Abstract: Background: Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. Methods: By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17?55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ?2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). Results: We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. Conclusion: Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype.

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