Vitamin D–Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?

Abstract

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.

Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes

“…Indeed, both the KO studies in mouse and the genetic evidence in humans indicate that defect in the CYP2R1 gene results in vitamin D deficiency (i.e., low plasma 25-OH-D level) (12,13,49). In humans, this has been shown to result in symptomatic rickets, vitamin D-dependent rickets type 1B (15). These patients respond poorly to ordinary vitamin D supplementation but may benefit from 25-OH-D treatment (15).…”

“…In humans, this has been shown to result in symptomatic rickets, vitamin D-dependent rickets type 1B (15). These patients respond poorly to ordinary vitamin D supplementation but may benefit from 25-OH-D treatment (15). Figure 5-The PGC1a-ERRa pathway mediates the CYP24A1 induction in the kidney by fasting.…”

“…Cytochrome P450 (CYP) 2R1 is the predominant vitamin D 25-hydroxylase in the liver (11,12). A genetic defect in the CYP2R1 gene has been shown to cause an inherited form of vitamin D deficiency and rickets in children (13)(14)(15). Large-scale studies have identified CYP2R1 gene variants as one of the major genetic determinants of low 25-OH-D levels (16)(17)(18).…”

Osteomalacia in practice of endocrinologist: etiology, pathogenesis, differential diagnosis with osteoporosis

“…С клинической точки зрения, выраженный дефицит витамина D, возникающий вследствие заболевания печени, встречается редко, поскольку степень деструкции печени, необходимая для нарушения гидроксилирования витамина D в положении C25 ферментом CYP2R1 с образованием 25(OH)D, несовместима с долгосрочным выживанием. Описаны семьи, у которых клинические и биохимические признаки указывали на наследственный дефект 25-гидроксилирования [16][17][18]. Однако генетический анализ неродственных между собой людей не позволил выявить мутации ни на кодирующем участке, ни в точках сплайсинга гена CYP2R1 [19].…”

Vitamin D Metabolism Revised: Fall of Dogmas

“…Indeed, the major 25‐hydroxylase, CYP2R1, is highly regulated by a variety of “clinical” conditions (obesity, starvation, type 1 or type 2 diabetes) and a number of regulatory factors are now clearly identified, albeit there are still major missing links. Genetic silencing mutations in CYP2R1 can cause rickets or osteomalacia, but no activating mutations are so far described. Null mutations of the same gene cause the same phenotype in cats .…”