X-Linked Hypophosphatemia Caused by the Prevailing North American PHEX Variant c.*231A>G; Exon 13-15 Duplication Is Often Misdiagnosed as Ankylosing Spondylitis and Manifests in Both Men and Women

Abstract

Inactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.