title: A human vitamin D receptor mutation causes rickets and impaired Th1/Th17 responses.
abstract: We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D3). Genomic sequencing showed a homozygous point mutation (A133G) in the vitamin D receptor gene, leading to an amino acid change in the DNA binding domain (K45E), which was described previously. Hereditary vitamin D resistant rickets (HVDRR) was diagnosed. Functional studies in skin biopsy fibroblasts confirmed this. 1,25-(OH)2D3 reduced T helper (Th) cell population-specific cytokine expression of interferon γ (Th1), interleukins IL-17A (Th17) and IL-22 (Th17/Th22) in peripheral blood mononuclear cells (PBMCs) from the patient's parents, whereas IL-4 (Th2) levels were higher, reflecting an immunosuppressive condition. None of these factors were regulated by 1,25-(OH)2D3 in PBMCs from the boy. At present, both patients (boy is 23 years of age, girl is 7) have not experienced any major immune-related disorders. Although both children developed alopecia, the girl did so earlier than the boy. The boy showed complete recovery from the rickets at the age of 17 and does not require any vitamin D supplementations to date. In conclusion, we characterized two siblings with HVDRR, due to a mutation in the DNA binding domain of VDR. Despite a defective T cell response to vitamin D, no signs of any inflammatory-related abnormalities were seen, thus questioning an essential role of vitamin D in the immune system. Despite the fact that currently medicine is not required, close monitoring in the future of these patients is warranted for potential recurrence of vitamin D dependence and diagnosis of (chronic) inflammatory-related diseases.
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. Electronic address: b.vandereerden@erasmusmc.nl.
authors.forename: Bram C J
authors.initials: BC
authors.lastname: van der Eerden
authors.affiliation: Department of Pediatric Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Josine C
authors.initials: JC
authors.lastname: van der Heyden
authors.affiliation: Department of Rheumatology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: Schreuders-Koedam
authors.affiliation: Department of Rheumatology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Asmawidjaja
authors.affiliation: Department of Pediatric Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: de Muinck Keizer-Schrama
authors.affiliation: Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Annemieke M
authors.initials: AM
authors.lastname: Boot
authors.affiliation: Department of Rheumatology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.affiliation: Department of Pediatric Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Stenvert L S
authors.initials: SL
authors.lastname: Drop
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D017354:Point Mutation; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics*; D063730:Rickets, Hypophosphatemic / Q000235:genetics* / Q000276:immunology*; D035781:Siblings; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D018167:Receptors, Calcitriol
keywords: Calcium; Phosphorus; Rickets; T cells; Vitamin D; Vitamin D receptor