Abstract
ObjectiveVitamin D-dependent rickets type IA (VDDR-IA) is a rare autosomal recessive disorder characterized by the early onset of severe rickets. The objectives of this study were twofold: (1) to analyze the clinical characteristics and therapy of two patients with VDDR-IA from two separate Chinese families, and (2) investigate the CYP27B1 gene mutations in two large pedigrees.MethodsMedical history, clinical manifestations, physical examination, radiological findings and laboratory data were analyzed from two patients with VDDR-IA. Serum 1, 25-dihydroxyvitamin D [1, 25-(OH)2D3] of the two patients and their respective families were measured by ELISA and blood samples from both families was obtained for CYP27B1 gene sequence.ResultsTwo patients had typical manifestations and radiological evidence of rickets. Laboratory data showed hypocalcaemia and hypophosphataemia, along with high levels of serum alkaline phosphatase, parathyroid hormone and 25-hydroxyvitamin D3. However, serum 1,25-(OH)2D3 level were low in the patients but normal in their family members. Genetic sequence identified two patients were homozygous for a duplication mutation in exon 8 of CYP27B1 gene (c.1319_1325dupCCCACCC, p.Phe443Profs * 24). After treating with calcitriol and calcium, there was biochemical improvement with normalization of serum calcium and phosphorus, and radiographic evidence of compensatory skeletal mineralization. One patient developed nephrocalcinosis during follow-up.ConclusionsThis study identified a recurrent seven-nucleotide insertion of CYP27B1 in two large pedigrees, and compared the clinical characteristics and individual therapy of two affected patients. Additionally, our experience further supports the notion that nephrocalcinosis can occur even on standard doses of calcitriol and oral calcium, and normal level of serum calcium, phosphorus, PTH and 25-(OH)D3.
Highlights
Vitamin D consists of a group of biologically inactive, fat-soluble prohormones which exist in two major forms: ergocalciferol is mainly produced by plants and cholecalciferol is derived from 7-dehydrocholesterol in human skin by the action of UV sunlight rays in sunlight [1]
The second rate-limiting step [2] occurs mainly in kidney proximal tubules where 25-(OH)D3 is hydroxylated by the mitochondrial vitamin D1α-hydroxylase, a cytochrome P450 enzyme, to 1, 25-dihydroxyvitamin D3 [1, 25-(OH)2D3], acting through a special vitamin D receptor, the biological actions of 1, 25-(OH)2D3 encompass the regulation of calcium homeostasis, cellular differentiation, and immune function [1, 3, 4]
Genetic results Genetic sequence identified two patients were homozygous for a duplication mutation in exon 8 of CYP27B1 gene (c.1319_1325dupCCCACCC/p.Phe443Profs * 24)
Summary
Vitamin D consists of a group of biologically inactive, fat-soluble prohormones which exist in two major forms: ergocalciferol (vitamin D2) is mainly produced by plants and cholecalciferol (vitamin D3) is derived from 7-dehydrocholesterol in human skin by the action of UV sunlight rays in sunlight [1]. Both forms of vitamin D are activated by a two-step hydroxylation at carbons 25 and 1. Vitamin D-dependent rickets type IA (VDDR-IA), referred to as pseudo-vitamin D deficiency rickets, was first identified by Prader et al [5] in 1961 This is a rare autosomal recessive disorder caused by 1α-hydroxylase deficiency. These mutations involve all nine exons, and the most common type of CYP27B1 mutation is a missense mutation, representing more than half of those reports [13]
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