Vitamin D-dependent Rickets Research Articles

Vitamin D Dependent Rickets Type IB as a Rare Cause of Rickets, Case Report and Literature Review

Aim: The aim of this paper to report one case with vitamin D-dependent rickets, type IB. Methods: Diagnosis has been established based on physical examination, laboratory findings and radiological examination and confirmed by positive gentic mutation. Results: Here we report a 3 year old Saudi female who present with valgus deformity of the feet and delayed motor development with biochemical, radiological evidence of vitamin D disorders. Since vitamin D level was low she was assumed and treated as being due to vitamin D deficiency and treated with cholecalciferol / one alpha for 1 year, but there was no improvement, latter on referred to us where we did gentic study which show a positive gentic mutation at CYP27B1 confirming diagnosis of Vitamin D dependent Rickets 1B, and treatment with Calcitriol then patient show great improvement within 4 weeks, Alkaline phosphatase and PTH both drop to normal levels. Clinical and radiological evidence of the improvement was seen after 3 months of Calcitriol. Conclusions: In this paper, we raise the awareness that Rickets with low vitamin D25 level not always mean deficiency, especially if patient fail to improve with cholecalciferol, and in such case, a rare inherited disorder of Vitamin D activation and action should be looked for, and gentic study is helpful in such cases.

Clinical characteristics and long-term outcomes of 12 children with vitamin D-dependent rickets type 1A: A retrospective study.

Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by deficiency of the CYP27B1 gene. This study aims to investigate the phenotypic and genotypic features of VDDR1A children in southern China and evaluate the long-term therapeutic effects. Twelve children from southern China with VDDR1A were enrolled in this study. Their clinical, radiological, biochemical, and molecular findings were analyzed retrospectively. The rickets severity score (RSS), biochemical parameters, and height standard deviation score (HtSDS) were used to evaluate clinical outcomes. Six males and six females were included in this VDDR1A cohort. The age of onset was from 6 months to 1.8 years, and the age at diagnosis was 2.1 ± 0.8 years. The most common clinical symptoms at diagnosis were delayed walking (10/12) and severe growth retardation (9/12). HtSDS at diagnosis was negatively associated with age (p < 0.05). All patients presented with hypocalcemia, hypophosphatemia, increased serum alkaline phosphatase and parathyroid hormone, and high RSS at diagnosis. Two allelic variants of the CYP27B1 gene were identified in all patients, including nine different variants, four known and five novel, with c.1319_1325dupCCCACCC(p.Phe443Profs*24) being the most frequent. All patients were treated with calcitriol and calcium after diagnosis, and all patients but one were followed-up from 6 months to 15.6 years. HtSDS, RSS, and biochemical parameters were found to be improved during the first few years of the treatment. However, only five patients had good compliance. Although RSS and biochemical parameters were significantly improved, the HtSDS change was not significant from the time of diagnosis to the last visit, and seven patients remained of a short stature (HtSDS < -2). Our study extends the mutational spectrum of VDDR1A and finds a hotspot variant of the CYP27B1 gene in southern China. The results reconfirm the importance of early diagnosis and treatment compliance and reveal the challenge of height improvement in VDDR1A patients.

Vitamin D-dependent rickets type 1A

Vitamin D-dependent rickets type 1 is a rare autosomal recessive disorder caused by mutation of the CYP27B1 gene, that further leads to a decrease in the activity of 1A-hydroxylase and vitamin D metabolic disorder. The disease manifests itself by means of rickets-like changes, alike to the symptoms of vitamin D-deficiency rickets, what inhibits both the early diagnosis and timely appointment of an adequate pathogenetic therapy with the usage of active vitamin D metabolites. Etiology, pathogenesis, diagnosis, differential diagnosis, and treatment of vitamin D-dependent rickets type 1A issues are presented in this article. Using the example of the clinical case, it shows the principles of selecting an adequate dose of replacement therapy.

Rickets: It is Not Always Nutritional. A Rare Case of Vitamin D-Dependent Rickets (VDDR) Type I

Rickets is typically due to nutritional cause, namely vitamin D and calcium deficiency worldwide. When there is suboptimal response to conventional vitamin D and calcium supplementation, alternative causes have to be sought. We report a rare case of vitamin D-dependent rickets (VDDR) who presented with rachitic features but normal total 25-hydroxyvitamin D 25(OH)D level. Conventional inactive vitamin D supplementation was ineffective and high dose of alfacalcidol was required to maintain normocalcaemia.

Clinical presentation and molecular genetic analysis of a Sudanese family with a novel mutation in the CYP2R1 gene

The aim of this study was to identify the genetic basis of two female siblings - born to consanguineous Sudanese parents - diagnosed clinically as having the rare condition of 25-hydroxylase deficiency (vitamin D-dependent rickets type 1B). The initial diagnosis was established based on clinical data, laboratory and radiological findings retrospectively. Primers for all exons (5) of human CYP2R1 (NM_024514) were generated followed by Sanger sequencing on exons 1–5 for both girls and their parents. Homozygosity for a point mutation (c.85C > T) was detected, leading to a nonsynonymous variant at position 29 in exon 1, resulting in a premature stop codon (p.Q29X). This is a previously unknown variant that leads to a severely truncated protein and predicted to be among the 0.1 % most deleterious genomic variants(CADD score 36). To our knowledge, this family represents the first case series from Sudan with a confirmed CYP2R1 gene mutation and the 6th world-wide. With the lack of genetic facilities, diagnosis should be suspected by the persistently low 25 hydroxyvitamin D level in spite of proper treatment and after ruling out liver disease and malabsorption. Patients in this case series showed healing of rickets when treated with high doses of 1,25-dihydroxyvitamin D3 (1,25(OH)D3; calcitriol) and oral calcium.

An unusual presentation of vitamin D dependent rickets type 2 with low 25 (OH) D3 levels and alopecia: a case report of two siblings

Vitamin D-dependent rickets type 2 (VDDR2) is a rare autosomal recessive (AR) disorder caused either by a mutation in the Vitamin D receptor gene or overexpression of the binding protein leading to end-organ resistance to 1,25 (OH)2 vitamin D3 or defective hormonal actions respectively. It clinically represents growth retardation presenting in the 1st year of life and is frequently associated with alopecia totalis and markedly elevated levels of 1, 25(OH)2 D, which differentiates it from VDDR type 1. We hereby report siblings of a family, who presented with clinical, radiological features of rickets and alopecia totalis. To our knowledge, only a few cases have been reported in literature describing the AR-pattern and low 25(OH)D3 levels in VDDR2.

Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats

Active vitamin D form 1α,25-dihydroxtvitamin D3 (1,25(OH)2D3) plays pivotal roles in calcium homeostasis and osteogenesis via its transcription regulation effect via binding to vitamin D receptor (VDR). Mutated VDR often causes hereditary vitamin D-dependent rickets (VDDR) type II, and patients with VDDR-II are hardly responsive to physiological doses of 1,25(OH)D3. Current therapeutic approaches, including high doses of oral calcium and supraphysiologic doses of 1,25(OH)2D3, have limited success and fail to improve the quality of life of affected patients. Thus, various vitamin D analogues have been developed as therapeutic options. In our previous study, we generated genetically modified rats with mutated Vdr(R270L), an ortholog of human VDR(R274L) isolated from the patients with VDDR-II. The significant reduced affinity toward 1,25(OH)2D3 of rat Vdr(R270L) enabled us to evaluate biological activities of exogenous VDR ligand without 1α-hydroxy group such as 25(OH)D3. In this study, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)2D3 (AH-1) exerted much higher affinity for Vdr(R270L) in in vitro ligand binding assay than both 25(OH)D3 and 1,25(OH)2D3. A robust osteogenic activity of AH-1 was observed in Vdr(R270L) rats. Only a 40-fold lower dose of AH-1 than that of 25(OH)D3 was effective in ameliorating rickets symptoms in Vdr(R270L) rats. Therefore, AH-1 may be promising for the therapy of VDDR-II with VDR(R274L).

Cell-Dependent Pathogenic Roles of Filamin B in Different Skeletal Malformations.

Mutations of filamin B (FLNB) gene can lead to a spectrum of autosomal skeletal malformations including spondylocarpotarsal syndrome (SCT), Larsen syndrome (LRS), type I atelosteogenesis (AO1), type III atelosteogenesis (AO3), and boomerang dysplasia (BD). Among them, LRS is milder while BD causes a more severe phenotype. However, the molecular mechanism underlying the differences in clinical phenotypes of different FLNB variants has not been fully determined. Here, we presented two patients suffering from autosomal dominant LRS and autosomal recessive vitamin D-dependent rickets type IA (VDDR-IA). Whole-exome sequencing revealed two novel missense variants in FLNB, c.4846A>G (p.T1616A) and c.7022T>G (p.I2341R), which are located in repeat 15 and 22 of filamin B, respectively. The expression of FLNBI2341R in the muscle tissue from our LRS patient was remarkably increased. And in vitro studies showed that both variants led to a lack of filopodia and accumulation of the mutants in the perinuclear region in HEK293 cells. We also found that c.4846A>G (p.T1616A) and c.7022T>G (p.I2341R) regulated endochondral osteogenesis in different ways. c.4846A>G (p.T1616A) activated AKT pathways through inhibiting SHIP2, suppressed the Smad3 pathway, and impaired the expression of Runx2 in both Saos-2 and ATDC5 cells. c.7022T>G (p.I2341R) activated both AKT and Smad3 pathways and increased the expression of Runx2 in Saos-2 cells, while in ATDC5 cells it activated AKT pathways through inhibiting SHIP2, suppressed the Smad3 pathway, and reduced the expression of Runx2. Our study demonstrated the pathogenic mechanisms of two novel FLNB variants in two different clinical settings and proved that FLNB variants could not only directly cause skeletal malformations but also worsen skeletal symptoms in the setting of other skeletal diseases. Besides, FLNB variants differentially affect skeletal development which contributes to clinical heterogeneity of FLNB-related disorders.

Oral Rehabilitation of a Female Child with Vitamin D-dependent Rickets Type II A: A Case Report

Oral Rehabilitation of a Female Child with Vitamin D-dependent Rickets Type II A: A Case Report

Differentiated Approach to Surgical Treatment of Blount's Disease and Rickets-Like Diseases

Relevance. Blount's disease and vitamin-D-dependent rickets (VDDR) are nosologically different skeletal diseases in childhood. Considering the similarity of the clinical and radiological picture, orthopedists and pediatricians make mistakes in diagnostics, which leads to wrong treatment tactics.&#x0D; Objective: to establish clear indications for surgical treatment of Blount's disease and rickets-like diseases.&#x0D; Materials and Methods. Surgical treatment of 13 patients with varus lower extremity deformities with vitamin-D-dependent rickets and 29 patients with Blount's disease was carried out; 26 and 42 surgical interventions were made, respectively. The patients' age ranged from 6 months to 14 years.&#x0D; Results. Multilevel osteotomies with blocking and growing intramedullary rods should be performed for the treatment of rickety deformities. Applied plates are used only in single-level corrective osteotomies. The use of eight-shaped plates is indicated in the process of the growth zone functioning. In Blount's disease, we recommend: (1) blocking growth zones in patients with 1-4 degrees of deformity, II-VI stages according to Langenskiöld, and skeletal maturity of 23 to 33 points; (2) semicircular dissection in patients with 1-2 degrees of deformity, I-II stages according to Langenskiöld, and skeletal maturity of 18 to 23 points; (3) corrective osteotomies combined with simultaneous blocking of growth zones in patients with 3-4 degrees of deformity, V-VI stages according to Langenskiöld, and skeletal maturity of 30 to 33 points.&#x0D; Conclusions. The presented laboratory diagnostics enables differentiate diagnostics of the etiological affiliation of the varus deformity of the lower leg. If rickets is detected, pathogenetic conservative treatment should be performed; in case of Blount's disease, surgical treatment should be started using minimally invasive methods. In the absence of positive dynamics in case of rickets, guided growth should be applied. In case of multiplanar deformities, one should apply the methods of corrective and reinforced surgical treatment: multilevel osteotomies with a blocking intramedullary rod after the closure of the growth zones and osteotomy with a telescopic intramedullary rod in case of preserved growth zone. If Blount's disease is diagnosed early, timely and correctly, growth zone blocking is the method of choice. In case of recurrence, corrective osteotomies with blockage of growth zones should be performed.

Vitamin D-Dependent Rickets Type 1A in Two Siblings with a Hypomorphic CYP27B1 Variant Frequent in the African Population.

Vitamin D-dependent type 1A rickets (VDDR-1A) is a rare autosomal recessive disease due to the inability to convert 25-hydroxyvitamin D [25(OH)D] to the active form 1.25-dihydroxyvitamin D [1.25(OH) 2 D] by the enzyme 25(OH)D-1α-hydroxylase leading to low or low-normal serum levels of [1.25(OH) 2 D]. We report two sisters with rickets in whom the diagnosis of VDDR-1A was a challenge. They had normal 1.25(OH)2D levels, which are unusual with this condition but may be explained by the identified genotype. Both have compound heterozygous for two, most likely, hypomorphic CYP27B1 alleles: the novel p.(Arg117Gly) variant, and p.(Ala129Thr), which are present in 0.43% of the African population. This report illustrates the variability of clinical, laboratory, and radiological presentation between two sisters with the same genotype, during phases of faster or slower growth. Genetic testing was crucial for establishing the diagnosis that optimized the management and genetic counseling.

Консервативне лікування порушень метаболізму кісткової тканини у хворих на вітамін-D-залежний рахіт ІІ типу з генетичним ушкодженням формування колагену І типу

Мета дослідження: визначити вплив консервативної терапії на генетично зумовлені порушення метаболізму кісткової тканини у хворих на D-залежний рахіт ІІ типу з генетичним ушкодженням формування колагену І типу. Матеріали та методи. На базі консультативно-поліклінічного відділу ДУ «Інститут травматології та ортопедії НАМНУ» було обстежено та проліковано 13 пацієнтів із діагнозом вітамін-D-залежного рахіту ІІ типу з генетичним ушкодженням формування колагену І типу (ВДЗР(COL1)). Консервативне лікування пацієнтів з даним рахітоподібним захворюванням проводилось у 4 етапи. Перший етап включав повне обстеження пацієнта щодо рівня кальцію, фосфору крові та сечі, кальцидіолу та кальцитріолу крові, показників паратиреоїдного гормону та остеокальцину, а також маркера кісткоутворення P1NP і маркера остеорезорбції β-CTx. На першому етапі в обов’язковому порядку діти проходили генетичне дослідження для виявлення змін (поліморфізму) в алелях рецепторів до вітаміну D та колагену І типу. Обстеження на наступних етапах проводилось у повному обсязі, окрім генетичних досліджень. Результати. Виявлено, що генетично зумовлене порушення рецепції вітаміну D призводить до значного акумулювання активного метаболіту вітаміну D у сироватці крові, що при поєднанні даної патології з генетично детермінованим порушенням формування колагену І типу вірогідно впливало на процеси кісткоутворення/кісткоруйнування із залученням механізмів компенсації остеомаляційного процесу (система «паратгормон — вітамін D — остеокальцин»). Всебічне вивчення метаболізму вітаміну D та біохімічних показників життєдіяльності кісткової тканини у хворих на ВДЗР(COL1) дозволило впритул підійти до розуміння деяких питань патогенезу та сутності остеомаляційних, а в подальшому — остеопоротичних змін різного ступеня, об’єктивувати ці зміни у відповідних показниках біохімічного дослідження та залежно від змін розробити різні схеми медикаментозної корекції порушень кісткового обміну при даному захворюванні. Висновки. Порушення рецепції до кальцитріолу в поєднанні з генетично зумовленим порушенням формування колагену І типу відображає найбільш тяжкі порушення метаболізму кісткової тканини при вітамін-D-залежному рахіті, що, у свою чергу, викликає в організмі дитини, яка росте, прискорення кісткового обміну та прогресування остеомаляційних процесів поряд зі значним прискоренням розсмоктування кісткової тканини. Це, на нашу думку, пов’язано з формуванням недосконалого колагену, який організм дитини намагається перебудувати, хоча дане припущення потребує подальшого вивчення.

Clinical and genetic analysis of two Chinese families with vitamin D-dependent rickets type IA and follow-up

ObjectiveVitamin D-dependent rickets type IA (VDDR-IA) is a rare autosomal recessive disorder characterized by the early onset of severe rickets. The objectives of this study were twofold: (1) to analyze the clinical characteristics and therapy of two patients with VDDR-IA from two separate Chinese families, and (2) investigate the CYP27B1 gene mutations in two large pedigrees.MethodsMedical history, clinical manifestations, physical examination, radiological findings and laboratory data were analyzed from two patients with VDDR-IA. Serum 1, 25-dihydroxyvitamin D [1, 25-(OH)2D3] of the two patients and their respective families were measured by ELISA and blood samples from both families was obtained for CYP27B1 gene sequence.ResultsTwo patients had typical manifestations and radiological evidence of rickets. Laboratory data showed hypocalcaemia and hypophosphataemia, along with high levels of serum alkaline phosphatase, parathyroid hormone and 25-hydroxyvitamin D3. However, serum 1,25-(OH)2D3 level were low in the patients but normal in their family members. Genetic sequence identified two patients were homozygous for a duplication mutation in exon 8 of CYP27B1 gene (c.1319_1325dupCCCACCC, p.Phe443Profs * 24). After treating with calcitriol and calcium, there was biochemical improvement with normalization of serum calcium and phosphorus, and radiographic evidence of compensatory skeletal mineralization. One patient developed nephrocalcinosis during follow-up.ConclusionsThis study identified a recurrent seven-nucleotide insertion of CYP27B1 in two large pedigrees, and compared the clinical characteristics and individual therapy of two affected patients. Additionally, our experience further supports the notion that nephrocalcinosis can occur even on standard doses of calcitriol and oral calcium, and normal level of serum calcium, phosphorus, PTH and 25-(OH)D3.

Rickets in association with skin diseases and conditions: A review with emphasis on screening and prevention.

Rickets is a common disease worldwide. In the developed world, its prevalence dramatically decreased but still diagnosed in at-risk populations. The skin plays a critical role in vitamin D synthesis. Therefore, several skin diseases, especially keratinization disorders, could lead to impaired vitamin D metabolism and vitamin D deficient rickets. The article aimed to summarize the current knowledge of skin diseases and conditions associated with rickets. To examine the association between rickets and skin diseases, we performed a systematic review of the literature using PubMed database. The search included studies published from the database inception to August 2019. A total number of 75 articles were included. Identified conditions associated with rickets were ichthyosis being a more common skin diseases, alopecia, epidermal and melanocytic nevi, xeroderma pigmentosum, mastocytosis, psoriasis, and atopic dermatitis. Three types of rickets were identified: vitamin D-dependent rickets, hypocalcemic vitamin D-dependent rickets type 2, and hypophosphatemic rickets. Cutaneous skeletal hypophosphatemia syndrome is a newly described and under-recognized condition. It is defined by the association of epidermal or melanocytic nevi, hypophosphatemic rickets, and elevated levels of fibroblast growth factor 23. Rickets in patients with ichthyosis was mainly due to impaired ability of ichthyotic skin to synthesize vitamin D, poor UV penetration of the skin caused by keratinocyte proliferation, and dark phototype. The latter may be considered a risk factor for rickets in patients with ichthyosis. Despite its rarity, these associations should be properly recognized by dermatologists. Early diagnosis of rickets is important to prevent growth retardation and skeletal deformities.

Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With Vitamin D 25-Hydroxylase Deficiency (CYP2R1)

Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D3. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH)2 vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.

Novel VDR Mutations in Patients with Vitamin D–Dependent Rickets Type 2a: A Mild Disease Phenotype Caused by A Novel Canonical Splice-Site Mutation

Objective: Vitamin D-dependent rickets type 2A (VDDR2A) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor gene (VDR), leading to end-organ resistance to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). The objective of this study was to investigate VDR mutations in 11 patients from 8 Turkish-Arab families. Methods: All coding exons and intron-exon boundaries of the VDR gene were amplified by polymerase chain reaction from peripheral leukocyte DNA and sequenced. The effect of splice-site mutations on mRNA splicing was evaluated by a customized VDR mini-gene assay. Results: Homozygous VDR mutations were found in all the patients, including four novel mutations: c.473G>T (p.R158L), c.1-4A>G (IVS3-2A>G), c.755+1G>T, and c.352_356delGACAG (p.D118Sfs*7). The c.1-4A>G mutation was located in the canonical splice acceptor site and 4 base pairs from the original ATG start codon. The mutation resulted in both complete (60% of transcripts) and partial exon 4 skipping (15% of transcripts). The latter was due to activation of a cryptic splice acceptor site and did not disrupt the open reading frame. Both c.755+1G>T and c.352_356delGACAG resulted in frameshifts and a premature stop codon. Clinically, all the patients required continued treatment, except for patient IV-3, who presented with alopecia, hypocalcemia, and increased 1,25(OH)2D3 at 1.5 years of age as a result of the c.1-4A>G mutation. He stopped taking medication at 6 years of age and still maintained normal height and biochemical profile. Conclusion: We have identified four novel VDR mutations. Although canonical splice-site mutations cause premRNA splicing errors that usually lead to a severe disease phenotype, mild disease can also occur due to activation of a cryptic splice site. Abbreviations: 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3 (calcitriol); 25OHD3 = 25-hydroxyvitamin D3; PCR = polymerase chain reaction; PTH = parathyroid hormone; VDDR2A = vitamin D-dependent rickets type 2A; VDR = vitamin D receptor.

A genetic variant of CYP2R1 identified in a cat with type 1B vitamin D-dependent rickets: a case report

BackgroundVitamin D-dependent rickets is rare in animals and humans. Several types of this condition are associated with genetic variants related to vitamin D metabolism. This is the first report of type 1B vitamin D-dependent rickets in a cat.Case presentationHere, we describe the case of a 3-month-old female domestic short-haired cat previously fed on commercial kitten food that presented at our clinic with seizures, lethargy, and generalized pain. Serum and ionized calcium concentrations and 1,25-dihydroxycholecalciferol in this cat were low, and radiographs showed skeletal demineralization and abnormally wide growth plates on the long bones. Initially, simple vitamin D deficiency was suspected; however, the cat’s profile, which included fed a well-balanced commercial diet, together with the findings of additional laboratory tests and the cat’s unresponsiveness to various treatments, raised the suspicion of vitamin D-dependent rickets. Examination of the DNA sequences of CYP2R1 and CYP27B1 genes, which are genes linked with vitamin D metabolism, showed a CYP2R1 frameshift mutation in exon 5 (where T is deleted at position c.1386). This mutation alters the amino acid sequence from position 462, while the stop codon introduced at position 481 prematurely truncates the 501 amino acid full-length protein. With this knowledge, a new treatment regime based on a standard dose of calcitriol was started and this markedly improved the cat’s condition.ConclusionsTo the best of our knowledge, the present case is the first description of type 1B vitamin D-dependent rickets linked with a genetic variant of CYP2R1 in a cat.

The good and the bad of vitamin D inactivation

While disorders of impaired vitamin D activation and action have long been appreciated, the consequences of abnormalities in pathways leading to the inactivation of vitamin D metabolites have only recently been identified. Two recent articles have shed new light on this area of vitamin D biology. The report by Martineau et al., published in the JCI, describes a pathway in which binding of the vitamin D metabolite 24R,25(OH)2D3 to its effector molecule FAM57B2 plays an important role in endochondral ossification during bone repair. This work follows, and adds to, another recent JCI publication by Roizen et al., showing that rapid inactivation of vitamin D metabolites causes vitamin D deficiency, leading to vitamin D-dependent rickets.

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

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

CYP3A4 mutation causes vitamin D-dependent rickets type 3.

Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency.