Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia.

Gregorio Guabello, Vito Guarnieri, Alfredo Scillitani, Marco Castori, Mario Mastroianno, Francesco Petrizzelli, Mauro Celli, Salvatore Cannavò, Piera Vicchio, Emanuela Scarano, Rosaria Maddalena Ruggeri, Francesca Pigliaru, Luisa Politano, Andrea Palermo, Stefania Massuras, Agostino Gaudio, Enrico Grosso, Cosimo Giannini, Thomas Foiadelli, Rita Fischetto, Sabrina Corbetta, Francesco Conti, Grazia Nardella, Bartolomeo Augello, Tommaso Biagini, Claudia Battista, Domenico Trombetta, Antonio Stefano Salcuni, Flavia Pugliese, Luigia Cinque

Journal: Frontiers in endocrinology 2023;14():1205977

PMID: 37600704

Free Full Text on PubMed Central View on PubMed

Abstract

INTRODUCTION

Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys.

METHODS

There were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure.

RESULTS

There were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters.

DISCUSSION

We present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases.

Copyright © 2023 Cinque, Pugliese, Salcuni, Trombetta, Battista, Biagini, Augello, Nardella, Conti, Corbetta, Fischetto, Foiadelli, Gaudio, Giannini, Grosso, Guabello, Massuras, Palermo, Politano, Pigliaru, Ruggeri, Scarano, Vicchio, Cannavò, Celli, Petrizzelli, Mastroianno, Castori, Scillitani and Guarnieri.

Address: Department of Pediatrics, "G D'Annunzioof Pediatrics, " University of Chieti-Pescara, Foggia, Italy.; Unit of Endocrinology, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, Foggia, Italy.; Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia, Udine, Italy.; Laboratory of Oncology, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, Foggia, Italy.; Laboratory of Bioinformatics, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.; Department of Clinical and Molecular Medicine, La Sapienza University, Rome, Italy.; Endocrinology and Diabetology Service, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Galeazzi, Milan, Italy.; Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.; Clinical Genetics Unit, Department of Pediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy.; Pediatric Clinic, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo Foundation-University of Pavia, Pavia, Italy.; Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.; Department of Pediatrics, "G D'Annunzio" University of Chieti-Pescara, Chieti, Italy.; Medical Genetics, Città della Salute e della Scienza University Hospital, Torino, Italy.; Reumatology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Ortopedico Galeazzi, Milan, Italy.; Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy.; Cardiomiology and Medical Genetics, University Hospital of Campania Luigi Vanvitelli, Naples, Italy.; Endocrine Unit, Azienda Ospedaliera-Universitaria of Cagliari, Cagliari, Italy.; Unit of Endocrinology, Department of Human Pathology DETEV "G. Barresi", University of Messina, Messina, Italy.; Rare Diseases Unit, Department of Pediatrics, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria S. Orsola, Bologna, Bologna, Italy.; Department of Pediatrics, Jazzolino Hospital, Vibo Valentia, Italy.; Rare Bone Metabolism Center, Azienda Ospedaliera Universitaria (AOU) Policlinico Umberto I, Roma, Italy.; Scientific Direction, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, Foggia, Italy.

DOI: 10.3389/fendo.2023.1205977

Link outs

Free resources

Full Text Sources:

Miscellaneous:

https://assays.cancer.gov/non-CPTAC-3492

MeSH Terms: Adult, Humans, Hypophosphatasia, Phylogeny, Computational Biology, Diagnosis, Differential, Italy, Rare Diseases