ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Invest 2018;128:1913-1918

Two rare genetic forms of vitamin D–dependent rickets exist: VDDR-1 caused by mutations in the genes encoding either the renal 1-α hydroxylase (CYP27B1: VDDR-1A) or the hepatic 25-hydroxylase (CYP2R1: VDDR-1B) and VDDR-2 caused by mutations in the vitamin D receptor signalling due to mutations in the gene encoding the vitamin D receptor (VDR: VDDR-2A) or the heterogeneous nuclear ribonucleoprotein C (HNRNPC: VDDR-2B).

Here, the authors describe two cases of rickets in children who had detectable serum vitamin D₃ but low serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D which increased only after administration of very large doses of vitamin D or calcitriol and declined rapidly thereafter. Serum 24,25-dihydroxyvitamin D was low, suggesting that increased vitamin D metabolite inactivation by CYP24A1 did not account for apparent vitamin D deficiency. Whole exome sequencing analysis identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects. The protein encoded by CYP3A4, cytochrome P450 3A4, localizes to the endoplasmic reticulum and is mainly expressed in the liver and in the intestine. This gain-of-function mutation in CYP3A4 leads to vitamin D deficiency through accelerated vitamin D metabolite inactivation. The authors named this dominant form of VDDR as VDDR-3. In addition, this study suggests that genetic and induced variation in CYP3A4 activity and associated accelerated vitamin D inactivation may act as a modifier on the amount of vitamin D that is necessary to maintain vitamin D homeostasis. This finding expands the genetic forms of VDDR’s, summarised in the Table below.

Abbreviations: VDDR, vitamin D-dependent rickets; Ca, serum calcium; 25-OHD, 25-hydroxyvitamin D; 1,25(OH)₂D, 1,25, dihydroxyvitamin D; N, normal; ↑, increased; ↓, decreased

1. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, Hasegawa Y, Niimi H, Yanagisawa J, Tanaka T, Kato S. Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med. 1998;338(10):653–661.

2. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A. 2004;101(20):7711–7715.

3. Hughes, M. R., Malloy, P. J., Kieback, D. G., Kesterson, R. A., Pike, J. W., Feldman, D., O’Malley, B. W. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 1988;242:1702-1705.

4. Chen H, Hewison M, Hu B, Adams JS. Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance. Proc Natl Acad Sci U S A. 2003;100(10):6109–6114.

5. Roizen JD1, Li D2, O’Lear L1, Javaid MK3, Shaw NJ4, Ebeling PR5, Nguyen HH5, Rodda CP6, Thummel KE7, Thacher TD8, Hakonarson H2, Levine MA1. CYP3A4 mutation causes vitamin D-dependent rickets type 3. J Clin Invest. 2018 May 1;128(5):1913-1918.