CHU de Caen, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, Caen, France.
Université Caen Normandie, Medical School, Caen, France.
J Bone Miner Res. 2017 Sep;32(9):1893-1899. doi: 10.1002/jbmr.3181. Epub 2017 Jul 13.
Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH) D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B), a very rare condition that has only been reported to affect 4 families to date. We describe 7 patients from 2 unrelated families who presented with homozygous loss-of-function mutations of CYP2R1. Heterozygous mutations were present in their normal parents. We identified a new c.124_138delinsCGG (p.Gly42_Leu46delinsArg) variation and the previously published c.296T>C (p.Leu99Pro) mutation. Functional in vitro studies confirmed loss-of-function enzymatic activity in both cases. We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH) D. Siblings exhibited the three stages of rickets based on biochemical and radiographic findings. Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation. One index case presented with a partial improvement with 1alfa-hydroxyvitamin D or alfacalcidol (1α-OH-D ) treatment, and we observed a dramatic increase in the 1,25-(OH) D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D ), we documented normal 24-hydroxylase activity (CYP24A1). For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry). In conclusion, the current study further expands the CYP2R1 mutation spectrum. We note that VDDR1B could be easily mistaken for classical vitamin D deficiency. © 2017 American Society for Bone and Mineral Research.
维生素 D 需要两步羟化激活：第一步由肝 25-羟化酶（CYP2R1，11p15.2）催化，第二步由肾 1α-羟化酶（CYP27B1，12q13.1）催化，生成活性激素形式的 1,25-(OH) D。CYP2R1 的突变与维生素 D 依赖性佝偻病 1B（VDDR1B）有关，这是一种非常罕见的疾病，迄今为止仅报道了 4 个家族受其影响。我们描述了来自 2 个不相关家族的 7 名患者，他们均表现为 CYP2R1 纯合失活突变。其正常父母则携带杂合突变。我们发现了一种新的 c.124_138delinsCGG（p.Gly42_Leu46delinsArg）变异和先前报道的 c.296T>C（p.Leu99Pro）突变。体外功能研究证实了这两种情况均存在酶活性丧失。我们讨论了在面对正常/高浓度 1,25-(OH) D 时，正确诊断和特定生化模式（即提示经典维生素 D 缺乏的非常低的 25-OH-D）的困难。同胞们根据生化和影像学发现表现出佝偻病的三个阶段。有趣的是，成年患者无需维生素 D 补充即可维持正常的矿物质代谢。1 名指数病例在接受 1alfa-羟基维生素 D 或 alfacalcidol（1α-OH-D）治疗后出现部分改善，我们观察到血清 1,25-(OH) D 浓度显著升高，这表明辅助 25-羟化酶的作用。最后，在接受 calcifediol（25-OH-D）治疗的患者中，我们记录到正常的 24-羟化酶活性（CYP24A1）。根据个性化医疗的概念，我们首次证明了给予 25-OH-D 治疗的患者有显著改善（临床症状、生化数据和骨密度计）。总之，本研究进一步扩展了 CYP2R1 突变谱。我们注意到，VDDR1B 很容易被误诊为经典维生素 D 缺乏症。
