Late diagnosis of SLC34A3-related hereditary hypophosphatemic osteomalacia following a low-energy proximal humeral 4-part fracture

Abstract

Abstract Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare FGF23-independent renal phosphate-wasting disorder caused by biallelic variants in SLC34A3, typically diagnosed in childhood or early adulthood. Delayed recognition in elderly individuals is uncommon, and the clinical features leading to diagnosis in this population remain poorly characterized. We report a case of a 77-yr-old Japanese man with HHRH who remained undiagnosed until advanced age and was identified following a proximal humeral fracture sustained after a low-energy fall. The severity of the fracture, together with his history of multiple previous fractures, prompted biochemical evaluation for secondary causes of skeletal fragility. Biochemical assessment revealed hypophosphatemia with preserved renal function, elevated 1,25(OH)2D3 levels, hypercalciuria, and reduced renal phosphate reabsorption. Intact FGF23 was mildly above the assay reference limit and was not appropriately suppressed in the setting of hypophosphatemia. BMD was in the osteoporotic range at the FN, but it did not distinguish osteoporosis from an underlying mineralization disorder. Genetic analysis identified a homozygous synonymous variant in SLC34A3 (c.942G > C, p.Ala314=) in the context of a characteristic biochemical phenotype consistent with HHRH. Oral phosphate supplementation alone resulted in rapid normalization of serum phosphate levels, without deterioration in renal function or worsening hypercalciuria. This case suggests that SLC34A3-related phosphate-wasting disorders may remain clinically unrecognized until late adulthood. Importantly, it highlights the value of biochemical evaluation, including the measurement of serum phosphate and the assessment of renal phosphate handling, in patients with otherwise unexplained skeletal fragility. Phosphate-wasting disorders should be considered in patients with recurrent fractures or skeletal fragility that is not fully explained by BMD or the reported injury mechanism.