{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T03:16:05Z","timestamp":1778901365919,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T00:00:00Z","timestamp":1672099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Loss of function mutations in the PHEX gene could determine X-linked dominant hypophosphatemia. This is the most common form of genetic rickets. It is characterized by renal phosphate wasting determining an increase in fibroblast growth factor 23 (FGF-23), growth retard, bone deformities and musculoskeletal manifestations. In recent decades, analysis of the PHEX gene has revealed numerous different mutations. However, no clear genotype-phenotype correlations have been reported in patients with hypophosphatemic rickets (XLH). We report two cases of a 28-year-old-male (patient 1) and a 19-year-old male (patient 2) affected by XLH initially treated with phosphate and 1,25-dihydroxyvitamin\u2013D admitted to the Endocrinology unit because of the persistence of muscle weakness, bone pain and fatigue. After phosphate withdrawal, both patients started therapy with burosumab and symptoms ameliorated in three months. However, patient 1\u2019s biochemical parameters did not improve as expected so we decided to investigate his genetic asset. We herein describe a possible clinical implication for the missense \u201cde novo\u201d mutation, c.250G&gt;C (p.Ala84Pro) in the PHEX gene, reported in the PHEX database and classified as a variant of uncertain significance (VUS). The clinical implication of this mutation on disease burden and quality of life in adults is still under investigation.<\/jats:p>","DOI":"10.3390\/genes14010080","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T08:42:22Z","timestamp":1672216942000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Variant p.Ala84Pro Is Causative of X-Linked Hypophosphatemic Rickets: Possible Relationship with Burosumab Swinging Response in Adults"],"prefix":"10.3390","volume":"14","author":[{"given":"Maria Carmela","family":"Zagari","sequence":"first","affiliation":[{"name":"Endocrinology Rare Disease Unit, Department of Experimental and Clinical Medicine, Magna Gr\u00e6cia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Chiarello","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pugliese-Ciaccio Hospital, 88100 Catanzaro, Italy"},{"name":"Department of Experimental and Clinical Medicine, Magna Gr\u00e6cia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9242-0165","authenticated-orcid":false,"given":"Stefano","family":"Iuliano","sequence":"additional","affiliation":[{"name":"Endocrinology Rare Disease Unit, Department of Experimental and Clinical Medicine, Magna Gr\u00e6cia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"D\u2019Antona","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Gr\u00e6cia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Rocca","sequence":"additional","affiliation":[{"name":"Endocrinology Rare Disease Unit, Department of Experimental and Clinical Medicine, Magna Gr\u00e6cia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5451-593X","authenticated-orcid":false,"given":"Emma","family":"Colao","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Mater Domini University Hospital, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8836-5386","authenticated-orcid":false,"given":"Nicola","family":"Perrotti","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Gr\u00e6cia University of Catanzaro, 88100 Catanzaro, Italy"},{"name":"Medical Genetics Unit, Mater Domini University Hospital, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6539-7796","authenticated-orcid":false,"given":"Francesca","family":"Greco","sequence":"additional","affiliation":[{"name":"Endocrinology Rare Disease Unit, Department of Experimental and Clinical Medicine, Magna Gr\u00e6cia University, 88100 Catanzaro, Italy"},{"name":"Department of Human Movement Sciences and Health, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-7402","authenticated-orcid":false,"given":"Rodolfo","family":"Iuliano","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Gr\u00e6cia University of Catanzaro, 88100 Catanzaro, Italy"},{"name":"Medical Genetics Unit, Mater Domini University Hospital, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-2618","authenticated-orcid":false,"given":"Antonio","family":"Aversa","sequence":"additional","affiliation":[{"name":"Endocrinology Rare Disease Unit, Department of Experimental and Clinical Medicine, Magna Gr\u00e6cia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13023-019-1014-8","article-title":"FGF23 and its role in X-linked hypophosphatemia-related morbidity","volume":"14","author":"Mughal","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1590\/2175-8239-jbn-2020-0027","article-title":"X-linked hypophosphatemic rickets: A new mutation","volume":"43","author":"Maio","year":"2021","journal-title":"J. Bras. Nefrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41581-019-0152-5","article-title":"Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia","volume":"15","author":"Haffner","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1007\/s00223-010-9373-0","article-title":"Phenotype Presentation of Hypophosphatemic Rickets in Adults","volume":"87","author":"Brusgaard","year":"2010","journal-title":"Calcif. Tissue Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1002\/jbmr.340","article-title":"A clinician\u2019s guide to X-linked hypophosphatemia","volume":"26","author":"Carpenter","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R13","DOI":"10.1530\/EC-13-0103","article-title":"Therapeutic management of hypophosphatemic rickets from infancy to adulthood","volume":"3","author":"Linglart","year":"2014","journal-title":"Endocr. Connect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1056\/NEJMoa1714641","article-title":"Burosumab Therapy in Children with X-Linked Hypophosphatemia","volume":"378","author":"Carpenter","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","unstructured":"CHMP (2020). Assessment Report CRYSVITA, European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/variation-report\/crysvita-h-c-4275-ii-010-g-epar-assessment-report-variation_en.pdf."},{"key":"ref_9","unstructured":"FDA (2020). FDA Approves First Therapy for Rare Disease that Causes Low Phosphate Blood Levels, Bone Softening."},{"key":"ref_10","unstructured":"EMA (2017). New medicine for rare bone disease, Crysvita, a Medicine for the Treatment of X-Linked Hypophosphataemia, Recommended for Conditional Approval."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.3892\/ijmm.2016.2796","article-title":"Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets","volume":"38","author":"Li","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Paduano, F., Colao, E., Fabiani, F., Rocca, V., Dinatolo, F., Dattola, A., D\u2019Antona, L., Amato, R., Trapasso, F., and Baudi, F. (2022). Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy. Genes, 13.","DOI":"10.3390\/genes13071286"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories (2002). ATS statement: Guidelines for the six-minute walk test. Am. J. Respir. Crit. Care Med., 166, 111\u2013117.","DOI":"10.1164\/ajrccm.166.1.at1102"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.physio.2005.05.003","article-title":"Reference values for adult grip strength measured with a Jamar dynamometer: A descriptive meta-analysis","volume":"92","author":"Bohannon","year":"2006","journal-title":"Physiotherapy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S1063-4584(03)00089-X","article-title":"Reliability and validity of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index in Italian patients with osteoarthritis of the knee","volume":"11","author":"Salaffi","year":"2003","journal-title":"Osteoarthr. Cartil."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0304-3959(95)00156-5","article-title":"A validation study of an Italian version of the Brief Pain Inventory (Breve Questionario per la Valutazione del Dolore)","volume":"65","author":"Caraceni","year":"1996","journal-title":"Pain"},{"key":"ref_17","unstructured":"gnomAD, T.G.A.D (2022, July 28). Available online: https:\/\/gnomad.broadinstitute.org\/about."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bendl, J., Stourac, J., Salanda, O., Pavelka, A., Wieben, E.D., Zendulka, J., Brezovsky, J., and Damborsky, J. (2014). PredictSNP: Robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003440"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/jbmr.2307","article-title":"PHEX 3\u2032-UTR c.*231A>G near the polyadenylation signal is a relatively common, mild, American mutation that masquerades as sporadic or X-linked recessive hypophosphatemic rickets","volume":"30","author":"Mumm","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3390\/endocrines3030040","article-title":"Pathogenic Variants of the PHEX Gene","volume":"3","author":"Ohata","year":"2022","journal-title":"Endocrines"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"617738","DOI":"10.3389\/fcell.2021.617738","article-title":"Clinical and Genetic Characteristics of 153 Chinese Patients With X-Linked Hypophosphatemia","volume":"9","author":"Lin","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1530\/EJE-15-0661","article-title":"Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms","volume":"174","author":"Che","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e001714","DOI":"10.1136\/rmdopen-2021-001714","article-title":"Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension","volume":"7","author":"Briot","year":"2021","journal-title":"RMD Open"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"375","DOI":"10.3390\/endocrines3030030","article-title":"Adult Presentation of X-Linked Hypophosphatemia","volume":"3","author":"Ito","year":"2022","journal-title":"Endocrines"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s00223-021-00823-6","article-title":"Sclerostin Directly Stimulates Osteocyte Synthesis of Fibroblast Growth Factor-23","volume":"109","author":"Ito","year":"2021","journal-title":"Calcif. Tissue Int."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jurca, C., Iuhas, O., Kozma, K., Petchesi, C.D., Zaha, D., Bembea, M., Jurca, S., Paul, C., and Jurca, C. (2022). Effects of Burosumab Treatment on Two Siblings with X-Linked Hypophosphatemia. Case Report and Literature Review. Genes, 13.","DOI":"10.3390\/genes13081392"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1002\/jbmr.3417","article-title":"FGF23 Neutralizing Antibody Partially Improves Bone Mineralization Defect of HMWFGF2 Isoforms in Transgenic Female Mice","volume":"33","author":"Xiao","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1177\/0145561320940869","article-title":"Naso-Ethmoidal Phosphaturic Mesenchymal Tumor: A Rare Tumor Site for an Uncommon Paraneoplastic Syndrome","volume":"101","author":"Riminucci","year":"2022","journal-title":"Ear Nose Throat J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bone.2017.10.002","article-title":"Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia","volume":"106","author":"Tridimas","year":"2018","journal-title":"Bone"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.bone.2019.01.021","article-title":"Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia","volume":"121","author":"Zhang","year":"2019","journal-title":"Bone"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/80\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:52:29Z","timestamp":1760147549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/80"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,27]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["genes14010080"],"URL":"https:\/\/doi.org\/10.3390\/genes14010080","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,27]]}}}