{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:12:09Z","timestamp":1793211129676,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Alexion AstraZeneca Rare Disease"},{"name":"Ordensklinikum Linz and Duke University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hypophosphatasia (HPP) is the rare metabolic disorder caused by variants in the ALPL gene, resulting in deficient activity of tissue-nonspecific alkaline phosphatase (ALP). This leads to accumulation of substrates contributing to impaired bone mineralization. Hypophosphatasia manifests with a broad clinical spectrum; however, an increasing number of individuals with ALPL variants have been identified presenting the hallmark biochemical feature of HPP of low serum ALP activity, with or without elevated serum pyridoxal-5-phosphate (PLP) or urine phosphoethanolamine (PEA), while remaining asymptomatic. These ALPL carriers may represent a distinct subgroup within the HPP continuum, prompting the need for clearer classification. Using data from the Global ALPL Gene Variant Database, we identified 43 subjects who fulfilled the following criteria: low ALP (adjusted for age\/sex), at least one ALPL variant, and no overt or reported HPP-related symptoms. Their median age was 29\u00a0yr (range 0-64); 23 were female. Serum ALP activity was reduced in all cases, with 76% of subjects showing levels less than 50% below the lower limit of normal. In 19 of 43 individuals, PLP or PEA was also elevated. Thirty distinct genotypes were observed; 79% of subjects were heterozygous, while 21% harbored homozygous or compound heterozygous variants. The identified variants were largely missense (77%), mostly affecting regions without a specific domain (38%). Five variants showed a dominant-negative effect in vitro, yet produced no clinical manifestations. Some identified genotypes were also linked to adult, childhood, or odontohypophosphatasia phenotypes, underscoring significant genotype-phenotype variability. These findings refine our understanding of the HPP spectrum, identifying a cohort of asymptomatic ALPL carriers with biochemical phenotype of HPP. Recognizing this group is important for improving diagnostic criteria and preventing overdiagnosis and unnecessary treatment. Longitudinal studies are needed to clarify follow-up strategies and determine whether these individuals develop clinical manifestations later in life or remain asymptomatic.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf124","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T11:58:15Z","timestamp":1757505495000},"page":"259-269","source":"Crossref","is-referenced-by-count":9,"title":["Biochemical phenotype of hypophosphatasia in asymptomatic individuals carrying\n                    <i>ALPL<\/i>\n                    variants"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8579-1048","authenticated-orcid":false,"given":"Rodrigo","family":"Montero-Lopez","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz , 4021 Linz ,","place":["Austria"]},{"name":"Centre for Growth and Osteology, Department of Paediatrics and Adolescent Medicine, Kepler University Hospital GmbH , 4020 Linz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4419-8421","authenticated-orcid":false,"given":"Mariam R","family":"Farman","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz , 4021 Linz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"H\u00f6gler","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz , 4021 Linz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Rehder","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University Medical Center , Durham, NC 27705 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora","family":"Malli","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz , 4010 Linz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Webersinke","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz , 4010 Linz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl","family":"Rockman-Greenberg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Child Health Max Rady College of Medicine, Rady Faculty of Health Sciences , Winnipeg, MB R3A 1S1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Dahir","sequence":"additional","affiliation":[{"name":"Program for Metabolic Bone Disorders, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel \u00c1ngel","family":"Martos-Moreno","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Ni\u00f1o Jes\u00fas, IIS La Princesa , 28009 Madrid ,","place":["Spain"]},{"name":"Department of Pediatrics, Universidad Aut\u00f3noma de Madrid , 28029 Madrid ,","place":["Spain"]},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n. ISCIII , 28029 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3455-002X","authenticated-orcid":false,"given":"Agn\u00e8s","family":"Linglart","sequence":"additional","affiliation":[{"name":"AP-HP, Paris Saclay University, INSERM, Bic\u00eatre Paris Saclay Hospital , 94270 Le Kremlin-Bic\u00eatre ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Ozono","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Osaka University Graduate School of Medicine , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1154-3388","authenticated-orcid":false,"given":"Lothar","family":"Seefried","sequence":"additional","affiliation":[{"name":"Musculoskeletal Center W\u00fcrzburg, University Hospital W\u00fcrzburg , 97080 W\u00fcrzburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"del Angel","sequence":"additional","affiliation":[{"name":"Centre for Genomics Research, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca , Boston, MA 02210 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica Burner","family":"Nading","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center , Durham, NC 27705 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Huggins","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center , Durham, NC 27705 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric T","family":"Rush","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetics, Children's Mercy Hospital Kansas City , Kansas City, MO 64108 ,","place":["United States"]},{"name":"Department of Pediatrics, University of Missouri-Kansas City School of Medicine , Kansas City, MO 64108 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6079-4653","authenticated-orcid":false,"given":"Josephine T","family":"Tauer","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz , 4021 Linz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya S","family":"Kishnani","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center , Durham, NC 27705 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4328-6304","authenticated-orcid":false,"given":"Wolfgang","family":"H\u00f6gler","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz , 4021 Linz ,","place":["Austria"]},{"name":"Centre for Growth and Osteology, Department of Paediatrics and Adolescent Medicine, Kepler University Hospital GmbH , 4020 Linz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"2026030310315344000_ref1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.bone.2017.02.011","volume-title":"Bone","author":"Whyte","year":"2017"},{"issue":"20","key":"2026030310315344000_ref2","doi-asserted-by":"publisher","first-page":"7666","DOI":"10.1073\/pnas.85.20.7666","article-title":"A missense mutation in the human liver\/bone\/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia","volume":"85","author":"Weiss","year":"1988","journal-title":"Proc Natl Acad Sci"},{"key":"2026030310315344000_ref3","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.bone.2018.01.022","article-title":"Hypophosphatasia: biochemical hallmarks validate the expanded pediatric clinical nosology","volume":"110","author":"Whyte","year":"2018","journal-title":"Bone"},{"key":"2026030310315344000_ref4","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.jpeds.2016.01.045","article-title":"A diagnostic algorithm for children with low alkaline phosphatase activities: lessons learned from laboratory screening for hypophosphatasia","volume":"172","author":"Saraff","year":"2016","journal-title":"J Pediatr"},{"key":"2026030310315344000_ref5","first-page":"286","article-title":"Infantile hypophosphatasia: localization within chromosome region lp36.1-34 and prenatal diagnosis using linked DNA markers","volume":"46","author":"Greenberg","year":"1990","journal-title":"Am J Hum Genet"},{"key":"2026030310315344000_ref6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.bone.2019.05.031","article-title":"Tissue non-specific alkaline phosphatase activity and mineralization capacity of bi-allelic mutations from severe perinatal and asymptomatic hypophosphatasia phenotypes: results from an in vitro mutagenesis model","volume":"127","author":"Uday","year":"2019","journal-title":"Bone"},{"key":"2026030310315344000_ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2023.116947","article-title":"The global ALPL gene variant classification project: dedicated to deciphering variants","volume":"178","author":"Farman","year":"2024","journal-title":"Bone"},{"issue":"4","key":"2026030310315344000_ref8","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/nrendo.2016.14","article-title":"Hypophosphatasia-aetiology, nosology, pathogenesis, diagnosis and treatment","volume":"12","author":"Whyte","year":"2016","journal-title":"Nat Rev Endocrinol"},{"issue":"1","key":"2026030310315344000_ref9","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/1471-2350-10-51","article-title":"Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles","volume":"10","author":"Fauvert","year":"2009","journal-title":"BMC Med Genet"},{"issue":"4","key":"2026030310315344000_ref10","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1136\/jmg-2024-110383","article-title":"Disease burden by ALPL variant number in patients with non-life-threatening hypophosphatasia in the Global HPP Registry","volume":"62","author":"Kishnani","year":"2025","journal-title":"J Med Genet"},{"key":"2026030310315344000_ref11","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.jpeds.2019.01.049","article-title":"Natural history of perinatal and infantile hypophosphatasia: a retrospective study","volume":"209","author":"Whyte","year":"2019","journal-title":"J Pediatr"},{"key":"2026030310315344000_ref12","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1111\/j.1749-6632.2010.05387.x","article-title":"Physiological role of alkaline phosphatase explored in hypophosphatasia","volume":"1192","author":"Whyte","year":"2010","journal-title":"Ann N Y Acad Sci"},{"issue":"2","key":"2026030310315344000_ref13","first-page":"280","article-title":"Hyperphosphatemia in infantile hypophosphatasia: implications for carrier diagnosis and screening","volume":"46","author":"Chodirker","year":"1990","journal-title":"Am J Hum Genet"},{"issue":"2","key":"2026030310315344000_ref14","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41431-020-00732-6","article-title":"Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation","volume":"29","author":"Mornet","year":"2021","journal-title":"Eur J Hum Genet"},{"issue":"5","key":"2026030310315344000_ref15","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1097\/00005792-197909000-00001","article-title":"Adult hypophosphatasia. Clinical, laboratory, and genetic investigation of a large kindred with review of the literature","volume":"58","author":"Whyte","year":"1979","journal-title":"Medicine"},{"issue":"1","key":"2026030310315344000_ref16","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1007\/s00223-025-01356-y","article-title":"Diagnosis and treatment of hypophosphatasia","volume":"116","author":"Seefried","year":"2025","journal-title":"Calcif Tissue Int"},{"issue":"Fall 2024","key":"2026030310315344000_ref17","doi-asserted-by":"crossref","first-page":"28","DOI":"10.58858\/030105","article-title":"A rare case of subclinical hypophosphatasia in an adult patient","volume":"03","author":"Qiu","year":"2024","journal-title":"JOFP-CA"},{"issue":"1","key":"2026030310315344000_ref18","doi-asserted-by":"crossref","DOI":"10.1002\/mgg3.2056","article-title":"Not just a carrier: clinical presentation and management of patients with heterozygous disease-causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening","volume":"11","author":"Beck","year":"2023","journal-title":"Mol Genet Genomic Med"},{"issue":"5","key":"2026030310315344000_ref19","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2026030310315344000_ref20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00198-023-06844-1","article-title":"Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults","volume":"35","author":"Khan","year":"2024","journal-title":"Osteoporos Int"},{"key":"2026030310315344000_ref21","volume-title":"The ALPL Gene Variant Database","author":"The ALPL Gene Variant Consortium","year":"2024"},{"key":"2026030310315344000_ref22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000540692","article-title":"Challenges in hypophosphatasia: suspicion, diagnosis, genetics, management, and follow-up","volume":"5","author":"Montero-Lopez","year":"2024","journal-title":"Horm Res Paediatr"},{"key":"2026030310315344000_ref23","doi-asserted-by":"publisher","first-page":"117541","DOI":"10.1016\/j.bone.2025.117541","article-title":"Markedly discordant hypophosphatasia in a young girl","volume":"199","author":"Prakash","year":"2025","journal-title":"Bone"},{"issue":"4","key":"2026030310315344000_ref24","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/0002-9343(82)90474-0","article-title":"Adult hypophosphatasia with chondrocalcinosis and arthropathy","volume":"72","author":"Whyte","year":"1982","journal-title":"Am J Med"},{"issue":"6","key":"2026030310315344000_ref25","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1007\/s00774-020-01137-7","article-title":"Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mutation: a family report","volume":"38","author":"Kato","year":"2020","journal-title":"J Bone Miner Metab"},{"issue":"3","key":"2026030310315344000_ref26","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.jocd.2018.12.006","article-title":"Hypophosphatasia in adults: clinical spectrum and its association with genetics and metabolic substrates","volume":"23","author":"Lefever","year":"2020","journal-title":"J Clin Densitom"},{"issue":"1","key":"2026030310315344000_ref27","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.bone.2013.01.024","article-title":"Clinical spectrum of hypophosphatasia diagnosed in adults","volume":"54","author":"Berkseth","year":"2013","journal-title":"Bone"},{"issue":"1","key":"2026030310315344000_ref28","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-022-02572-7","article-title":"Identifying adult hypophosphatasia in the rheumatology unit","volume":"17","author":"Feurstein","year":"2022","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"2026030310315344000_ref29","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-1062-0","article-title":"Frequency and age at occurrence of clinical manifestations of disease in patients with hypophosphatasia: a systematic literature review","volume":"14","author":"Szabo","year":"2019","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"2026030310315344000_ref30","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1007\/s11033-024-09906-7","article-title":"Whole genome sequencing in adults with clinical hallmarks of hypophosphatasia negative for ALPL variants","volume":"51","author":"Seefried","year":"2024","journal-title":"Mol Biol Rep"},{"issue":"3","key":"2026030310315344000_ref31","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1007\/s00223-022-01039-y","article-title":"Diagnostic approach to patients with low serum alkaline phosphatase","volume":"112","author":"Riancho","year":"2023","journal-title":"Calcif Tissue Int"},{"issue":"11","key":"2026030310315344000_ref32","doi-asserted-by":"crossref","first-page":"e63781","DOI":"10.1002\/ajmg.a.63781","article-title":"New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry","volume":"194","author":"Kishnani","year":"2024","journal-title":"Am J Med Genet A"},{"issue":"7","key":"2026030310315344000_ref33","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1002\/humu.24010","article-title":"Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia","volume":"41","author":"del Angel","year":"2020","journal-title":"Hum Mutat"},{"issue":"7993","key":"2026030310315344000_ref34","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"issue":"6","key":"2026030310315344000_ref35","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1007\/s00774-017-0888-6","article-title":"Genetic analysis of adults heterozygous for ALPL mutations","volume":"36","author":"Taillandier","year":"2018","journal-title":"J Bone Miner Metab"},{"issue":"6","key":"2026030310315344000_ref36","doi-asserted-by":"crossref","DOI":"10.1093\/jbmrpl\/ziaf044","article-title":"The ALPL gene variant project: results of the first 100 reclassified variants","volume":"9","author":"Farman","year":"2025","journal-title":"JBMR Plus"},{"key":"2026030310315344000_ref37","doi-asserted-by":"crossref","first-page":"116504","DOI":"10.1016\/j.bone.2022.116504","article-title":"Urine phosphoethanolamine is a specific biomarker for hypophosphatasia in adults","volume":"163","author":"Shajani-Yi","year":"2022","journal-title":"Bone"},{"issue":"4","key":"2026030310315344000_ref38","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1038\/sj.ejhg.5200190","article-title":"Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia","volume":"6","author":"Mornet","year":"1998","journal-title":"Eur J Hum Genet"},{"issue":"10","key":"2026030310315344000_ref39","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1038\/ejhg.2014.10","article-title":"Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia","volume":"22","author":"Hofmann","year":"2014","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"2026030310315344000_ref40","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1016\/j.bone.2011.06.006","article-title":"Epigenetic regulation of alkaline phosphatase in human cells of the osteoblastic lineage","volume":"49","author":"Delgado-Calle","year":"2011","journal-title":"Bone"},{"issue":"12","key":"2026030310315344000_ref41","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-021-05893-8","article-title":"Polymorphic variants of alkaline phosphatase gene correlate with clinical signs of adult hypophosphatasia?","volume":"32","author":"Masi","year":"2021","journal-title":"Osteoporos Int"},{"issue":"8","key":"2026030310315344000_ref42","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41574-022-00682-7","article-title":"Skeletal and extraskeletal disorders of biomineralization","volume":"18","author":"Collins","year":"2022","journal-title":"Nat Rev Endocrinol"},{"issue":"3","key":"2026030310315344000_ref43","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1111\/j.1469-1809.2011.00642.x","article-title":"A molecular-based estimation of the prevalence of hypophosphatasia in the European population","volume":"75","author":"Mornet","year":"2011","journal-title":"Ann Hum Genet"},{"issue":"5","key":"2026030310315344000_ref44","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1007\/s00774-021-01219-0","article-title":"Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family","volume":"39","author":"Kato","year":"2021","journal-title":"J Bone Miner Metab"},{"issue":"3","key":"2026030310315344000_ref45","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1002\/ajmg.a.37991","article-title":"Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of hypophosphatasia","volume":"173","author":"Tenorio","year":"2017","journal-title":"Am J Med Genet A"},{"issue":"1","key":"2026030310315344000_ref46","doi-asserted-by":"publisher","DOI":"10.1186\/s12891-019-2420-8","article-title":"Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry","volume":"20","author":"H\u00f6gler","year":"2019","journal-title":"BMC Musculoskelet Disord"},{"key":"2026030310315344000_ref47","article-title":"Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults","volume":"35","author":"Khan","year":"2024","journal-title":"Osteoporos Int"},{"issue":"7","key":"2026030310315344000_ref48","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1097\/ICO.0000000000001947","article-title":"Ectopic ocular surface calcification in patients with hypophosphatasia treated with asfotase alfa","volume":"38","author":"Gospe","year":"2019","journal-title":"Cornea"},{"issue":"9","key":"2026030310315344000_ref49","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1002\/jbmr.4038","article-title":"Visualization of mineral-targeted alkaline phosphatase binding to sites of calcification in vivo","volume":"35","author":"Amadeu de Oliveira","year":"2020","journal-title":"J Bone Miner Res"},{"issue":"1","key":"2026030310315344000_ref50","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1210\/jc.2015-3462","article-title":"Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia","volume":"101","author":"Whyte","year":"2016","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmr\/advance-article-pdf\/doi\/10.1093\/jbmr\/zjaf124\/64240862\/zjaf124.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/41\/3\/259\/64240862\/zjaf124.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/41\/3\/259\/64240862\/zjaf124.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T15:31:59Z","timestamp":1772551919000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/41\/3\/259\/8251397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,9,11]]},"published-print":{"date-parts":[[2026,3,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmr\/zjaf124","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3]]},"published":{"date-parts":[[2025,9,11]]}}}