{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:14:14Z","timestamp":1791429254029,"version":"4.3.3"},"reference-count":34,"publisher":"Walter de Gruyter GmbH","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec id=\"j_jpem-2021-0104_abs_001\">\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec id=\"j_jpem-2021-0104_abs_002\">\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls:\u00a0\u226412 years: &lt;125\u00a0U\/L; &gt;12 years: &lt;50\u00a0U\/L Boys:\u00a0\u226414 years: &lt;125\u00a0U\/L; &gt;14 years: &lt;70\u00a0U\/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5\u2032-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the <jats:italic>ALPL<\/jats:italic> gene was performed in patients with clinical and\/or laboratory abnormalities suspicious for HPP.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec id=\"j_jpem-2021-0104_abs_003\">\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous <jats:italic>ALPL<\/jats:italic> mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec id=\"j_jpem-2021-0104_abs_004\">\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A diagnostic algorithm based on decreased AP is able to identify patients with <jats:italic>ALPL<\/jats:italic> mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1515\/jpem-2021-0104","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T21:47:27Z","timestamp":1632347247000},"page":"169-178","source":"Crossref","is-referenced-by-count":6,"title":["Screening for hypophosphatasia: does biochemistry lead the way?"],"prefix":"10.1515","volume":"35","author":[{"given":"Corinna Melanie","family":"Held","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology , Medical Centre, University of Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anic","family":"Guebelin","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology , Medical Centre, University of Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Krebs","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology , Medical Centre, University of Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn Oliver","family":"Sass","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences , Institute for Functional Gene Analytics (IFGA), Research Group Inborn Errors of Metabolism, Bonn-Rhein-Sieg University of Applied Science , Rheinbach , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wurm","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology , Medical Centre, University of Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekkehart","family":"Lausch","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology , Medical Centre, University of Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascha","family":"van der Werf-Grohmann","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology , Medical Centre, University of Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl Otfried","family":"Schwab","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology , Medical Centre, University of Freiburg , Freiburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"2022020803263078885_j_jpem-2021-0104_ref_001","doi-asserted-by":"crossref","unstructured":"Mornet, E. Hypophosphatasia. Orphanet J Rare Dis 2007;2:40. https:\/\/doi.org\/10.1186\/1750-1172-2-40.","DOI":"10.1186\/1750-1172-2-40"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_002","doi-asserted-by":"crossref","unstructured":"Berkseth, KE, Tebben, PJ, Drake, MT, Hefferan, TE, Jewison, DE, Wermers, RA. Clinical spectrum of hypophosphatasia diagnosed in adults. Bone 2013;54:21\u20137. https:\/\/doi.org\/10.1016\/j.bone.2013.01.024.","DOI":"10.1016\/j.bone.2013.01.024"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_003","doi-asserted-by":"crossref","unstructured":"Baumgartner-Sigl, S, Haberlandt, E, Mumm, S, Scholl-B\u00fcrgi, S, Sergi, C, Ryan, L, et al.. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. 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Pediatr Bone 2012:771\u201394. https:\/\/doi.org\/10.1016\/b978-0-12-382040-2.10028-0.","DOI":"10.1016\/B978-0-12-382040-2.10028-0"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_010","doi-asserted-by":"crossref","unstructured":"Taillandier, A, Domingues, C, Dufour, A, Debiais, F, Guggenbuhl, P, Roux, C, et al.. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metabol 2018;36:723\u201333. https:\/\/doi.org\/10.1007\/s00774-017-0888-6.","DOI":"10.1007\/s00774-017-0888-6"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_011","doi-asserted-by":"crossref","unstructured":"Fauvert, D, Brun-Heath, I, Lia-Baldini, A-S, Bellazi, L, Taillandier, A, Serre, J-L, et al.. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. 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Bone 2017;102:15\u201325. https:\/\/doi.org\/10.1016\/j.bone.2017.02.011.","DOI":"10.1016\/j.bone.2017.02.011"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_015","unstructured":"Dortschy, R, Robert-Koch-Institut, editors. Bev\u00f6lkerungsbezogene Verteilungswerte ausgew\u00e4hlter Laborparameter aus der Studie zur Gesundheit von Kindern und Jugendlichen in Deutschland (KiGGS). Berlin; 2009."},{"key":"2022020803263078885_j_jpem-2021-0104_ref_016","unstructured":"Thomas, L, editor. Labor und Diagnose: Indikation und Bewertung von Laborbefunden f\u00fcr die medizinische Diagnostik. Bd. 2: \u2026 8. Aufl. Frankfurt\/Main: Th-Books Verl.-Ges; 2012."},{"key":"2022020803263078885_j_jpem-2021-0104_ref_017","unstructured":"Steen, G, Van der Zwaal, M. Reference values for Vitamin B1 and Vitamin B6 in whole blood. Dialog 2007;207:3\u20134."},{"key":"2022020803263078885_j_jpem-2021-0104_ref_018","unstructured":"Shapira, E, editor. Biochemical genetics: a laboratory manual. 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Eur J Pediatr 2016;175:433\u20137. https:\/\/doi.org\/10.1007\/s00431-015-2641-2.","DOI":"10.1007\/s00431-015-2641-2"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_023","doi-asserted-by":"crossref","unstructured":"Bayramli, R, Cevlik, T, Guran, T, Atay, Z, Bas, S, Haklar, G, et al.. Clinical significance of hypophosphatasemia in children. Calcif Tissue Int 2020;106:608\u201315. https:\/\/doi.org\/10.1007\/s00223-020-00677-4.","DOI":"10.1007\/s00223-020-00677-4"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_024","doi-asserted-by":"crossref","unstructured":"Saraff, V, Narayanan, VK, Lawson, AJ, Shaw, NJ, Preece, MA, H\u00f6gler, W. A diagnostic algorithm for children with low alkaline phosphatase activities: lessons learned from laboratory screening for hypophosphatasia. 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J Clin Endocrinol Metab 2000;85:743\u20137. https:\/\/doi.org\/10.1210\/jcem.85.2.6373.","DOI":"10.1210\/jcem.85.2.6373"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_033","doi-asserted-by":"crossref","unstructured":"Lia-Baldini, AS, Muller, F, Taillandier, A, Gibrat, JF, Mouchard, M, Robin, B, et al.. A molecular approach to dominance in hypophosphatasia. Hum Genet 2001;109:99\u2013108. https:\/\/doi.org\/10.1007\/s004390100546.","DOI":"10.1007\/s004390100546"},{"key":"2022020803263078885_j_jpem-2021-0104_ref_034","doi-asserted-by":"crossref","unstructured":"Fukushima, K, Kawai-Kowase, K, Yonemoto, Y, Fujiwara, M, Sato, H, Sato, M, et al.. Adult hypophosphatasia with compound heterozygous p.Phe327Leu missense and c.1559delT frameshift mutations in tissue-nonspecific alkaline phosphatase gene: a case report. 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