Renal Fanconi syndrome and vitamin D deficiency: chicken or egg?

BACKGROUND: Renal Fanconi syndrome (RFS) refers to a generalized dysfunction of the proximal tubule, including impaired 1-α hydroxylation of vitamin D. Consequently, rickets is a typical complication. Clinical observations in children with severe nutritional vitamin D deficiency sometimes include proximal tubular dysfunction, raising the possibility that lack of vitamin D could not only be a consequence of RFS but also a cause of it, although this has never been confirmed. Observations in Mendelian disorders with their genetically defined pathophysiology can provide clearer insights. METHODS: We performed a retrospective review of 2 cases with vitamin D deficiency due to loss-of-function variants in CYP27B1. Additionally, we performed an in silico search for vitamin D-responsive elements (VDRE) in the promoter region of genes encoding proximal tubular transporters. RESULTS: Both cases presented with clinical rickets that had been resistant to supplementation with cholecalciferol. Biochemistries at presentation showed a non-anion gap metabolic acidosis, generalized aminoaciduria and urinary phosphate wasting consistent with proximal tubular dysfunction. Symptoms resolved upon treatment with active vitamin D. VDRE motifs were identified in the promoters of SLC34A1 and SLC34A3. CONCLUSIONS: Our observations support the notion of vitamin D deficiency as a cause of RFS and suggest that unresolved cases of RFS should be actively investigated for it.