Twelve novel Italian cases of hypophosphatasia: challenging cases with an extremely variable phenotype
9 affiliations
- 1Inborn Errors of Morphogenesis Reseach Unit and Division of Medical Genetics, Fondazione Istituto di Ricerca a Carattere Scientifico (IRCCS)-Casa Sollievo della Sofferenza
- 2Computational Biology and Bioinformatics Unit, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricerca a Carattere Scientifico (IRCCS)
- 3Unit of Endocrinology, Fondazione Istituto di Ricerca a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza
- 4Rare Bone Diseases Center, AOU Policlinico Umberto I
- 5Pediatric Unit, Istituto di Ricerca a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna
- 6Department of Medical and Cardiovascular Sciences, Sapienza University
- 7Unit of Endocrinology, Fondazione Istituto di Ricerca a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico
- 8Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome
- 9Unit of Endocrinology, Azienda Ospedaliera-Universitaria of Cagliari
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.
Methods: 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.
Results: 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.
Conclusions: 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.
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BibTeX
@article{casamassima2026twelve,
title = {{Twelve novel Italian cases of hypophosphatasia: challenging cases with an extremely variable phenotype}},
author = {Giulia Casamassima and Tommaso Biagini and Flavia Pugliese and Anna Maria Grieco and Francesco Petrizzelli and Tommaso Mazza and Mauro Celli and Emanuela Scarano and Federica Tamburrino and Luciano Colangelo and Cristina Eller-Vainicher and Anda Mihaela Naciu and Gaia Tabacco and Giovanni Rossini and Francesca Pigliaru and Andrea Palermo and Silvia Morlino and Bartolomeo Augello and Antonio Petracca and Marco Castori and Alfredo Scillitani and Vito Guarnieri},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1966666},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1966666/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Twelve novel Italian cases of hypophosphatasia: challenging cases with an extremely variable phenotype
AU - Giulia Casamassima
AU - Tommaso Biagini
AU - Flavia Pugliese
AU - Anna Maria Grieco
AU - Francesco Petrizzelli
AU - Tommaso Mazza
AU - Mauro Celli
AU - Emanuela Scarano
AU - Federica Tamburrino
AU - Luciano Colangelo
AU - Cristina Eller-Vainicher
AU - Anda Mihaela Naciu
AU - Gaia Tabacco
AU - Giovanni Rossini
AU - Francesca Pigliaru
AU - Andrea Palermo
AU - Silvia Morlino
AU - Bartolomeo Augello
AU - Antonio Petracca
AU - Marco Castori
AU - Alfredo Scillitani
AU - Vito Guarnieri
PY - 2026
DA - 2026/10/28
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1966666
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1966666/full
AB - 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. Methods: 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. Results: 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. Conclusions: 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.
SN - 1664-2392
ER -