50 Years Ago in TheJournalofPediatrics: Resistance Is Futile—The Path to Discovery of the Cause of Rickets Not Amenable to Vitamin D Therapy

Abstract

Lewy JE, Cabana EC, Repetto HA, Canterbury JM, Reiss E. Serum parathyroid hormone in hypophosphatemic vitamin D-resistant rickets. J Pediatr 1972;81:294-300.Nutritional rickets has been recognized since the 17th century. Advances in the diagnosis of rickets and treatment with vitamin D were notable in the early 1900s.1Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective.Pediatrics. 2003; 112: e132-e135Crossref PubMed Scopus (197) Google Scholar However, a condition with a new classification emerged: vitamin D–resistant rickets (VDRR) with hypophosphatemia and phosphaturia, which was expanded to include various heritable forms of VDRR. A landmark 1937 paper by Albright et al launched decades of investigation into the etiology of this condition.2Albright F. Butler A.M. Bloomberg E. Rickets resistant to vitamin D therapy.Am J Dis Child. 1937; 54: 529-547Crossref Google ScholarThe report by Lewy et al is an important chapter in the chronicle of discovery. Determining the relationship between parathyroid hormone, phosphate, and calcium was another stitch in the tapestry of heritable causes of VDRR. The realization that parathyroid hormone alone does not provoke phosphaturia in VDRR led to the discovery of PHEX, the causative gene in X-linked hypophosphatemic rickets (XLH) and fibroblast growth factor-23 (FGF23), which is inappropriately elevated in XLH. FGF23 binds to a receptor in the distal convoluted tubule and inhibits Na-Pi cotransport and 1α hydroxylase, which converts 25(OH2)D to its active component 1,25(OH2)D. Inactivation of this enzyme is the putative reason that supplementation with vitamin D is ineffective in these conditions. FGF23 regulation of phosphate and its effects on vitamin D revolutionized not only our understanding of VDRR, but also chronic kidney disease.3Levine B.S. Kleeman C.R. Felsenfeld A.J. The journey from vitamin D-resistant rickets to the regulation of renal phosphate transport.Clin J Am Soc Nephrol. 2009; 4: 1866-1877Crossref PubMed Scopus (28) Google Scholar The development of burosumab, a monoclonal antibody approved as a treatment for XLH, ushers in a new inspiring era and another chapter of discovery.4Haffner D. Leifheit-Nestler M. Grund A. Schnabel D. Rickets guidance: part II—management.Pediatr Nephrol. 2022 Mar; 29https://doi.org/10.1007/s00467-022-05505-5Crossref Scopus (1) Google Scholar Lewy JE, Cabana EC, Repetto HA, Canterbury JM, Reiss E. Serum parathyroid hormone in hypophosphatemic vitamin D-resistant rickets. J Pediatr 1972;81:294-300. Nutritional rickets has been recognized since the 17th century. Advances in the diagnosis of rickets and treatment with vitamin D were notable in the early 1900s.1Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective.Pediatrics. 2003; 112: e132-e135Crossref PubMed Scopus (197) Google Scholar However, a condition with a new classification emerged: vitamin D–resistant rickets (VDRR) with hypophosphatemia and phosphaturia, which was expanded to include various heritable forms of VDRR. A landmark 1937 paper by Albright et al launched decades of investigation into the etiology of this condition.2Albright F. Butler A.M. Bloomberg E. Rickets resistant to vitamin D therapy.Am J Dis Child. 1937; 54: 529-547Crossref Google Scholar The report by Lewy et al is an important chapter in the chronicle of discovery. Determining the relationship between parathyroid hormone, phosphate, and calcium was another stitch in the tapestry of heritable causes of VDRR. The realization that parathyroid hormone alone does not provoke phosphaturia in VDRR led to the discovery of PHEX, the causative gene in X-linked hypophosphatemic rickets (XLH) and fibroblast growth factor-23 (FGF23), which is inappropriately elevated in XLH. FGF23 binds to a receptor in the distal convoluted tubule and inhibits Na-Pi cotransport and 1α hydroxylase, which converts 25(OH2)D to its active component 1,25(OH2)D. Inactivation of this enzyme is the putative reason that supplementation with vitamin D is ineffective in these conditions. FGF23 regulation of phosphate and its effects on vitamin D revolutionized not only our understanding of VDRR, but also chronic kidney disease.3Levine B.S. Kleeman C.R. Felsenfeld A.J. The journey from vitamin D-resistant rickets to the regulation of renal phosphate transport.Clin J Am Soc Nephrol. 2009; 4: 1866-1877Crossref PubMed Scopus (28) Google Scholar The development of burosumab, a monoclonal antibody approved as a treatment for XLH, ushers in a new inspiring era and another chapter of discovery.4Haffner D. Leifheit-Nestler M. Grund A. Schnabel D. Rickets guidance: part II—management.Pediatr Nephrol. 2022 Mar; 29https://doi.org/10.1007/s00467-022-05505-5Crossref Scopus (1) Google Scholar