Bone Abstracts

In this case report, we present a brother and sister with hereditary vitamin D resistant rickets (HVDRR). Both children presented at the age of 18 months with severe rickets and elevated serum levels of 1,25-(OH)₂D₃. They differ from each other in that the girl presented with hypophosphatemia instead of hypocalcemia. Besides, she developed alopecia earlier than the boy and needed more 1,25-(OH)₂D₃ supplementation. Interestingly, the boy does not require supplementation anymore since the age of 19.

We performed DNA sequencing of both patients along with their three siblings and their parents, who are first cousins. Both patients carry a homozygous point mutation (A133G) in the vitamin D receptor (VDR) gene, leading to an amino acid change in the DNA binding domain (K45E). Both parents were heterozygous for the same mutation. We collected skin fibroblasts from the boy. 1,25-(OH)₂D₃ was unable to inhibit their proliferation (in contrast to a healthy subject). Moreover, 1,25-(OH)₂D₃ failed to enhance 24-hydroxylase activity and VDR expression. Binding of 1,25-(OH)₂D₃ to the VDR, however, was not affected in the patient.

Since 1,25-(OH)₂D₃ plays a role in the innate and adaptive immune system, we screened the 1,25-(OH)₂D₃ response of peripheral blood mononuclear cells (PBMCs) from the boy, his parents and healthy controls. Both the T helper cell (Th) population-specific transcription of Tbet (Th1), Gata3 (Th2) and Roryt (Th17) as well as production of cytokines, such as interferon γ (Th1) and interleukins IL4 (Th2), IL10 (Th17) and IL22 (memory T cells) was altered in control PBMCs. No transcriptional or translational changes were observed in the PBMCs from the boy further supporting the inability to respond to 1,25-(OH)₂D₃.

Collectively, these data show that the A133G mutation in the VDR prevents nuclear binding, which leads to unresponsive 1,25-(OH)₂D₃ downstream signalling. Although 1,25(OH)₂D₃ acts on the immune system and has been associated with autoimmune diseases such as diabetes and multiple sclerosis, the patient, who is 1,25-(OH)₂D₃ insensitive, has no immunopathies but long-term follow-up necessary to monitor this. The treatment independence of the boy may be related to enhanced calcium uptake capacity in the intestine between 15 and 25 years of age, an age range he currently is in. The intriguing differences in onset of alopecia between the boy and the girl as well as their respective reduced serum calcium and phosphate at 18 months of age remain to be scrutinized.