{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:47:47Z","timestamp":1785764867763,"version":"3.56.0"},"reference-count":111,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Hypophosphatasia (HPP) encompasses a group of inherited metabolic bone disorders characterized by defective skeletal mineralization and variable clinical severity in childhood. Substantial allelic heterogeneity contributes to a broad pediatric clinical spectrum, ranging from life-threatening perinatal disease to milder phenotypes characterized by chronic functional impairment. Historically, management relied primarily on supportive interventions aimed at sustaining survival, without modifying the underlying enzymatic defect. The introduction of enzyme replacement therapy (ERT) with asfotase alfa has fundamentally altered the natural history of pediatric HPP by supplementing deficient alkaline phosphatase activity at sites of active mineralization, thereby improving skeletal integrity, enhancing survival in severe forms, and supporting long-term functional gains. This therapeutic shift has redirected clinical priorities from survival alone toward sustained functional development and health-related quality of life. Nevertheless, variability in disease expression and therapeutic response persists, reflecting both diagnostic timing and the molecular heterogeneity of ALPL variants, whose phenotypic consequences cannot be predicted with complete certainty. Growing recognition of the importance of early diagnosis has prompted exploratory efforts toward systematic identification strategies, including neonatal screening initiatives reported in selected populations, which suggest the potential for earlier therapeutic intervention during active skeletal development. Together, these considerations highlight pediatric HPP as a model of precision-oriented management in rare metabolic bone disease, where timely diagnosis and targeted enzyme replacement must be aligned with long-term, multidisciplinary care to optimize outcomes.<\/jats:p>","DOI":"10.3390\/ijms27156921","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evolving Therapeutic Paradigms in Pediatric Hypophosphatasia: From Survival-Driven Care to Integrated Precision Management"],"prefix":"10.3390","volume":"27","author":[{"given":"Alexandru","family":"Florescu","sequence":"first","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora Cristina","family":"Vintil\u0103","sequence":"additional","affiliation":[{"name":"Endocrinology Department, Saint Spiridon County Hospital, 700111 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Vasiliu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7050-8430","authenticated-orcid":false,"given":"Oana Viola","family":"B\u0103dulescu","sequence":"additional","affiliation":[{"name":"Grigore T. 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