Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A

Abstract

Objective: Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in the 1α-hydroxylase gene (CYB27B1). As it may be confused with nutritional rickets and hypophosphatemic rickets, genetic analysis is important for making a correct diagnosis.

Methods: We analysed genomic DNA from 11 patients from eight different Turkish families. The patients were recruited for our studies if they presented with a diagnosis of VDDR.

Results: The mean ± standard deviation age at diagnosis was 13.1±7.4 months. Seven patients had mild hypocalcemia at presentation while four patients had normal calcium concentrations. All patients underwent CYP27B1 gene analysis. The most prevalent mutation was the c.195 + 2T>G splice donor site mutation, affecting five out of 11 patients with VDDR1A. Two patients from the fourth family were compound heterozygous for c.195 + 2T>G and c.195 + 2 T>A in intron-1. Two patients, from different families, were homozygous for a previously reported duplication mutation in exon 8 (1319_1325dupCCCACCC, Phe443Profs*24). One patient had a homozygous splice site mutation in intron 7 (c.1215 + 2 T>A) and one patient had a homozygous mutation in exon 9 (c.1474 C>T).

Conclusion: Intron-1 mutation was the most common mutation, as previously reported. All patients carrying that mutation were from same city of origin suggesting a “founder” or a “common ancestor” effect. VDDR1A should definitely be considered when a patient with signs of rickets has a normal 25-OHD level or when there is unresponsiveness to vitamin D treatment.

Keywords: Vitamin D; vitamin D dependent rickets; CYP27B1 gene; 1α hydroxylase.

Figure 1

X-rays of this patient before (A) and at the 6th month of calcitriol treatment (B) (A) Abnormal cupping, widening and fraying of the metaphyses consistent with rickets. (B) Recovery of cupping and fraying, and a provisional calcification zone suggesting healing rickets

Figure 2

A) Wild type sequence of exon 8 in CYP27B1 gene. B) Sequencing analysis of the CYP27B1 gene exon 8 showing the homozygous mutation (1319_1325dupCCCACCC, Phe443Profs*24)