The Journal of Clinical Endocrinology & Metabolism, 2022, 107, e2087–e2094 https://doi.org/10.1210/clinem/dgab914 Advance access publication 22 December 2021 Clinical Research Article Received: 14 September 2021. Editorial Decision: 16 December 2021. Corrected and Typeset: 20 January 2022 © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com ALPL Genotypes in Patients With Atypical Femur Fractures or Other Biochemical and Clinical Signs of Hypophosphatasia Francesca Marini, 1,2 Laura Masi, 3 Francesca Giusti, 1 Luisella Cianferotti, 1,3 Federica Cioppi, 3 Gemma Marcucci, 1,3 Simone Ciuff, 1 Emmanuel Biver, 4, Giuseppe Toro, 5 Giovanni Iolascon, 5 Teresa Iantomasi, 1 and Maria Luisa Brandi 2, 1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy 2 F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, Florence, Italy 3 University Hospital of Florence, Azienda Ospedaliero-Universitaria Careggi (AOUC), Florence, Italy 4 Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland 5 Department of Medical and Surgical Specialties and Dentistry, University of Campania “Luigi Vanvitelli”, Naples, Italy Correspondence: Maria Luisa Brandi, MD, PhD, F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, Via Reginaldo Giuliani 195/A, 50141 Florence, Italy. Email: marialuisa.brandi@unifi.it; marialuisa@marialuisabrandi.it. Abstract Context: Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue nonspecific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the ad- ministration of contraindicated antiresorptive drugs that, in patients with HPP, substantially increase the risk of atypical femur fractures (AFFs) and worsen the fracture healing process that is usually already compromised in these patients. Objective: Performing ALPL genetic testing to identify rare variants in suspected adult patients with HPP. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP. Methods: Patients with suspected adult HPP were retrospectively selected for the genetic testing of the ALPL gene. Patients included were from 3 main European Bone Units (Florence, Naples, and Geneva); 106 patients with biochemical and/or clinical signs suggestive of a mild form of HPP were included. Results: Genetic testing led to the identification of a heterozygote rare variant in 2.8% of cases who were initially referred as suspected osteo- porosis. The analysis of frequencies of ALPL common variants showed a high prevalence (30.8%) of homozygosity in subjects who developed an AFF, in association with normal serum total ALP activity. Conclusion: The results suggest homozygosity of common ALPL variants as a possible genetic mark of risk for these fractures. Key Words: hypophosphatasia, tissue nonspecific alkaline phosphatase (TNSALP), ALPL gene, rare variants, common variants, atypical femur fracture (AFFs) Abbreviations: AFF, atypical femur fracture; ALP, alkaline phosphatase; BMD, bone mineral density; HPP, hypophosphatasia; TNSALP, tissue nonspecific alka- line phosphatase. Hypophosphatasia (HPP) is a rare metabolic disorder caused by defciency of alkaline phosphatase (ALP) enzyme ac- tivity, leading to defective bone and tooth mineralization. Six categories have been described, following a classifca- tion based on the age of diagnosis, which is associated with relative severity: perinatal lethal, prenatal benign, infantile, childhood, adult, and odonto-HPP (1). Generally, the younger the age of onset, the more severe the clinical phenotype is, ranging from a perinatal lethal form, with virtually no skel- etal mineralization, to mild forms with late adult onset (1, 2). While during infancy and childhood the diagnosis of HPP can readily be made, based on specifc clinical, radiographic, and basic laboratory fndings, a clear diagnosis of adult HPP is more diffcult since adults commonly present a varying spectrum of nonspecifc manifestations. Many adults with HPP report the occurrence of some symptoms during their childhood, but the diagnosis is commonly not made until later in life (1, 2). Atypical femur fractures (AFFs) and stress fractures are 2 clinical hallmarks of adult HPP (1, 2). AFFs are fragility fractures affecting the subtrochanteric or diaphyseal area of the femur with a transverse morphology, originating at the lateral cortex, occurring in patients with HPP mainly after prolonged treatment with antiresorptive drugs. Stress fractures occur as a consequence of physical stress on the metatarsal bones or tibia, and they can be recurrent, multiple, and commonly slow to heal. Low serum activity of unfractionated ALP is a biochemical hallmark of HPP, that, however, is not diagnostic by itself, as Downloaded from https://academic.oup.com/jcem/article/107/5/e2087/6479120 by guest on 21 December 2023