ESPE Abstracts

Introduction: X-linked hypophosphatemia (XLH) is a rare hereditary condition caused by mutation in the gene encoding the phosphate-regulating endopeptidase homolog, X-linked (PHEX). It is characterized by altered phosphate homeostasis with persistent hypophosphatemia and hyperphosphaturia resulting in deficient skeletal mineralization, rickets, bone deformity, growth failure, dental problems, joint pain and impairment.

Case Presentation: We report a family affected by XLH, with two adults siblings (case II-2 and II-3) and two children, daughters of case II-2 (case III-1, a 4 years old girl, and III-2, a 18 months old girl), harbouring a rare PHEX intron mutation, c.1586+6T>C. This variant alters mRNA splicing causing partial exon skipping as previously demonstrated by in vitro study but clinical phenotype has not been described. All the patients exhibited features of severe short stature, genu valgum and waddling gait; children suffered from active rickets while adults have an history of vitamin D- unresponsive rickets and orthopaedic surgeries for progressive bone deformities associated to reduced joint excursion and severe bone pain impairing daily living activities. Laboratory investigation revealed low serum phosphorus according to reference values for age with increased renal wasting (Tubular Reabsorption of Posphate, TRP < 90%), elevated blood alkaline phosphatase and normal calcium levels in all subjects. Burosumab therapy has been started in paediatric patients. In the first semester of treatment a linear growth improvement of 0.44 SDS and 0.4 SDS was registered for case III-1 and III-2, respectively. Growth velocity rate increased from -0.61 SDS to 0.17 for case III-2 and almost doubled for case III-1 (from -2.39 SDS to 1.42 SDS). Serum phosphate increased up to normal range in both patients with a clear upward trend in TRP values. Recently also adult patients started burosumab for compassionate use.

Discussion and Conclusion: Data inhere presented extend the phenotypic characterization of rare intronic mutations in the PHEX gene. This report suggests this splicing donor site alteration has complete penetrance and severe expressivity. Correct and precocious diagnosis is mandatory to start the appropriate treatment timely. We are confident that precocious therapy onset in infancy will positively address growth failure and major skeletal abnormalities in our pediatric patients as some preliminary data in prepubertal cohorts have suggested.