Hypophosphatemic rickets in an Italian multicentric cohort of 24 subjects: a clinical and molecular characterisation

Purpose: Rickets is a rare bone disorder due to altered calcium, vitamin D, and phosphorus metabolism, caused by nutritional deficiencies or, in 13% of cases, genetic origin. Few data are available on an Italian cohort of rickets. Methods: Twenty-four patients with confirmed low serum phosphorus levels and reduced renal tubular phosphate reabsorption were recruited from different tertiary care centres over the last 5 years. Biochemical, clinical, and anamnestic data were also collected. DNA was extracted and subjected to targeted next-generation sequencing. Results: Twenty-four single-nucleotide variants were identified in the PHEX (eight pathogenic, five likely pathogenic, three variants of uncertain significance), CYP27B1 (two pathogenic, four likely pathogenic), and SLC34A3 (one pathogenic, one likely pathogenic) genes. Five large genomic deletions involving one or more PHEX exons were detected. Eight of 20 PHEX and both SLC34A3 variants were novel, and segregation analysis identified 11 familial and three de novo cases. Biochemical data confirmed high serum alkaline phosphatase and low 25-hydroxyvitamin D3 levels, whereas the main clinical manifestations were short stature (76.1%), bone deformities (85.7%), musculoskeletal pain (71.4%), and muscle weakness (55.5%). Conclusions: Our study provides clinical and genetic descriptions of rickets in a cohort of Italian patients. Moreover, we expanded the spectrum of mutations associated with the genetic forms of this disorder and suggested a high-throughput sequencing approach to provide a molecular diagnosis for adequate follow-up of patients.