Endocrine Abstracts (2018) 55 P33 | DOI: 10.1530/endoabs.55.P33

A case of vitamin D-dependent rickets type 2A (VDDR2A), caused by compound-heterozygous mutations in the vitamin D receptor (VDR)

Victoria Stokes1, Alistair Pagnamenta2,3, Mark Stevenson1, Kate E Lines1, Brian Shine4, Jenny Taylor2,3, Tristan Richardson5 & Rajesh V Thakker1

1Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK; 2Wellcome Centre for Human Genetics, Oxford, UK; 3Oxford NIHR Biomedical Research Centre, Oxford, UK; 4Department of Clinical Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK; 5Department of Endocrinology, The Royal Bournemouth Hospital, Bournemouth, UK.

Case history: Vitamin D-dependent rickets type 2 (VDDR2) is an autosomal recessive condition caused by resistance to 1,25(OH)2D3, either through vitamin D receptor (VDR) mutations (type A) or abnormal expression of interfering proteins (type B), resulting in hypocalcaemia despite elevated plasma 1,25(OH)2D3 and parathyroid hormone concentrations. We report a proband, born to Caucasian non-consanguineous parents, who presented with rickets and alopecia aged 2 years. Investigations 20 years ago revealed abnormalities of plasma biochemistry that were consistent with VDDR2. A VDR mutation was not detected, although cellular studies identified an impaired VDR function. She was treated with high doses of oral calcium and alfacalcidol which ameliorated her rickets, and ultimately attained a normal height.

Investigations: Biochemistry at diagnosis showed a low adjusted calcium of 2.03 mmol/l (NR 2.25–2.55), low phosphate of 0.78 mmol/l (NR 1.29–1.79), elevated alkaline phosphatase of 1101 U/l (NR <300), elevated parathyroid hormone of 1283 ng/l (NR <660), normal 25(OH)D3 of 20 nmol/l and high 1,25(OH)2D3 of 466–650 pmol/l (NR 48–156).

Results and treatment: Next generation sequencing was undertaken to expedite simultaneous analysis of the VDR and other possible genes involved in the aetiology of VDDR2B. This revealed compound heterozygous variants c.800C>A and c.1171C>T in VDR. These predict p.Ala267Asp and p.Arg391Cys alterations at evolutionarily conserved residues and were inherited from the father and mother, respectively. Although neither variant was observed in Genome Aggregation Database, the p.Arg391Cys variant has been previously reported in a patient with VDDR2A.

Conclusions and points for discussion: We report a Caucasian female, who was born to non-consanguineous parents, with VDDR2A caused by compound heterozygous mutations of VDR. Of the reported kindreds with VDDR2A (n=53), the majority with a known pedigree are the offspring of related, or likely to be related, parents (95%) and have homozygous mutations (92%). The prevalence is highest in Middle Eastern and South American populations (32 and 16% respectively), and only 11 and 14% occur in the North African and Caucasian populations, respectively. However, VDDR2A is less likely to be due to homozygous mutations in the Caucasian population (67% vs 92%), possibly reflecting the lower reported rate of consanguinity (17% vs 95%). In summary, this case illustrates the clinical utility of scientific advances in sequencing techniques and the increased likelihood of the occurrence of compound heterozygous mutations giving rise to VDDR2A in the Caucasian population.

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