Genetic background of infantile hypophosphatemia: a narrative review.

BACKGROUND AND

OBJECTIVE

Infantile hypophosphatemia (defined as a serum phosphate level below 1.6 millimoles per liter before 6 months of age and below 1.48 millimoles per liter between 6 months and 1 year of age) is one of the most common electrolyte disorders in clinical practice, which may be caused by acquired or genetic factors. Currently, the summary of the characteristics of infantile hereditary hypophosphatemia remains incomplete, which poses challenges to early identification and clinical treatments. This paper aims to review the genetic background of infantile hypophosphatemia, with the expectation of supporting clinical decision-making.

METHODS

We conducted a comprehensive literature search using PubMed and the China National Knowledge Infrastructure (CNKI), with a specific focus on the genetic mechanisms and infant phenotypes of hereditary hypophosphatemia. This review primarily encompasses English-language literature published between 2015 and 2025; however, where appropriate, earlier published literature and Chinese-language literature have also been included.

KEY CONTENT AND FINDINGS: The genetic background of infantile hypophosphatemia can be summarized from two aspects: (I) increased secretion of fibroblast growth factor 23 (FGF23) caused by genetic factors; (II) etiologies not mediated by FGF23, such as pathogenic variants associated with genes encoding channel proteins, as well as genes encoding enzymes or receptors in the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] metabolic pathway. These factors lead to a reduction in intestinal phosphate absorption and bone resorption, as well as an increase in renal phosphate excretion, ultimately resulting in a decrease in serum phosphate levels.

CONCLUSIONS

In cases of infants with hypophosphatemia of unknown etiology, the possibility of genetic factors should be taken into consideration. We have enumerated more than ten genetic disorders associated with infantile hypophosphatemia. These disorders involve pathogenic variants in over a dozen genes and affect multiple target organs, primarily including the kidneys, intestines, and bones. These diseases can be classified according to whether they are mediated by FGF23. We believe that this review would offer valuable insights into the clinical diagnosis and treatment of infantile hypophosphatemia related to genetic etiologies.