X-Linked Hypophosphatemia in a Family Cohort: Clinical Variability, Genetic Confirmation and Modern Therapeutic Perspectives.

Background/

Objectives

X-linked hypophosphatemia (XLH) is the most common form of inherited rickets, caused by pathogenic mutations in the PHEX gene (phosphate-regulating endopeptidase homolog, X-linked). These mutations increase fibroblast growth factor 23 (FGF23) activity, resulting in renal phosphate wasting and defective bone mineralization. The disorder manifests with variable skeletal, dental, and extraskeletal involvement. Conventional therapy with oral phosphate and active vitamin D offers limited benefit, whereas burosumab, an anti-FGF23 monoclonal antibody, has transformed disease management.

Methods

The index case, a 43-year-old woman, remained undiagnosed until adulthood, leading to severe deformities, osteoarthritis, chronic pain, and complete edentulism. Her 55-year-old sister presented with a milder phenotype. The 20-year-old nephew, diagnosed in childhood and intermittently treated with phosphate and alfacalcidol, developed short stature, genu varum, and early degenerative joint disease. Following genetic confirmation, he began burosumab therapy, which normalized phosphate metabolism, reduced pain, and improved mobility.

Results

XLH demonstrates marked intrafamilial phenotypic variability despite identical PHEX mutations. In this series, delayed recognition in adults led to irreversible skeletal deformities, osteoarthritis, and dental loss, whereas earlier diagnosis in the younger patient allowed timely intervention. Conventional therapy only partially mitigated complications, while burosumab achieved rapid biochemical correction and symptomatic improvement. This contrast highlights the importance of early genetic testing, family screening, and prompt initiation of targeted treatment.

Conclusions

This family cluster underscores the critical need for early diagnosis, genetic confirmation, cascade screening, and lifelong multidisciplinary care. Burosumab represents a therapeutic paradigm shift in XLH, capable of altering disease trajectory when initiated early.