Compound Heterozygous Mutations in Vitamin D Receptor Gene in Two Sisters With Hereditary Vitamin D Resistant Rickets Type II

Abstract

Background: Hereditary vitamin D resistant rickets (HVDRR) type II , is a rare autosomal recessive disorder with known heterogeneity in clinical features, response to treatment and presence or absence of vitamin D receptor (VDR) gene mutation. Here, we described VDR gene mutations in 2 sisters with HVDRR with correlation to clinical features, and response to treatment. Methods: Vitamin D receptor gene sequence analysis was performed for exons 2 and 3, in addition to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for exons 7 and 8. Patients, their parents, their elder sister and brother were studied. Treatment with high dose vitamin D, response to therapy, and 30 months follow up were recorded for both patients. Results: A novel heterozygous point mutation (c.A155G) at the initiation codon of exon 3 was found in the 2 patients, their father and their healthy brother. This point mutation changed the amino acid (aa) at position 51 of the VDR from serine to glycine (p.Ser51Gly) at the start of the second zinc finger of the DNA-binding domain of the VDR. Exon 7 showed a heterozygous mutation in both patients and their mother. The mutation was located at the 970 base pair (bp) of VDR. Patients responded well to high doses oral calcium and Alfacalcidol without relapse of their rickets for the whole follow up period. Conclusion: Compound heterozygous mutation was identified in the VDR gene in 2 sisters with HVDRR. This mutation resulted in HVDRR without alopecia that was responsive to high dose vitamin D therapy. J Endocrinol Metab. 2011;1(4):174-181 doi: https://doi.org/10.4021/jem41w