100 and 200, many HPP patients may well be undiagnosed.

HPP is classified into six categories based on symptoms and severity: perinatal (severe), perinatal (benign), infantile, childhood, adult and odontohypophosphatasia. Adult HPP is rare, and the first symptoms appear at 18 years of age or older. In HPP, metabolic abnormalities in the processing of inorganic phosphate from inorganic pyrophosphate can lead to bone fractures, dental abnormalities due to bone hypoplasia, and non-specific symptoms, such as general malaise, myalgia and arthralgia. While HPP typically exhibits bone-related symptoms, such as fractures and bone pain in children, non-bone-related symptoms may represent a clinical obstacle to a prompt diagnosis of HPP in adult cases. We report here a 22-year-old Japanese man with adult HPP whose only complaint on clinical presentation was recurrent joint pain. This case highlights the importance of vigilance for HPP in adult patients with arthralgia and low serum ALP levels but without the typical bone-related conditions.

Case presentation

A 22-year-old man visited an orthopedic clinic for acute right elbow pain with swelling without any overt cause. When he was 20 years old, bilateral knee pain had appeared suddenly but resolved spontaneously. At age 22, he experienced right elbow pain attacks with swelling and visited an orthopedic clinic. Rheumatoid arthritis was suspected, and the patient was referred to the department of rheumatology and clinical immunology in our hospital. While the pain had abated at his first visit, laboratory results revealed a markedly low serum ALP level of 9 U/L (IFCC, reference range (RR): 38–113 U/L) and he was referred to an endocrinologist for a possible metabolic disorder. Neither he nor his family members had a history of premature loss of primary teeth, fragility fractures, muscle weakness, infantile seizure or abnormalities in growth. He was taking multivitamin supplements, including vitamin B6, but was taking no other medications. On initial examination, his vital signs were body temperature 37.0°C, blood pressure 108/86 mmHg, pulse 64 beats/min, height 167.1 cm and body weight 57.6 kg (body mass index: 20.6 kg/m2). There was mild spontaneous pain on forceful knee flexion, but the rest of the physical examination was unremarkable.

Investigation

The laboratory data are presented in Table 1. The serum ALP level was substantially low at 6 U/L (RR: 38–113 U/L); serum bone-specific ALP was also low at 1.9 U/L (RR: 3.7–20.9 U/L). Serum-corrected calcium and inorganic phosphorus levels were 9.4 and 3.8 mg/dL, respectively, with normal levels of intact PTH and 1,25-dihydroxyvitamin D3. Serum C-reactive protein and rheumatoid factor levels were within the reference range, but the matrix metalloproteinase-3 level was slightly elevated (122 ng/mL; RR: 36.9–121 ng/mL). Anti-CCP antibodies were negative.

Table 1

Laboratory data at referral.

Value Reference range
White cell count (/μL) 3800 3300–8600
Red cell count (/μL) 457,000 435,000–555,000
Hemoglobin (g/dL) 13.9 13.7–16.8
Hematocrit (%) 41.4 40.7–50.1
Platelet count (/μL) 364,000 158,000–348,000
Albumin (g/dL) 4.0 4.1–5.1
Creatinine kinase (U/L) 165 59–248
Aspartate aminotransferase (IU/L) 24 13–30
Alanine aminotransferase (IU/L) 22 10–42
Lactate dehydrogenase (IU/L) 154 124–222
ALP (U/L) 7.0 38–113
Blood urea nitrogen (mg/dL) 19.4 8–20
Creatinine (mg/dL) 0.93 0.65–1.07
Sodium (mmol/L) 139 138–145
Potassium (mmol/L) 3.9 3.6–4.8
Chloride (mmol/L) 102 101–108
Magnesium (mg/dL) 2.0 1.8–2.6
Calcium (mg/dL) 9.4 8.8–10.1
Inorganic phosphorus (mg/dL) 3.8 2.7–4.6
Copper (μg/dL) 101 68–128
Zinc (μg/dL) 83 80–130
1,25-Dihydroxyvitamin D3 (pg/mL) 56.4 20–60
Total-P1NP (μg/mL) 59.4 18.1–74.1
Thyroid-stimulating hormone (μIU/mL) 1.74 0.61–4.23
Free thyroxine (ng/dL) 1.21 0.75–1.45
Intact PTH (pg/mL) 18 10–65
TRACP-5b (mU/dL) 394 170–590
Bone-specific ALP (U/L) 1.9 3.7–20.9

ALP, alkaline phosphatase.

X-rays and CT scan of the right elbow and bilateral knees did not show any past or present fractures, but x-rays of the knees showed several small cysts, suggesting repeated and chronic inflammation within the joints (Fig. 1). A full-mouth x-ray showed no physiological dental or skeletal abnormalities. Ultrasound examination of the right elbow and both knee joints showed mild to moderate synovial thickening and increased blood flow, suggesting chronic inflammation within the joints (Fig. 2). T2-weighted magnetic resonance imaging scans of the right elbow and bilateral knees showed high-signal areas within the joints, suggesting effusion and synovial inflammation (Fig. 3). Bone scintigraphy showed a slightly prominent hyperaccumulation in the epiphyseal region but no findings suggestive of a fracture or pseudo-fracture (Fig. 4). Bone density of the femoral neck and lumbar spine was 1.001 g/cm2 (T-score = −0.1) and 0.098 g/cm2 (T-score = +1.0), respectively. A left knee joint fluid puncture was performed in our hospital at a time when there was no joint pain; a large amount of serous joint fluid was obtained, but calcium pyrophosphate crystals could not be noted.

Figure 1
Figure 1

Right elbow x-ray (A) and CT (B) images during right elbow pain at 19 years of age.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 1; 10.1530/EDM-24-0121

Figure 2
Figure 2

Ultrasonography of the right elbow joint (A) and the left knee joint (B).

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 1; 10.1530/EDM-24-0121

Figure 3
Figure 3

MRI T2-weighted (A) and STIR (B) images of the right elbow and STIR (C) of the bilateral knee.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 1; 10.1530/EDM-24-0121

Figure 4
Figure 4

Bone scintigraphy of the patient.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 1; 10.1530/EDM-24-0121

The findings of repeated joint pain and markedly low serum ALP levels suggested the possibility of HPP. Additional evaluation of ALP activities revealed elevated levels of urine phosphoethanolamine (732.4 μmol/gCr; RR: 31.0–110.0 μmol/gCr), plasma pyrophosphate (6.46 μmol/L; RR: 2.36–4.44 μmol/L) (3) and plasma pyridoxal-5′-phosphate (267.6 nmol/L; RR: 20.5–151 nmol/L) (4), which are consistent with a diagnosis of HPP. Subsequent genetic testing of the patient after counseling by a professional genetic counselor revealed two compound heterozygous variants of HPP in ALPL, one pathogenic, i.e. c.1559del, and one likely pathogenic, i.e. c.979T>C. Genetic testing of his parents revealed a heterozygous c.1559delT variant in his father and a heterozygous c.979T>C variant in his mother, both of them having slightly reduced serum ALP of 24 and 31 U/L, respectively (Fig. 5). Based on the clinical symptoms and the laboratory and genetic tests, a diagnosis of adult HPP due to compound heterozygous ALPL variants was confirmed.

Figure 5
Figure 5

Patient’s family tree chart. The patient’s twin brother exhibited severe hypophosphatasia, and his parents also had mild hypophosphatasia. All of them did not present any apparent clinical symptoms. ALP, serum alkaline phosphatase. ALP, alkaline phosphatase.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 1; 10.1530/EDM-24-0121

Treatment

After confirmation of HPP by genetic testing, enzyme replacement therapy was undertaken to prevent or mitigate the recurrent arthralgia. The patient was administered 2 mg/kg asfotase alfa by subcutaneous injection three times a week.

Outcome and follow-up

While the injection site was swollen for about a week after the start of treatment, the swelling relieved spontaneously and the patient experienced no adverse effects thereafter. Six months after the beginning of treatment with asfotase alfa, the patient’s levels of urine phosphoethanolamine (108.4 μmol/gCr; RR: 31.0–110.0 μmol/gCr), plasma pyrophosphate (2.21 μmol/L; RR: 2.36–4.44 μmol/L) and plasma pyridoxal-5′-phosphate (34.8 nmol/L; RR: 20.5–151 nmol/L) were improved to within the normal range. After 1 year of treatment, the patient had experienced no further recurrence of joint pain. Incidentally, he reported 20% improvement in pain when the knees were both strongly flexed in the Brief Pain Inventory – Short Form (BPI-SF).

His identical twin brother had no symptoms except markedly reduced serum ALP (7 U/L) (Fig. 5); he declined additional examination and genetic testing. He will be observed for any fragility fractures or other symptoms that might suggest the onset of adult HPP.

Discussion

We report here the treatment of a rare case of adult HPP, which was characterized by recurrent, sudden episodes of joint pain but without bone-related symptoms. Adult HPP tends to present clinically with relatively mild symptoms and has a better prognosis than pediatric-onset cases. Consequently, the disease often remains undiagnosed, despite the estimated number of ALPL gene variant carriers in Japan. The most frequent variants are c.1559del and c.979T>C among Japanese HPP patients, generally 0.0040 and 0.0014, respectively (5). The compound heterozygous combination of c.1559del and c.979T>C is often found in perinatal and pediatric HPP cases exhibiting mild symptoms. However, reports of adult HPP cases involving these compound heterozygous ALPL variants are few. In the present case, more than 3 years passed from the onset of symptoms to the definitive diagnosis of HPP by genetic testing, primarily due to the non-specificity of the symptoms.

Even so, the recurrent arthralgia in our case played a crucial role in guiding the diagnostic process, as it prompted further investigation into HPP-specific biochemical markers. Extracellular accumulation of pyrophosphate due to reduced TNSALP activities may lead to calcium pyrophosphate dihydrate (CPPD) deposition and arthropathies such as pseudogout (6). In previous reports, joint puncture in several HPP patients revealed CPPD crystals in the joint fluid; prolonged accumulation of CPPD can lead to irreversible destruction of joint structures (6). However, the significance of joint symptoms induced by HPP may well go unrecognized in clinical settings.

A previous study found that 13 of 524 patients in a rheumatology outpatient clinic who presented with arthralgia and low serum ALP levels had abnormalities in the ALPL gene (7). These patients were initially misdiagnosed with rheumatoid arthritis, spondyloarthritis or unclassified myopathies, and approximately 8 years passed from the onset of symptoms to the diagnosis of HPP. Importantly, the present case exhibited repeated arthralgia as the sole and chief complaint. While there are several previous case reports of diagnosis or suspicion of adult HPP on the basis of arthralgia, cases presenting solely with arthralgia are rare. In 2014, three Spanish sisters in whom arthralgia alone raised suspicion of HPP were reported (8). In addition, a case of a 32-year-old Japanese man in whom multiple joint pain led to suspicion of HPP has been reported. In this case, periarticular calcification was found in the right elbow joint and surgical debridement relieved the pain (9). However, the ALPL variant reported in that case was likely pathogenic. The present case underscores the usefulness of plasma pyrophosphate, urinary phosphoethanolamine and plasma pyridoxal-5′-phosphate measurements in identifying adult HPP (1, 3, 4). Regardless of the presence or absence of typical symptoms associated with HPP, close examination of these TNSALP substrates may aid in the diagnosis of HPP. An intriguing aspect of this case is the patient’s monozygotic twin brother, who likely carries the same compound heterozygous mutation and demonstrates low serum ALP levels, yet remains asymptomatic. While the patient who we described reported only acute joint pain episodes, additional investigative approaches revealed chronic joint inflammation through ultrasound examinations, MRI studies and questionnaire-based assessments. In contrast, the twin brother underwent only a basic symptomatic evaluation and declined more extensive diagnostic investigations, including genetic screening. Nonetheless, the potential clinical utility of a comprehensive diagnostic workup, particularly an assessment of ALP substrates, may merit consideration in future management strategies.

Enzyme replacement therapy with asfotase alfa is approved for use in both pediatric-onset and adult-onset cases in Japan, although in European countries and the United States, it is permitted only in pediatric-onset HPP (3). Because reports regarding non-skeletal symptoms of adult HPP are extremely limited, and the treatment is expensive and has not been on the market for a long time (3), this report should offer valuable insights for future treatment of adult HPP. In a previously reported case of adult HPP with periarticular calcification of a large joint, treatment with asfotase alfa improved osteochondrosis and prevented progression of calcification after 12 months of therapy (10). Consistently, in our case, we found that asfotase alfa was also effective in treating recurring arthritis due to HPP, which may offer an additional treatment option to relieve joint symptoms in adult HPP patients.

In conclusion, we treated a case of adult-onset HPP in which repeated arthralgia and low serum ALP levels led to suspicion of adult HPP, which was confirmed by genetic testing and successfully treated with asfotase alfa.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent was obtained from the patient for publication of this case report.

Author contribution statement

HY and TM were involved in diagnosis and management of the patient and in writing manuscript. AO, KN, DY and TY were involved in diagnosis and management of the patient. TS, NH, NI and TA performed biochemical analysis. HM and HK performed genetic analysis. All authors reviewed and approved the final draft.

References

  • 1

    Mornet E . Hypophosphatasia. Best Pract Res Clin Rheumatol 2008 22 113127. (https://doi.org/10.1016/j.berh.2007.11.003)

  • 2

    Michigami T , Tachikawa K , Yamazaki M , et al. Hypophosphatasia in Japan: ALPL mutation analysis in 98 unrelated patients. Calcif Tissue Int 2020 106 221231. (https://doi.org/10.1007/s00223-019-00626-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Hidaka N , Murata H , Tachikawa K , et al. The effect of asfotase alfa on plasma and urine pyrophosphate levels and pseudofractures in a patient with adult-onset hypophosphatasia. JBMR Plus 2023 7 e10842. (https://doi.org/10.1002/jbm4.10842)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Akiyama T , Kubota T , Ozono K , et al. Pyridoxal 5′-phosphate and related metabolites in hypophosphatasia: effects of enzyme replacement therapy. Mol Genet Metab 2018 125 174180. (https://doi.org/10.1016/j.ymgme.2018.07.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Nagata M , Setoh K , Takahashi M , et al. Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: the Nagahama Study. J Hum Genet 2020 65 337343. (https://doi.org/10.1038/s10038-019-0712-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Chuck AJ , Pattrick MG , Hamilton E , et al. Crystal deposition in hypophosphatasia: a reappraisal. Ann Rheum Dis 1989 48 571576. (https://doi.org/10.1136/ard.48.7.571)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Feurstein J , Behanova M , Haschka J , et al. Identifying adult hypophosphatasia in the rheumatology unit. Orphanet J Rare Dis 2022 17 435. (https://doi.org/10.1186/s13023-022-02572-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Guañabens N , Mumm S , Möller I , et al. Calcific periarthritis as the only clinical manifestation of hypophosphatasia in middle-aged sisters: calcific periarthritis in hypophosphatasia. J Bone Miner Res 2014 29 929934. (https://doi.org/10.1002/jbmr.2110)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Iida K , Fukushi J , Fujiwara T , et al. Adult hypophosphatasia with painful periarticular calcification treated with surgical resection. J Bone Miner Metab 2012 30 722725. (https://doi.org/10.1007/s00774-011-0338-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Koga M , Kinoshita Y , Kato H , et al. Massive calcification around large joints in a patient subsequently diagnosed with adult-onset hypophosphatasia. Osteoporos Int 2022 33 505509. (https://doi.org/10.1007/s00198-021-06145-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

  • Collapse
  • Expand
  • Figure 1

    Right elbow x-ray (A) and CT (B) images during right elbow pain at 19 years of age.

  • Figure 2

    Ultrasonography of the right elbow joint (A) and the left knee joint (B).

  • Figure 3

    MRI T2-weighted (A) and STIR (B) images of the right elbow and STIR (C) of the bilateral knee.

  • Figure 4

    Bone scintigraphy of the patient.

  • Figure 5

    Patient’s family tree chart. The patient’s twin brother exhibited severe hypophosphatasia, and his parents also had mild hypophosphatasia. All of them did not present any apparent clinical symptoms. ALP, serum alkaline phosphatase. ALP, alkaline phosphatase.

  • 1

    Mornet E . Hypophosphatasia. Best Pract Res Clin Rheumatol 2008 22 113127. (https://doi.org/10.1016/j.berh.2007.11.003)

  • 2

    Michigami T , Tachikawa K , Yamazaki M , et al. Hypophosphatasia in Japan: ALPL mutation analysis in 98 unrelated patients. Calcif Tissue Int 2020 106 221231. (https://doi.org/10.1007/s00223-019-00626-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Hidaka N , Murata H , Tachikawa K , et al. The effect of asfotase alfa on plasma and urine pyrophosphate levels and pseudofractures in a patient with adult-onset hypophosphatasia. JBMR Plus 2023 7 e10842. (https://doi.org/10.1002/jbm4.10842)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Akiyama T , Kubota T , Ozono K , et al. Pyridoxal 5′-phosphate and related metabolites in hypophosphatasia: effects of enzyme replacement therapy. Mol Genet Metab 2018 125 174180. (https://doi.org/10.1016/j.ymgme.2018.07.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Nagata M , Setoh K , Takahashi M , et al. Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: the Nagahama Study. J Hum Genet 2020 65 337343. (https://doi.org/10.1038/s10038-019-0712-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Chuck AJ , Pattrick MG , Hamilton E , et al. Crystal deposition in hypophosphatasia: a reappraisal. Ann Rheum Dis 1989 48 571576. (https://doi.org/10.1136/ard.48.7.571)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Feurstein J , Behanova M , Haschka J , et al. Identifying adult hypophosphatasia in the rheumatology unit. Orphanet J Rare Dis 2022 17 435. (https://doi.org/10.1186/s13023-022-02572-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Guañabens N , Mumm S , Möller I , et al. Calcific periarthritis as the only clinical manifestation of hypophosphatasia in middle-aged sisters: calcific periarthritis in hypophosphatasia. J Bone Miner Res 2014 29 929934. (https://doi.org/10.1002/jbmr.2110)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Iida K , Fukushi J , Fujiwara T , et al. Adult hypophosphatasia with painful periarticular calcification treated with surgical resection. J Bone Miner Metab 2012 30 722725. (https://doi.org/10.1007/s00774-011-0338-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Koga M , Kinoshita Y , Kato H , et al. Massive calcification around large joints in a patient subsequently diagnosed with adult-onset hypophosphatasia. Osteoporos Int 2022 33 505509. (https://doi.org/10.1007/s00198-021-06145-5)

    • PubMed
    • Search Google Scholar
    • Export Citation