{
  "abstract": "Context: Hypophosphatasia (HPP) is an inborn error of bone metabolism affecting the musculoskeletal and nervous systems. It is caused by monoallelic or biallelic pathogenic variants of the ALPL gene, which encodes the tissue non-specific alkaline phosphatase (TNSAP). Given its marked clinical variability ranging from prenatal presentations to symptoms onset in late adulthood, HPP often runs undetected with potential harms for affected individuals.\n\nMethods: Clinical, molecular, in silico , in vitro , and, when accessible, family studies were carried out on 12 HPP individuals with variable clinical presentations. Variants were classified according to the American College of Medical Genetics and Genomics recommendations.\n\nResults: Four cases were diagnosed as infantile, one as adult HPP. The other cases were completely asymptomatic (nr 4) or showed symptoms not strictly HPP-related (nr 3) but were all identified incidentally based on the biochemical low ALP value or severe bone fragility phenotype. Twelve “pathogenic o likely pathogenic variants” were identified including 9 missense (1 novel, 8 previously reported), 2 in frame indels and one multiexonic deletion. In vitro characterization of the seven point variants without previously described functional data confirmed a dramatic decreased enzymatic activity of some mutated enzymes.\n\nConclusions: Improving the recognition of HPP is essential because its rarity and extreme variable presentation with many asymptomatic cases lead to misdiagnosis or delay. Increased clinical awareness and attention to persistently low ALP levels are crucial to achieve earlier and more accurate diagnosis.",
  "abstract_shown": true,
  "affiliations": [
    "Inborn Errors of Morphogenesis Reseach Unit and Division of Medical Genetics, Fondazione Istituto di Ricerca a Carattere Scientifico (IRCCS)-Casa Sollievo della Sofferenza",
    "Computational Biology and Bioinformatics Unit, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricerca a Carattere Scientifico (IRCCS)",
    "Unit of Endocrinology, Fondazione Istituto di Ricerca a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza",
    "Rare Bone Diseases Center, AOU Policlinico Umberto I",
    "Pediatric Unit, Istituto di Ricerca a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna",
    "Department of Medical and Cardiovascular Sciences, Sapienza University",
    "Unit of Endocrinology, Fondazione Istituto di Ricerca a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico",
    "Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome",
    "Unit of Endocrinology, Azienda Ospedaliera-Universitaria of Cagliari"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
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        0
      ],
      "name": "Giulia Casamassima"
    },
    {
      "affs": [
        1
      ],
      "name": "Tommaso Biagini"
    },
    {
      "affs": [
        2
      ],
      "name": "Flavia Pugliese"
    },
    {
      "affs": [
        0
      ],
      "name": "Anna Maria Grieco"
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    {
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        1
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      "name": "Francesco Petrizzelli"
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    {
      "affs": [
        1
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      "name": "Tommaso Mazza"
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    {
      "affs": [
        3
      ],
      "name": "Mauro Celli"
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    {
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        4
      ],
      "name": "Emanuela Scarano"
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    {
      "affs": [
        4
      ],
      "name": "Federica Tamburrino"
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    {
      "affs": [
        5
      ],
      "name": "Luciano Colangelo"
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    {
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        6
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      "name": "Cristina Eller-Vainicher"
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        7
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      "name": "Anda Mihaela Naciu"
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    {
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      "name": "Gaia Tabacco"
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    {
      "affs": [
        7
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      "name": "Giovanni Rossini"
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    {
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        8
      ],
      "name": "Francesca Pigliaru"
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    {
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        7
      ],
      "name": "Andrea Palermo"
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    {
      "affs": [
        0
      ],
      "name": "Silvia Morlino"
    },
    {
      "affs": [
        0
      ],
      "name": "Bartolomeo Augello"
    },
    {
      "affs": [
        0
      ],
      "name": "Antonio Petracca"
    },
    {
      "affs": [
        0
      ],
      "name": "Marco Castori"
    },
    {
      "affs": [
        2
      ],
      "name": "Alfredo Scillitani"
    },
    {
      "affs": [
        0
      ],
      "name": "Vito Guarnieri"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dr32r39rmygjw.bib",
  "cited_by": 0,
  "doi": "10.3389/fendo.2026.1966666",
  "fulltext_url": null,
  "id": "dr32r39rmygjw",
  "issns": [
    "1664-2392"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1966666/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2712|Alkaline Phosphatase Research Studies"
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  "openalex": "W7224085537",
  "pdf_url": "https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2026.1966666/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-28",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/dr32r39rmygjw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:20Z",
      "native_id": "10.3389/fendo.2026.1966666",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1966666/full"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Alkaline Phosphatase Research Studies",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Twelve novel Italian cases of hypophosphatasia: challenging cases with an extremely variable phenotype",
  "title_text": "Twelve novel Italian cases of hypophosphatasia: challenging cases with an extremely variable phenotype",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:20Z",
  "url": "https://research.draconitic.com/paper/dr32r39rmygjw",
  "venue": "Frontiers in Endocrinology",
  "versions": []
}