Vitamin D Hydroxylation-deficient Rickets Type 1A Misdiagnosed as Normocalcemic Primary Hyperparathyroidism.

Vitamin D hydroxylation-deficient rickets type 1A is an autosomal recessive disorder caused by pathogenic variants in CYP27B1 gene, which encodes for 1α-hydroxylase, the enzyme responsible for the conversion of 25-OH vitamin D into its active form 1,25(OH)2 vitamin D. We report the case of a 3-year-old female Mexican patient with growth retardation and progressive bone deformity, whose laboratory studies showed 25-OH vitamin D deficiency, a normal serum calcium and an elevated intact parathyroid hormone level that remained high despite calcitriol, cholecalciferol, and calcium supplementation. 99mTc sestamibi gammagram showed findings suggestive of parathyroid hyperplasia. Bone histomorphometry showed an image consistent with hyperparathyroidism without findings of osteomalacia, so normocalcemic primary hyperparathyroidism was suspected and a subtotal parathyroidectomy was performed, with the patient developing postoperative hypoparathyroidism. When she arrived at our clinic at age 18 years, she showed calcium- and calcitriol-dependent hypocalcemia, with secondary hyperparathyroidism and low levels of 1,25(OH)2 vitamin D in the absence of a 25-OH vitamin D deficiency, reflecting a defect in 1α-hydroxylation. Molecular testing revealed compound heterozygous variants in CYP27B1 gene. This is the first reported case of an inherited disorder of vitamin D metabolism that was diagnosed and surgically treated as primary hyperparathyroidism.

Altered expression of the vitamin D metabolizing enzymes CYP27B1 and CYP24A1 under the context of prostate aging and pathologies.

Low circulating levels of vitamin D are common at older ages and have been linked to an increased risk of prostate disease, including cancer. However, it has not yet been determined whether aging affects the ability of prostate cells to locally metabolize vitamin D into its active metabolite calcitriol and thus mediate the vitamin D signaling in autocrine and paracrine ways. By using a suitable rat model to interrogate spontaneous prostatic modifications over the course of aging, here we showed that both CYP27B1 and CYP24A1 enzymes, which are key players respectively involved with calcitriol synthesis and deactivation, were highly expressed in the prostate epithelium. Furthermore, as the animals aged, a drastic reduction of CYP27B1 levels was detected in total protein extracts and especially in epithelial areas of lesions, including tumors. On the other hand, CYP24A1 expression significantly increased with aging and remained elevated even in altered epithelia. Such intricate unbalance in regard to vitamin D metabolizing enzymes was strongly associated with reduced bioavailability of calcitriol in the senile prostate, which in addition to decreased expression of the vitamin D receptor, further limits the protective actions mediated by vitamin D signaling. This evidence was corroborated by the increased proliferative activity exactly at sites of lesions where the factors implicated with calcitriol synthesis and responsiveness had its expression inhibited. Taken together, our results emphasize a set of modifications over the course of aging with a high potential to hamper vitamin D signaling on the prostate. These findings highlight a crosstalk between vitamin D, aging, and prostate carcinogenesis, offering new potential targets in the prevention of malignancies and other aging-related disorders arising in the gland.

Association of Vitamin D Metabolism Gene Polymorphisms with Autoimmunity: Evidence in Population Genetic Studies.

A high prevalence of vitamin D (calcidiol) serum deficiency has been described in several autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (AR), and systemic lupus erythematosus (SLE). Vitamin D is a potent immunonutrient that through its main metabolite calcitriol, regulates the immunomodulation of macrophages, dendritic cells, T and B lymphocytes, which express the vitamin D receptor (VDR), and they produce and respond to calcitriol. Genetic association studies have shown that up to 65% of vitamin D serum variance may be explained due to genetic background. The 90% of genetic variability takes place in the form of single nucleotide polymorphisms (SNPs), and SNPs in genes related to vitamin D metabolism have been linked to influence the calcidiol serum levels, such as in the vitamin D binding protein (VDBP; rs2282679 GC), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the vitamin D receptor (FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) VDR). Therefore, the aim of this comprehensive literature review was to discuss the current findings of functional SNPs in GC, CYP2R1, CYP27B1, and VDR associated to genetic risk, and the most common clinical features of MS, RA, and SLE.

Expression of vitamin D receptor, CYP27B1 and CYP24A1 hydroxylases and 1,25-dihydroxyvitamin D3 levels in stone formers.

The expression of vitamin D receptor (VDR) and 1,25-dihydroxyvitamin D3 [1,25(OH)D] levels exceed the values of controls in some but not all hypercalciuric stone formers (HSF). We aimed to evaluate serum 1,25(OH)D levels, the expression of VDR, CYP27B1, and CYP24A1 hydroxylases in HSF in comparison with normocalciuric stone formers (NSF) and healthy subjects (HS). Blood samples, 24-h urine collections and a 3-day dietary record were obtained from 30 participants from each of the groups. The expression of VDR, CYP27B1, and CYP24A1 was measured by flow cytometry. HSF presented significantly higher urinary volume, sodium, magnesium, oxalate, uric acid, and phosphorus than NSF and HS. Calcium intake was lower in HSF versus NSF and HS (442 ± 41 vs 594 ± 42 and 559 ± 41 mg/day, respectively, p = 0.027). Ionized calcium was significantly lower in HSF than NSF (1.29 ± 0.0 vs 1.31 ± 0.0 mmol/L, p < 0.01). Serum 1,25(OH)D was significantly higher in HSF and NSF than HS (22.5 ± 1.2; 22.2 ± 1.2 vs 17.4 ± 1.2 pg/ml, p = 0.007) but serum 25(OH)D, PTH, klotho and plasma FGF-23 did not differ between groups. VDR expression was higher in HSF and NSF than HS (80.8 ± 3.2; 78.7 ± 3.3 vs 68.6 ± 3.2%, p = 0.023). Although CYP27B1 and CYP24A1 expressions were similar among all groups, the ratio of 1,25(OH)D/CYP24A1 was higher in HSF and NSF than in HS (1.43 ± 0.25 and 0.56 ± 0.10 vs 0.34 ± 0.06, p = 0.00). Stone formers, regardless of urinary calcium excretion, had higher VDR expression and 1,25(OH)D levels than HS, even in ranges considered normal. Higher 1,25(OH)D/CYP24A1 ratio suggested a lower degradation of 1,25(OH)D by CYP24A1 in HSF and NSF.