Vitamin D-Dependent Rickets and the Genetic Approach to Rickets

Hereditary calcipenic forms of rickets (VDDR1A due to CYP27B1, VDDR1B due to CYP2R1, VDDR2A due to VDR, VDDR2B due to overexpression of hnRNP C1/C2 and VDDR3 due to gain of function of CYP3A4), with nutritional rickets as the main differential diagnosis and the general diagnostic approach to rickets in children.

Literature and regulatory information updated: 17 October 2026.

0. Initial Reference Table

The sources for the second table are Levine (2020), the guidance of Haffner and colleagues (2022), OMIM, Orphanet, VariantValidator and the cohorts and cases cited in sections 2, 3 and 9 [5, 6, 23–29].

1. Introduction

1.1. Rickets as a syndrome

The 2016 global consensus on nutritional rickets defines rickets as a disorder of chondrocyte differentiation and growth plate mineralisation, accompanied by defective osteoid mineralisation, and defines nutritional rickets as the form caused by vitamin D deficiency and/or low calcium intake in children; diagnosis rests on history, physical examination and biochemistry and is confirmed by radiographs (strong recommendation, high-quality evidence) [7]. Osteomalacia denotes abnormal matrix mineralisation in already formed bone; the term is used for the same defect after closure of the growth plates, and a child with rickets also has osteomalacia [7]. The 2022 guidance of the International Pediatric Nephrology Association (IPNA), written by Haffner and colleagues as an educational review and not as a formal guideline with graded evidence, lists more than 20 acquired or hereditary causes of rickets and identifies a final common pathway: insufficient phosphate availability for terminal differentiation and apoptosis of hypertrophic chondrocytes, which depends on extracellular phosphate through phosphorylation of mitogen-activated protein kinase (MAPK) intermediates and the mitochondrial caspase 9 pathway [6].

For teaching purposes, the terms calcipenic rickets and phosphopenic rickets are retained [6]. In calcipenic rickets, insufficient intake or action of calcium and vitamin D raises PTH, which reduces tubular phosphate reabsorption and causes hypophosphataemia; in phosphopenic rickets, hypophosphataemia is primary, due to renal loss mediated by fibroblast growth factor 23 (FGF23), a tubular defect, or insufficient phosphate intake and absorption [5, 6]. Vitamin D-dependent rickets (VDDR) comprises the genetic forms of the calcipenic group, and this article covers them together with the general diagnostic approach to rickets, because recognising them depends on distinguishing them from nutritional rickets, which remains the most frequent cause worldwide [6, 7]. The hereditary hypophosphataemic forms and hypophosphatasia are part of the differential diagnosis.

1.2. Historical overview

Levine (2020) summarises the steps that led to the concept of hereditary vitamin D-dependent rickets. In 1919, Edward Mellanby proposed a chemical basis for the efficacy of cod liver oil; Elmer McCollum, with John Howland and later with Edwards Park and Paul Shipley, showed that the antirachitic substance was a new vitamin, to which he gave the letter D; Alfred Hess and Lester Unger demonstrated the antirachitic effect of sunlight, and Harriette Chick confirmed, in controlled studies, the efficacy of sunlight and cod liver oil [5]. The availability of cheap vitamin D reduced the prevalence of rickets, and failure to respond to usual doses came to signal other diseases: in 1937, Albright described a child with refractory rickets and proposed hereditary resistance to vitamin D, but most hereditary "resistant" cases had normal calcium and low phosphate and came to be recognised as X-linked hypophosphataemia (XLH), originally called familial vitamin D-resistant rickets [5]. This origin explains why the expression "vitamin D-resistant rickets" was applied to XLH and why it still appears in old labels, such as that of ergocalciferol in the United States [30]. A reference source in clinical genetics writes "XL hypophosphatasia (vitamin-D-resistant rickets)" as an example of X-linked dominant inheritance; this refers to X-linked hypophosphataemia and not to hypophosphatasia, which is a different disease caused by ALPL [11, 31].

The first true defect of vitamin D response was described in 1961 by Prader, Illig and Heierli, in a hereditary form of rickets with hypocalcaemia and a mineralisation defect that did not respond to conventional vitamin D, called "hereditary pseudodeficiency"; the original title attributed autosomal dominant transmission to it, but recessive inheritance was established later [5, 32]. In 1973, Fraser and colleagues attributed the disease to an inborn error in the conversion of 25(OH)D to 1α,25(OH)2D [33]. In 1978, Brooks and colleagues described a 22-year-old woman with hypocalcaemia, secondary hyperparathyroidism, osteomalacia and osteitis fibrosa cystica, normal 25(OH)D (14 ng/mL) and very high 1,25(OH)2D (137 pg/mL), which rose to 297 pg/mL with 4000 IU/day of vitamin D3; partial correction with elevated 1,25(OH)2D reflected end-organ resistance, and the authors proposed the name "vitamin D-dependent rickets type II" [34].

The molecular basis was established between 1988 and 2018. Hughes and colleagues (1988) identified, in two families with homozygous children, different point mutations in the DNA-binding domain of the vitamin D receptor (VDR), one in each zinc finger, with normal hormone binding and reduced affinity for DNA [35]. Labuda and colleagues (1990) mapped the type I form to 12q14 in French-Canadian families (76 individuals, 14 sibships, 17 affected), with linkage disequilibrium consistent with a founder effect [36]. In 1997, St-Arnaud and colleagues cloned the rat 1α-hydroxylase cDNA and mapped the human gene to the pseudodeficiency locus, and Fu and colleagues cloned the human cDNA from keratinocytes and identified null mutations in one patient; in 1998, Kitanaka and colleagues described four homozygous missense mutations that abolished enzyme activity [37–39]. Chen and colleagues (2003 and 2006) attributed resistance with a normal receptor to overexpression of a protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, identified as hnRNP C1/C2 [40, 41]. Cheng and colleagues (2004) identified CYP2R1 as the biologically relevant 25-hydroxylase in a patient homozygous for p.(Leu99Pro) [42]. Thacher and colleagues (2015) showed in Nigeria a dose-dependent effect of CYP2R1 alleles, which they described as semidominant inheritance [43]. Roizen and colleagues (2018) described VDDR3, caused by a recurrent gain-of-function variant in CYP3A4 [29].

1.3. Nomenclature and reclassifications

The term "dependent" arose from the observation that the original patients with the type I form responded to vitamin D, but only at unusually high and sustained doses, which is why "dependency" was preferred to "deficiency" [12, 43]. Levine acknowledges that the designation is pathophysiologically imprecise and retains it because patients become dependent, for life, on special treatment regimens [5]. The current classification distinguishes failure of activation (VDDR1: VDDR1B without 25(OH)D, VDDR1A without 1,25(OH)2D), resistance to 1,25(OH)2D (VDDR2: VDDR2A due to VDR variants, VDDR2B due to a nuclear ribonucleoprotein that interferes with VDR binding to DNA) and excessive inactivation of metabolites (VDDR3) [5]. VDDR2A is synonymous with hereditary 1,25(OH)2D-resistant rickets (HVDRR, hereditary vitamin D-resistant rickets) and with vitamin D-resistant rickets type IIA; it should not be confused with the historical use of "vitamin D-resistant rickets" for XLH [5, 13]. The hereditary rickets unit of the skeletal dysplasia atlas by Spranger and colleagues describes VDDR1B as loss of function of "25-alpha-hydroxylase"; the enzyme is vitamin D 25-hydroxylase, which hydroxylates carbon 25, with no alpha position [44, 45].

In 2024, Duan and colleagues proposed a "VDDR1C" due to heterozygous loss of function of CYP4A22, in a proband and the mother [8]. The journal published an expression of concern in 2024 and retracted the article in 2025 (online publication on 28 January), by agreement of the editor-in-chief, the ASBMR (American Society for Bone and Mineral Research) and the authors: after the letter from Levine and colleagues, additional genetic analyses identified in the proband and the mother a structural variant in PHEX, consistent with XLH and not detectable by the initial approaches [9, 46]. The letter had pointed out that the biochemistry (very low phosphate with normal calcium and PTH, baseline calciuria of 80 mg/24 h, mother with very low phosphate) was more suggestive of hypophosphataemic rickets and that the variant c.901del p.(Glu301Argfs*80) (NM_001010969.4) was present in 1976 heterozygotes in gnomAD v2, with an allele frequency of 0.6997% and a maximum of 4.094% in East Asia, in a gene not constrained against loss of function (pLI = 0) [10]. "VDDR1C" is not an entity and does not appear in this article as such; the episode illustrates the risk of attributing causality to a common variant without excluding phosphopenic causes and structural variants of PHEX.

1.4. Definition of the entities in scope

VDDR1A is the autosomal recessive disease caused by biallelic loss-of-function variants in CYP27B1, which encodes 25-hydroxyvitamin D 1α-hydroxylase, with selective 1,25(OH)2D deficiency and normal or high 25(OH)D [5, 12]. VDDR1B is caused by loss-of-function variants in CYP2R1, the main hepatic 25-hydroxylase, with low 25(OH)D and a reduced response to conventional doses of vitamin D; heterozygotes may have an attenuated phenotype [5, 43]. VDDR2A is target-tissue resistance to 1,25(OH)2D due to biallelic VDR variants, with elevated 1,25(OH)2D and alopecia in about half of patients [5]. VDDR2B has a similar phenotype with a normal VDR sequence; OMIM classifies it as a phenotype with unknown molecular basis and describes overexpression of hnRNP C1/C2 in the cells of one patient [23, 41]. VDDR3 is the autosomal dominant form caused by the recurrent gain-of-function variant c.902T>C p.(Ile301Thr) in CYP3A4, which accelerates inactivation of vitamin D metabolites [24, 29]. Nutritional rickets, defined in 1.1, by definition excludes hereditary rickets due to disorders of vitamin D metabolism and hypophosphataemic rickets [7].

2. Molecular Genetics and Pathophysiology

2.1. Vitamin D metabolism and the final common pathway of rickets

Previtamin D3 forms in the basal layers of the epidermis under ultraviolet B radiation (UVB, 290–315 nm) from 7-dehydrocholesterol and thermally isomerises to vitamin D3 (colecalciferol) over about three days; melanin, ageing, clothing and sunscreen reduce this production, and vitamin D2 (ergocalciferol) derives from ergosterol in yeasts and fungi [5, 7]. 25-hydroxylation occurs mainly in the liver through microsomal CYP2R1 and produces 25(OH)D, the most abundant circulating metabolite and the best indicator of vitamin D status [5]. 1α-hydroxylation, the rate-limiting step of activation, occurs in the mitochondria of the renal proximal tubule through CYP27B1, whose expression is induced by PTH and suppressed by FGF23; renal CYP24A1 inactivates 25(OH)D and 1,25(OH)2D by 24-hydroxylation, and CYP3A4 in the liver and small intestine constitutes a secondary inactivation pathway [5, 12]. The genomic actions of 1,25(OH)2D are mediated by the VDR, a nuclear receptor that forms heterodimers with the retinoid X receptor (RXR) and binds to vitamin D response elements (VDRE); non-genomic actions through a putative membrane receptor have been described [5, 13].

Hypocalcaemia from any calcipenic form stimulates PTH secretion, which reduces tubular reabsorption of phosphate and bicarbonate and causes hypophosphataemia and hyperchloraemic acidosis [5]. PTH causes internalisation and degradation of the sodium-phosphate cotransporters NaPi2a and NaPi2c in the proximal tubule [6]. Low extracellular phosphate prevents caspase 9-mediated apoptosis of hypertrophic chondrocytes, and this is the final common pathway linking the calcipenic and phosphopenic forms [5, 6]. Without effective 1,25(OH)2D, PTH also cannot release sufficient calcium and phosphorus from bone [5]. The contrast with FGF23-mediated phosphopenic forms is useful diagnostically: in XLH, elevated FGF23 internalises the NaPi-IIa and NaPi-IIc cotransporters, reduces 1α-hydroxylase and increases 24-hydroxylase, which explains a low or inappropriately normal 1,25(OH)2D with normal or mildly elevated PTH [6, 11].

2.2. VDDR1A — CYP27B1

CYP27B1 (12q14.1; HGNC:2606; OMIM 609506; MANE Select transcript NM_000785.4, protein NP_000776.1) encodes a mitochondrial P450 monooxygenase that hydroxylates 25(OH)D at C1α; the enzyme also 1α-hydroxylates 24R,25(OH)2D3 and 25(OH)D2 [12, 25]. The location 12q13.1–q13.3 or 12q13.3 found in texts from 1997–2017 results from the in situ hybridisation mapping of that period [37, 39, 44]. The block prevents vitamin D-dependent intestinal calcium absorption and causes hypocalcaemia, secondary hyperparathyroidism, renal phosphate wasting and a growth plate mineralisation defect [12]. 25(OH)D is normal or high because of supplementation and because CYP24A1, which clears 25(OH)D, is not induced in the absence of calcitriol [5, 12]. The receptor is intact and, therefore, the missing hormone can simply be replaced [12].

The spectrum includes missense, nonsense, frameshift and splicing variants [21]. In the Turkish national cohort of 118 patients, the four most frequent variants were c.195+2T>G (splice donor, 42 patients), the 7 bp duplication c.1319_1325dup p.(Phe443ProfsTer24) (25 patients), c.574A>G p.(Lys192Glu) (17 patients) and c.1474C>T p.(Arg492Trp) (12 patients), and they accounted for about 81% of the cohort, suggesting a hotspot or founder effect in Turkey [26]. In 29 unrelated Saudi families, the variant c.1286G>C p.(Arg429Pro) was present in 22 patients from 15 families (51.7% of families), with four novel variants [27]. In Vietnam, c.1319_1325dup was present in 18 of 19 children [28]. The French-Canadian founder variant, historically described as "958delG", corresponds, in the Saguenay–Lac-Saint-Jean newborn screening series, to c.262delG, normalised as NM_000785.4:c.262del p.(Val88TrpfsTer71) (ClinVar 1664, pathogenic; a ClinVar search for "958delG" retrieves this record); the founder effect, first documented by linkage disequilibrium, translates into a carrier frequency of 1/29 (70 heterozygotes among 2000 newborns), close to the estimate of 1/27 calculated in 1991 by the Hardy-Weinberg law from the number of affected births [17, 25, 36, 47]. The 13 affected children from the region genotyped in the same study were all homozygous for c.262del and the 27 parents tested were all heterozygous [17]. In the French-Canadian population only two other variants have been described, each in a single patient in 1998: a 7 bp insertion in exon 8 with a frameshift at codon 443 and c.1166G>A p.(Arg389His) [17]. The text of the French PNDS attributes the Saguenay founder effect to the latter, but the supporting argument document of the same PNDS and the original article indicate c.262del, which is the variant used in the screening test [17, 18]. Complete loss of activity is associated with earlier and more severe disease, and some missense variants with residual activity with milder phenotypes [21]; even so, clinical and biochemical severity varies widely between families and even between patients with identical variants, and the Turkish cohort found no clinically relevant genotype–phenotype correlation [12, 26]. The French retrospective series of Méaux and colleagues (24 patients, 18 probands and 6 siblings, from 19 families, 10 centres in France and Belgium) found an exception [48]. Seventeen variants were identified (11 missense, 3 frameshift, 2 truncating and 1 at the splice acceptor site), homozygous in 11 of 19 families, with known consanguinity in 9; the duplication c.1319_1325dup p.(Phe443ProfsTer24) was present in 4 patients (1 homozygous and 3 compound heterozygous), and NM_000785.4:c.385G>A p.(Ala129Thr) in 4 families (3 homozygous and 1 compound heterozygous with p.(Trp328Leu)) [48]. In the comparison between probands, the 3 homozygotes for p.(Ala129Thr) were diagnosed later than the remaining 16 (median 5.0 years, 2.2–8.7, versus 1.2 years, 0.5–7.9; p = 0.04); higher calcium (2.26 versus 1.85 mmol/L; p = 0.06), lower PTH (4.7 versus 7.5 times the upper limit of normal; p = 0.07) and lower ALP (759 versus 2082 IU/L; p = 0.23) were trends without statistical significance in a very small sample [48]. None of the p.(Ala129Thr) carriers had hypotonia, seizures or fractures; they were diagnosed because of limb deformities, and 1,25(OH)2D was normal in 2 homozygotes [48]. In earlier functional assays, this variant reduces 1α-hydroxylase activity by about 50% and allows formation of active vitamin D with supraphysiological doses of native vitamin D, which is consistent with the milder phenotype [48]. In these partial forms the initial calcium may be normal or low-normal and the biochemistry may suggest hypophosphataemic rickets, which delays diagnosis: a homozygous sister identified at 5.5 years by family screening had only moderately elevated ALP (600 IU/L), and in a migrant child diagnosed at 6 years it was necessary to exclude the hypophosphataemic forms by sequencing PHEX, FGF23, DMP1, SLC34A1 and SLC34A3 [18, 48]. The authors used transcript NM_000785.3 as reference, with the same coding numbering [48]. In ClinVar, this variant is listed as likely benign (record 722611), a classification that does not incorporate the data from the French series [47, 48].

2.3. VDDR1B — CYP2R1

CYP2R1 (11p15.2; HGNC:20580; OMIM 608713; NM_024514.5, NP_078790.2) encodes the microsomal P450 that carries out 25-hydroxylation of vitamins D2 and D3 and also of the prodrugs alfacalcidol and doxercalciferol [25, 45]. Cheng and colleagues showed that p.(Leu99Pro) abolishes activity; Thacher and colleagues showed complete loss of activity with p.(Leu99Pro) and marked reduction with p.(Lys242Asn), with normal protein expression [42, 43]. Activity of accessory 25-hydroxylases persists, which explains the partial response to 1α-hydroxylated prodrugs; Molin and colleagues hypothesised that CYP3A4 hydroxylates alfacalcidol more efficiently [5, 45, 49].

The gene-dosage effect distinguishes this form from the others. In Nigeria, p.(Leu99Pro) homozygotes had baseline 25(OH)D3 of 3.1 ± 1.7 ng/mL, heterozygotes 13.4 ± 2.3 ng/mL and controls 25.9 ± 6.1 ng/mL (p < 0.001), and the increases on the third day after 50,000 IU of oral vitamin D3 were 9.8 ± 2.7, 19.9 ± 9.6 and 30.6 ± 16.0 ng/mL, respectively (p = 0.03); the authors spoke of semidominant inheritance, whereas OMIM, GenCC and UniProt classify it as autosomal recessive [43, 45]. Heterozygotes have less severe childhood bone disease and near-normal homeostasis in adulthood [5, 43]. Clinical expression also depends on calcium intake: in the Nigerian families dietary calcium intake was 15–175 mg/day [43]. The variants described include p.(Leu99Pro), the most common; p.(Lys242Asn) in Nigeria; p.(Gly42_Leu46delinsArg) and p.(Leu99Pro) in two French families; c.768dup and c.367+1G>A in compound heterozygotes from the Middle East, without functional studies; c.41_50dup in Indian siblings; and, in Chinese twin girls, the compound c.75dup p.(Gly26ArgfsTer68) with c.1115G>C p.(Cys372Ser), the latter with reduced expression and partial loss of activity [5, 49–51].

Common variation at the locus has a different meaning. The polymorphism rs10741657 was associated with 25(OH)D concentration at genome-wide significance in the SUNLIGHT meta-analysis of 33,996 individuals of European ancestry (p = 3.3 × 10⁻²⁰), alongside GC, DHCR7/NADSYN1 and CYP24A1; this is a modest quantitative influence, with no diagnostic value or therapeutic indication [45, 52].

2.4. VDDR2A — VDR

VDR (12q13.11; HGNC:12679; OMIM 601769; NM_000376.3, NP_000367.1, VDRA isoform of 427 amino acids) encodes the nuclear receptor for calcitriol, which is also the receptor for lithocholic acid [13, 25, 53]. Pathogenic variants lie in the DNA-binding domain or the ligand-binding domain or truncate the protein, and the VDR-RXR heterodimer can no longer activate transcription; 1,25(OH)2D is not lacking but ineffective [13]. Alopecia results from failure of the hair follicle cycle, which depends on ligand-independent actions of the VDR: Vdr-null mice develop their first coat and fail to re-enter anagen [5]. Alopecia is associated with variants that affect DNA binding, heterodimerisation with RXR or receptor production; variants that alter only ligand affinity or interaction with coactivators do not cause alopecia [5]. In the Tunisian series of Ben Ameur and colleagues, the five patients with the substitution designated p.Lys45Glu, in the DNA-binding domain, had alopecia; this protein designation was not normalised to HGVS in the sources consulted [13, 54].

Genotype does not fully predict phenotype: eight patients from four unrelated Arab families, all with p.Tyr295* (ClinVar record 7747, NM_000376.3:c.885C>A p.(Tyr295Ter)), had highly variable phenotype and developmental milestones [47, 55]. Abalı and colleagues described c.454C>T p.(Gln152Ter) in the homozygous state in two patients and the novel variants c.756-2A>G and c.66dup p.(Ile23AspfsTer20) [25, 56]. A homozygous microdeletion including exon 9 was identified in a Swedish girl [57], and the variant c.1027C>T p.(Arg343Cys), recorded in ClinVar as likely pathogenic, caused in an infant a presentation with hypophosphataemia without hypocalcaemia [47, 58]. Common VDR polymorphisms (FokI, BsmI, ApaI, TaqI) do not predict bone mineral density (BMD) or fractures: in the GENOMOS meta-analysis of 26,242 participants from nine European teams, BMD differences were below 0.011 g/cm² and fracture odds ratios were 0.98–1.02, with a possible 9% effect of the Cdx2 promoter A allele on vertebral fractures [59].

2.5. VDDR2B — resistance with a normal receptor

OMIM uses the prefix "%" in entry 600785, which denotes a Mendelian phenotype with unknown molecular basis, and defines VDDR2B as rickets due to abnormal expression of a hormone response element-binding protein that interferes with VDR function [23]. The entity rests on two data sets. The first is a patient described by Hewison and colleagues (1993) with alopecia, hypocalcaemia, elevated ALP and 1,25(OH)2D, no mutations in the VDR coding region, normal ligand binding and no nuclear localisation of the complex; in this patient's cells, Chen and colleagues found suppression of transactivation by wild-type VDR due to overexpression of a nuclear protein of the hnRNP family that binds to the response element of RXR-VDR heterodimers, with a dominant-negative effect, and later identified it as hnRNP C1/C2 [23, 40, 41]. Transfection of hnRNPC1 and hnRNPC2 cDNA inhibited VDRE-directed transactivation, siRNA increased it, and chromatin immunoprecipitation at the CYP24 promoter showed reciprocal and cyclical occupancy of the VDRE by VDR and hnRNP C1/C2, lost in the patient's cells [41]. The mechanism is analogous to steroid hormone resistance in New World primates [40]. The second is a cluster of more than 200 Black patients in the department of Cauca, in south-western Colombia, described by Giraldo and colleagues (1995): well nourished, with lower limb deformities, without alopecia, myopathy, seizures or aminoaciduria, with calcium in the low-normal range, normal phosphate, elevated ALP, normal 25(OH)D and elevated 1,25(OH)2D, and a normal VDR cDNA sequence [23].

Sources diverge in their interpretation. Levine (2020) and Thacher and colleagues (2015) state that the gene or the molecular defect is unknown, and Levine asks whether it is a distinct entity [5, 43]. The guidance of Haffner and colleagues attributes the disease to "mutations in HNRNPC", and Roizen and colleagues describe HNRNPC as a VDR coactivator [29, 60]. In the sources consulted there is no germline variant in HNRNPC associated with this resistance, and Orphanet associates HNRNPC only with a syndromic intellectual disability, not with ORPHA:93160 [3, 23]. The table of Haffner and colleagues assigns to VDDR2B the OMIM number 264700, which belongs to VDDR1A [6, 23]. In this article VDDR2B is treated as a phenotype with an unestablished molecular basis, with overexpression of hnRNP C1/C2 demonstrated in one patient.

2.6. VDDR3 — CYP3A4 gain of function

CYP3A4 (7q22.1; HGNC:2637; OMIM 124010; MANE transcript NM_017460.6, NP_059488.2) is the main hepatic and intestinal P450 enzyme [25, 61]. Roizen and colleagues identified by trio exome sequencing, in two unrelated girls without variants in CYP2R1, CYP27B1, VDR and CYP24A1, the same heterozygous de novo variant NM_017460.6:c.902T>C p.(Ile301Thr) (published on NM_017460.5, with the same numbering), absent from public databases and from more than 3000 exomes; isoleucine 301 is conserved and forms part of substrate recognition site 4 (SRS-4), and the absence of a shared haplotype excluded a common founder [29]. Both had a very high 4β,25(OH)2D/25(OH)D ratio, in the range of patients treated with rifampicin, with normal 4β-hydroxycholesterol, indicating selectivity for vitamin D [29]. In a two-hybrid system, the apparent catalytic efficiency on 1,25(OH)2D3 was 0.014 for the wild-type enzyme, 0.14 for p.(Ile301Thr) and 0.08 for CYP24A1 — about ten times the wild type and twice CYP24A1 —, whereas activity on luciferin-IPA was reduced (30.0 ± 1.6 versus 50.1 ± 1.6; p < 0.001) [29]. In 2026, Nakaya and colleagues showed in vitro that the mutant acquires 11α-hydroxylase activity, producing 11α,25-dihydroxyvitamin D3 and 1α,11α,25-trihydroxyvitamin D3, metabolites with much lower affinity for the VDR; docking places the 3β-OH of 25(OH)D3 in a hydrogen bond with threonine 301 [62, 63]. These are preclinical data that complement the earlier hypothesis of increased 4β-hydroxylation.

Inheritance is autosomal dominant; the four published patients have the same variant (ClinVar 982369, pathogenic, single submitter), with no ClinGen gene–disease validity assertion and a GenCC classification of "limited" [15, 16, 29, 47, 61]. The phenotype reproduces the effect of pharmacological CYP3A4 inducers (rifampicin, phenytoin, barbiturates, glucocorticoids), which cause vitamin D deficiency [15, 29]. The same gene has a distinct pharmacogenetic relevance: the CYP3A4*22 allele (rs35599367) reduces the clearance of tacrolimus, ciclosporin and some statins, and the Dutch Pharmacogenetics Working Group (DPWG) issues an actionable recommendation only for quetiapine in poor metabolisers [61].

2.7. Normalised variants

For the CYP2R1 variants whose published notation was an insertion or a deletion-insertion, the HGVS form was generated by automatic mapping in VariantValidator and corresponds to the same change described in normalised form [25]. The VDR records p.(Arg30Ter), p.(Gly33Asp), p.(Arg73Ter), p.(Arg73Gln), p.(His305Gln) and p.(Arg391Cys/Ser/His) are listed in ClinVar as pathogenic on NM_000376.3; the correspondence of p.(Gly33Asp) with the first zinc finger mutation described by Hughes and colleagues has not been established [35, 47]. The sources of the table are VariantValidator, ClinVar and the patient series [15, 21, 25–29, 43, 47, 49–51, 56, 58].

3. Clinical Spectrum and Manifestations by System

3.1. Manifestations common to calcipenic rickets

The 2016 global consensus organises the manifestations of nutritional rickets into three domains, which also apply to the hereditary calcipenic forms [7]:

Presentation varies with age. In the young infant, irritability, poor feeding and sometimes apnoea and stridor predominate, with craniotabes and a large fontanelle, and radiological signs may be absent because they require prolonged PTH elevation; in the older infant, growth and developmental delay, hypotonia, widening of the wrists and ankles, rosary and hypocalcaemic seizures appear, and tachycardia, tachypnoea, hepatomegaly and oedema suggest heart failure due to cardiomyopathy; in the child, abnormal dentition with enamel hypoplasia, bowed limbs and fractures predominate; in the adolescent, symptomatic hypocalcaemia, bone pain, muscle weakness and a waddling gait may mimic a myopathy [6]. Peaks of symptomatic hypocalcaemia occur in infancy and at puberty [6]. The skeletal dysplasia atlas summarises the cardinal manifestations of hereditary rickets: lower limb bowing, mild to moderate short stature with short limbs, delayed dentition and enamel hypoplasia, muscle weakness and motor delay, craniosynostosis in XLH and alopecia in VDDR2A; the vitamin D-dependent forms usually manifest earlier than the hypophosphataemic forms, with muscle weakness and rosary, whereas XLH usually presents with genu varum at 2–3 years and without muscle weakness [44]. Bone pain is a frequent symptom in vitamin D deficiency and in hypophosphataemic rickets [64]. Some patients with hereditary rickets present only in adulthood, with short stature, limb deformity and bone pain [44].

The French PNDS details the oral manifestations, which result from disturbed mineralisation of enamel, dentine, cementum and alveolar bone and may affect both dentitions or only one [18]. The most frequent is a structural enamel defect of hypoplastic type, localised or generalised (hypoplastic amelogenesis imperfecta), with discolouration, especially of the incisors, canines and molars, with aesthetic impairment and greater susceptibility to caries, requiring direct and indirect restorations; dentine hypoplasia, with wide pulp chambers and short roots on radiographs, causes hypersensitivity and endodontic infections, and changes in the cementum and alveolar bone explain early and severe generalised periodontitis [18]. Systemic treatment progressively improves the dentine, cementum and alveolar bone, but not the enamel already formed; when treatment is early, the later-forming permanent teeth (premolars, second and third molars) may be spared [18]. Some children have craniostenosis, with a risk of raised intracranial pressure [18]. Signs of rickets are absent at birth, so diagnosis is not possible by prenatal ultrasound or in the neonatal period; in VDDR1A and 2, calcium and phosphate abnormalities appear in the first months and clinical and radiological signs in the first two years, and in VDDR1B they may appear later [18].

3.2. VDDR1A

Infants are normal at birth and become symptomatic between 2 and 24 months: early presentation includes hypotonia, irritability, tetany or seizures due to hypocalcaemia and poor weight gain; late diagnosis occurs with classic rickets, fractures, frontal bossing, long bone deformity, rib cage changes and impaired linear growth [5, 12]. Without treatment, skeletal deformity and short stature progress; with adequate treatment rickets heals and growth is normal [5]. Recent cohorts give the scale of the presentation. In the Turkish national cohort of the CEDD-NET network (118 patients, 57 female), the median age at diagnosis was 1.7 years (0.2–18.3), and the most frequent complaints were skeletal deformity (61), short stature (45) and delayed walking (42) [26]. In a Vietnamese tertiary centre (19 children from 17 families), the median age at diagnosis of rickets was 19.2 months; they had thickened wrists and ankles in 19/19, genu varum or valgum in 18/19, growth delay in 18/19, rosary in 12/19 and late walking in 11/19, and all had metaphyseal cupping, widening and fraying, with pseudofractures in 6, severe hypocalcaemia, normal or slightly low phosphate and normal 25(OH)D [28]. In Saudi Arabia, 45 patients from 29 families had a median age of 1 year at presentation and a typical profile [27]. Earlier series described 22 patients from 13 Turkish families and 9 patients from another cohort, with a systematic review [65, 66].

Diagnosis may be delayed until adulthood. A 25-year-old Brazilian woman, treated for 24 years with vitamin D3 and calcium, was 1.49 m tall, had undergone eight orthopaedic procedures and had a PTH of 863 pg/mL when VDDR1A was confirmed (section 10) [21]. A 25-year-old Turkish woman presented with muscle weakness and low back pain after pregnancy, with calcium 8 mg/dL, PTH 640 ng/L, ALP 345 U/L, inappropriately normal 1,25(OH)2D (43.1 pg/mL), "H-shaped" vertebrae on computed tomography, DXA (dual-energy X-ray absorptiometry) with a Z-score of −2.7 at the spine and femoral neck and myopathy on electromyography; after one year of symptoms she became wheelchair-dependent and walked again two months after starting vitamin D and calcium, with a loss of 3 cm in height over two years, and homozygosity in CYP27B1 confirmed VDDR1A [67]. The increased calcium requirements of pregnancy and lactation can thus decompensate an unrecognised form.

The French series of Méaux and colleagues describes the presentation in a European cohort [48]. In the probands, the median age at first symptoms was 11 months (2–100) and at clinical diagnosis 18 months (6–104; 1.5 years, 0.5–8.7, in the 19 patients with a clinical diagnosis, including siblings), with a median interval of 4 months (3–20) between the two; two infants developed the disease at 4 and 5.5 months, earlier than previously described [48]. Among 20 symptomatic patients, 85% had bone deformities (genu varum 7, genu valgum 5, costal rosary 9, scoliosis 2, enlarged anterior fontanelle 3), 60% neurological signs (muscle weakness 55%, psychomotor delay 32%, walking difficulty 27%; axial hypotonia in 6 infants under 2 years; hypocalcaemic seizures in 2), 60% growth delay, 50% bone pain, 40% dental anomalies (delayed eruption, enamel hypoplasia, infections), 33% frequent benign infections and 28% pathological fractures; median height was −1.5 SD (−4.5 to +1.0) [48]. Radiographs were abnormal in 15 of 18 patients (metaphyseal widening in 78%, moderate demineralisation in 56% and marked in 25%, Looser-Milkman lines in 3), and none had nephrocalcinosis at diagnosis [48]. Median total calcium was 1.97 mmol/L (1.40–2.40), abnormal in 17 of 21, and normal in 3 p.(Ala129Thr) homozygotes and in a sibling diagnosed at birth; PTH was elevated in 15 of 16 (median 387 pg/mL, 6.6 times the upper limit), phosphate low in 18 of 21 (−3.4 SD) and ALP elevated in all (median 1968 IU/L, 521–7000); 1,25(OH)2D was low or at the lower limit in 9 of 11 (median 14 pg/mL) [48]. Contrary to the classic profile of normal or elevated 25(OH)D, median 25(OH)D was 23 ng/mL (7–81), below 20 ng/mL in 10 of 17 and below 12 ng/mL in 2, which the authors attribute to insufficient supplementation in Europe; a low 25(OH)D therefore does not exclude VDDR1A [48].

In the Saguenay–Lac-Saint-Jean case-note review, 15 children born between 1990 and 2020 and diagnosed clinically had normal birth weight and length (3311 ± 383 g; 49.2 ± 2.3 cm) and were diagnosed at 13.8 ± 5.0 months (4–20) [17]. The reasons for diagnosis were developmental delay (8), poor weight gain (3), multiple fractures (2) and seizures (1); 7 were diagnosed in the emergency department and 7 were admitted [17]. Length was more affected than weight: it was below the 1st centile in 5 of 8 boys and 3 of 5 girls, whereas weight remained within the normal range in almost all [17]. At diagnosis, PTH was 64.4 ± 25.2 pmol/L (n = 12), total calcium 1.7 ± 0.2 mmol/L, ionised calcium 0.9 ± 0.1 mmol/L, ALP 2216 ± 1052 U/L, phosphate 1.1 ± 0.2 mmol/L, 25(OH)D 104.8 ± 35.0 nmol/L and 1,25(OH)2D 4.6 ± 2.6 pmol/L (n = 11) [17].

In the French series, one patient with VDDR1A had bilateral cataract at 4 years, and the authors recommend closer surveillance of the eyes, teeth, kidneys and blood pressure; the PNDS therefore includes ophthalmological examination in the initial assessment and at transition to adulthood [18, 48].

3.3. VDDR1B

The clinical and radiological picture is that of rickets with low calcium, low phosphate and high ALP, and the distinction is biochemical; the disease is easily confused with nutritional deficiency, and Molin and colleagues asked whether it was rare or underdiagnosed [45, 49]. p.(Leu99Pro) homozygotes have the most severe phenotype, with clinical rickets and undetectable 25(OH)D despite extensive sun exposure [5]. In Nigerian family 1, the homozygous proband presented at 12.5 years with leg pain and anterior tibial bowing since 2 years of age; he had started walking at 9 months and stopped walking at 3 years, consumed about 50 mg/day of calcium from dairy products and had a 25(OH)D of 8 ng/mL [43]. The homozygous father, aged 49, had no deformities in childhood, but had a 25(OH)D of 4.9 ng/mL, moderately elevated PTH and thoracic vertebral fractures in a context of spinal tuberculosis and immobility [43]. In the two French families, the affected siblings showed the three biochemical and radiological stages of rickets, and the adults maintained normal mineral metabolism without supplementation [49]. The phenotype improves with age; the hypotheses are vitamin D-independent intestinal calcium absorption under post-pubertal sex steroids and the activity of other 25-hydroxylases [5]. In the Chinese twin girls, 25(OH)D was in the "sufficiency" range under supplementation and fell to mild deficiency one week after stopping, which shows that a normal 25(OH)D under supplementation does not exclude VDDR1B [51]. The Indian siblings had a picture of nutritional rickets that did not resolve with repeated therapeutic doses and relapsed on stopping [50].

3.4. VDDR2A

Patients are normal at birth and develop signs of vitamin D deficiency between 2 and 8 months; hair is normal at birth and alopecia appears later [5]. The atlas states that alopecia may be present at birth [44]. About half of patients have alopecia, partial or total, sometimes with sparing of the eyelashes, associated with the more severe forms, with very early hypocalcaemia and a poorer response to treatment [5]. In consanguineous series the proportion is higher: 7 of 8 Tunisian children from 7 families and 8 of 8 Saudi patients from 5 families [13, 54, 68]. Alopecia does not improve with treatment, even with complete correction of bone disease over 11 years of follow-up [55]. The presentation can mislead: a 9-month-old infant with normocalcaemia, hypophosphataemia, hyperparathyroidism and very high ALP was initially treated as hypophosphataemic rickets, until the very high 1,25(OH)2D pointed to VDDR2A [58].

The natural history changes at puberty. In childhood, fractional intestinal calcium absorption and bone calcium accretion are low; after puberty, absorption, accretion and bone structure recover, and many patients maintain normocalcaemia with modest oral calcium or without supplementation, with near-normal PTH and normal BMD despite persistently elevated 1,25(OH)2D [5, 69]. Although monocytes and lymphocytes have lower expression of antimicrobial proteins and a pro-inflammatory profile, patients do not have more infections or inflammatory diseases, do not have common asthma (normal allergy tests and lung function, with protection against provoked bronchial hyperreactivity), do not have hypertension or echocardiographic abnormalities, and reproductive history is normal [69].

According to the French PNDS, alopecia, partial or total, usually appears before 24 months, may be accompanied by follicular papules and, more rarely, by sensorineural deafness, described in a sibship of four patients [18]. In the proposed genotype–phenotype correlation cited by the PNDS, all patients with variants in the DNA-binding domain had alopecia, compared with only one third of those with variants in the ligand-binding domain, and patients with alopecia had more severe resistance; in the absence of alopecia, a ligand-binding domain variant should be considered, which justifies a trial of high-dose active vitamin D [18].

3.5. VDDR2B

The phenotype described is similar to that of VDDR2A without a defect in VDR [5]. In the Colombian cluster, more than 200 patients had lower limb deformities with good nutritional status and without alopecia, myopathy or seizures [23]. The patient studied by Hewison and by Chen had alopecia [23]. The guidance of Haffner and colleagues reports alopecia in about half of patients with VDDR2A and in fewer patients with VDDR2B, with absent eyelashes and eyebrows [6]. The number of patients cannot be specified [5].

3.6. VDDR3

The four published patients had early-onset rickets, low 25(OH)D and 1,25(OH)2D and a poor response to native and activated vitamin D [15, 16, 24]. Proband 1.1 of Roizen and colleagues, of European ancestry and living in Australia, had bowed limbs and an unsteady gait at 20 months and, at 2.5 years, measured 81.3 cm (6th centile) and weighed 11.5 kg (35th centile); proband 2.1, of Middle Eastern ancestry, walked only at 4.5 years and was treated in Jordan, Spain and the Netherlands before being assessed in the United Kingdom at 16 years, at 154.3 cm (9th centile) [29]. The Brazilian patient had bowed legs, an unsteady gait and growth arrest from 12 months (section 10) [15]. The Saudi girl, daughter of first cousins, had delayed speech and walking, walked at 3 years with genu valgum, and her father had a history of rickets, short stature and surgically corrected genu varum [16]. The sources consulted do not describe extraskeletal manifestations or changes in other CYP3A4 metabolic pathways [29].

3.7. Serious complications of calcipenic rickets

Hypocalcaemic dilated cardiomyopathy is the complication that can kill and occurs even in developed countries; pelvic narrowing after severe rickets in girls causes obstructed labour, with a risk of maternal and fetal death, which worsens in subsequent pregnancies [7, 22]. In a retrospective study, 7 of 45 infants and children aged 2–14 months with nutritional rickets had fractures, all of them mobile and with severe radiological rickets, and no fracture was considered typical of abuse; in the Canadian national survey, 11 of 108 cases had fractures [7]. The consensus reports 17.5% for the first proportion, which arithmetically corresponds to 15.6% [7]. Vitamin D deficiency without radiological rickets does not increase fracture risk [7]. Congenital rickets, with biochemical and radiological signs in the first four weeks, has about 80 published cases, from mothers with osteomalacia, severe vitamin D deficiency, low calcium intake and hypocalcaemia at delivery, and rarely from maternal hypocalcaemia of other causes (poorly treated hypoparathyroidism, renal failure, phosphate enemas, iatrogenic hypermagnesaemia) [7].

4. Clinical Recognition and Warning Signs

4.1. When to suspect rickets

Rickets should be considered in any child with progressive limb deformity, widening of the wrists and ankles, costal rosary, delayed walking or dentition, a large fontanelle, fractures with minimal trauma or signs of hypocalcaemia [6, 7]. In the presence of a large fontanelle, investigation should exclude hypothyroidism, rickets and congenital infections and include the bone-metabolic profile (calcium, phosphate, PTH) [70]. When abuse is suspected, the history should include dietary deficiency, and rickets and scurvy are part of the differential diagnosis of fractures [71]. In a child with cataract, Lowe syndrome warrants a skeletal survey to exclude rickets [72]. The practical approach of Uday and Högler proposes suspecting it in those with risk factors and signs of hypocalcaemia (seizure, tetany, paraesthesiae, heart failure due to cardiomyopathy) or of hypophosphataemia (weakness, developmental delay, fatigue, hypotonia, deformities), and points out that growth delay is not mandatory, because adequate growth may mask the disease [22].

4.2. Clues to a hereditary form and to the type

Nutritional rickets is the first hypothesis in most children, but coexistence of a hereditary form with mild symptoms and low 25(OH)D is not unusual, and failure to respond to vitamin D with calcium requires the diagnosis to be reconsidered [6, 22]. Da Rocha Ribas and Borba list the alarm signs of non-nutritional rickets: early and severe disease, persistent deformities, normal or elevated 25(OH)D with active rickets, marked secondary hyperparathyroidism and a documented inadequate response to conventional vitamin D [21]. The Indian siblings with VDDR1B add family history, the need for higher than usual doses and relapse on stopping treatment [50]. Unaffected parents, consanguinity or an affected sibling point to the autosomal recessive forms (VDDR1A, VDDR1B, VDDR2A, VDDR2B, autosomal recessive hypophosphataemic rickets, hereditary hypophosphataemic rickets with hypercalciuria, nephropathic cystinosis) [6]. The clinical clues from the guidance of Haffner and colleagues are summarised in the following table [6]:

Chvostek and Trousseau signs suggest hypocalcaemia and therefore a calcipenic form [6]. Muscle weakness is usually more marked in nutritional rickets, and dental abscesses, enthesopathy and calcification of the spinal ligaments appear to be specific to XLH [11]. Presentation is generally more severe in VDDR than in nutritional rickets, but overlap precludes diagnosis by physical examination alone [6].

4.3. Emergency signs

Hypocalcaemic seizure, tetany, stridor and apnoea in an infant require immediate measurement of ionised calcium, intravenous correction and cardiac assessment [6, 22]. Hypocalcaemic dilated cardiomyopathy manifests as tachycardia, tachypnoea, hepatomegaly and oedema, or as cardiorespiratory arrest; hypocalcaemic infants and infants with nutritional rickets should undergo an electrocardiogram (ECG), chest radiograph and echocardiogram [6, 22]. In the Birmingham series, three breastfed, unsupplemented infants aged 5–6 months presented with cardiac arrest, respiratory arrest with seizure, or respiratory distress attributed to bronchiolitis, with a left ventricular ejection fraction of 25–30% and QTc up to 547 ms; one died on the sixth day [73]. In patient 2, a further seizure with respiratory arrest occurred on the third day, after switching from intravenous to oral calcium [73].

4.4. Newborn screening and population screening

There is no biochemical newborn screening for VDDR. The 2016 global consensus advises against population screening with 25(OH)D, ALP or radiographs (strong recommendation) and recommends that screening be based on clinical findings and radiographs; ALP has a low positive predictive value as a screening test, because it also rises in acute illness, with drugs, in liver disease, during growth spurts and in transient hyperphosphatasaemia of infancy [7]. The consensus and the Endocrine Society advise against routine measurement of 25(OH)D in healthy children, and the 2022 French consensus recommends measuring it when there are symptoms of rickets [7, 74, 75]. Two genomic newborn screening studies are registered (Baby Detect, Belgium, 6824 newborns, completed; Early Check, USA, 30,000, active); the sources consulted do not indicate whether the panels include the VDDR genes [76].

The exception is genetic and population-based. In the Saguenay–Lac-Saint-Jean region, a real-time PCR test (TaqMan probes, two independent sets of primers and probes) targeting the founder variant c.262del was developed and validated on 12 samples previously genotyped in certified clinical laboratories (7 without the variant, 2 heterozygous, 3 homozygous), with complete concordance [17]. Between May 2020 and July 2021, the test was offered in the four maternity units of the region: two buccal mucosa swabs were collected about 36 hours after birth and parents received the result on average 14 ± 7 days later [17]. A total of 2000 newborns were tested; 73 families declined and 94 could not be contacted, with an uptake of 96.5% [17]. Seventy carriers (1/29) were identified, whose status was not disclosed to the parents, and one homozygous child, who started calcitriol within two weeks of the molecular diagnosis, confirmed in a certified laboratory [17]. In the anonymous survey, answered by 336 participants, 93.7% considered the test essential or useful, 96.1% would recommend it and 97.0% agreed that it should be offered to all children with at least one grandparent from Saguenay–Lac-Saint-Jean, Haute-Côte-Nord or Charlevoix [17]. A child diagnosed at 1 month because of family history and treated since then had, at 14 months, a PTH of 3.7 pmol/L, total calcium of 2.61 mmol/L and ALP of 333 U/L, close to reference values, whereas the 15 clinically diagnosed children had, at the same age, the severe abnormalities described for VDDR1A (section 3) [17]. The authors conclude that the screening meets the criteria of the Quebec screening committee in this founder population; the limitations are the detection of a single patient, the absence of long-term data on benefit and the lack of carrier frequency estimates for Charlevoix and Haute-Côte-Nord, and the result is not transferable to populations without a founder variant [17].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria for rickets

The diagnosis of rickets rests on typical clinical symptoms (widened wrists, frontal bossing, limb deformity, waddling gait, muscle weakness, growth delay) and on radiological findings (metaphyseal fraying, widening of the growth plates) in the presence of ALP elevated for age [6]. The global consensus requires radiological confirmation for nutritional rickets and stresses that biochemistry alone is not sufficient and may not distinguish vitamin D deficiency from calcium deficiency, which often coexist [7]. There are no validated formal diagnostic criteria for VDDR; the diagnosis of each form rests on the biochemical profile (5.5) and on genetic confirmation [5, 12]. Before applying the algorithm, metabolic acidosis and the rickets of chronic kidney disease (CKD), which do not present with hypophosphataemia, should be excluded [6].

5.2. Imaging

Radiographs are most informative at the rapidly growing plates: distal ulna, knee and ankle metaphyses [6]. Early signs are increased physeal height, widening of the plate and loss of definition of the zone of provisional calcification; late signs are disorganisation, cupping, splaying, cortical spurs, stippling, delayed appearance of the epiphyseal centres and deformities of the weight-bearing long bones [6]. The skeletal dysplasia atlas adds the coarse trabecular pattern, pseudofractures, ectopic ossification at tendon insertions and in the paravertebral ligament (especially in XLH) and, at a late stage, diffuse osteosclerosis, especially axial [44]. Milkman pseudofractures or Looser zones — radiolucent lines of 2–5 mm with sclerotic margins — occur mainly in adolescents and adults with XLH [6]. Thacher's Rickets Severity Score (RSS), from 0 to 10 points, grades metaphyseal fraying and concavity and the proportion of the plate affected at the wrist and knee; it requires simultaneous radiographs of both regions [6]. In XLH the bones are radiologically dense, unlike nutritional rickets and the calcipenic forms, which are osteopenic [11]. A table in a Brazilian textbook includes osteopenia among the radiological findings of XLH, which contradicts GeneReviews [11, 77]. Metaphyseal dysplasias are difficult to distinguish from rickets on radiographs alone, and biochemistry makes the distinction [78, 79]. In the approach to nutritional rickets, Uday and Högler also propose a chest radiograph (cardiomegaly) and, in adults, a hip radiograph (Looser zones) [22]. Bone biopsy is rarely necessary; when performed, it confirms osteomalacia by increased osteoid thickness and volume and a mineralisation lag time greater than 100 days with tetracycline labelling [11, 22].

5.3. First-line biochemistry

The guidance of Haffner and colleagues proposes the following initial set [6]:

Bone ALP accounts for 80–90% of total ALP in children, and total ALP is usable once liver disease has been excluded; it has a four-phase course, with peaks in infancy and at puberty [6]. In untreated calcipenic rickets it may reach ten or more times the upper limit, and in phosphopenic rickets one to three times; total ALP Z-scores in untreated patients were 11.2 ± 2.6 in VDDR, 7.1 ± 3.8 in nutritional rickets and 4.2 ± 1.6 in hypophosphataemic rickets (p < 0.001), with considerable overlap [6]. A normal or low ALP points to Blount disease, the metaphyseal dysplasias and hypophosphatasia [5, 6]. Calcium should be measured as ionised calcium or corrected for albumin; in calcipenic rickets it is usually low, but may be at the lower limit of normal in the early stages [6]. On blood gas analysis, ionised calcium is approximately half of albumin-corrected calcium [22]. Phosphate is low in most forms and lower in the phosphopenic ones; in the calcipenic forms it may remain at the lower limit of normal until PTH-mediated renal loss demineralises bone; values depend on age, should be interpreted against local references and collected after an overnight fast [6]. PTH is very high in untreated calcipenic rickets and is the best marker of response; it is normal or slightly elevated in FGF23-mediated forms, often suppressed in hereditary hypophosphataemic rickets with hypercalciuria and very high in CKD, with high phosphate and creatinine [6]. PTH and ALP rise before calcium and phosphate and well before radiological changes [22]. Magnesium is part of the initial biochemistry in the approach of Uday and Högler [22].

The urinary calcium/creatinine ratio is low in calcipenic rickets and in FGF23-mediated forms, and high in primary tubular defects; a value above 4 mg/kg/day in a 24-hour urine collection defines hypercalciuria, and a spot sample should be confirmed [6]. The presence of hypouricaemia, glycosuria, bicarbonaturia, low-molecular-weight proteinuria or aminoaciduria suggests Fanconi syndrome [11]. The reference values used in the guidance are as follows [6]:

Independent of age are TRP (85–95%), intact PTH (1.5–6.5 pmol/L), the 25(OH)D thresholds (sufficiency > 50 nmol/L or 20 ng/mL; insufficiency 30–50 nmol/L or 12–20 ng/mL; deficiency < 30 nmol/L or 12 ng/mL) and calcium intake after 12 months (sufficient > 500 mg/day; insufficient 300–500 mg/day; deficient < 300 mg/day) [6, 7]. The original table gives "ng/L" for 25(OH)D; the correct unit is ng/mL [6].

5.4. Tubular reabsorption of phosphate

TRP is calculated as 1 − [(urinary phosphate ÷ plasma phosphate) × (plasma creatinine ÷ urinary creatinine)]; if TRP is below 0.86, TmP/GFR equals TRP × plasma phosphate, in an untimed urine sample after an overnight fast [11, 77]. The guidance of Haffner and colleagues uses the second morning urine with simultaneous serum and the formula TmP/GFR = plasma phosphate − (urinary phosphate ÷ urinary creatinine) × plasma creatinine; in children they recommend the Brodehl formula, reliable in both fasting and non-fasting states, and advise against the Walton and Bijvoet nomogram, which slightly overestimates values [6, 11, 60]. The normal values of Payne (1998) cited by the XLH GeneReviews are as follows [11]:

TRP is not reliable, because it does not take the filtered load into account and may be normal when TmP/GFR is already reduced [6]. TmP/GFR does not distinguish calcipenic from phosphopenic rickets, because both have renal phosphate wasting, mediated by PTH or by FGF23 and the transporters [6]. In dietary phosphate deficiency or reduced phosphate bioavailability, TmP/GFR may be "falsely" reduced, because by construction it is always equal to or lower than serum phosphate; the clue is a very low urinary phosphate/creatinine ratio, and TmP/GFR should be assessed only after phosphate supplementation, which is why the algorithm uses the urinary phosphate/creatinine ratio [6].

5.5. Biochemical profiles of the calcipenic forms

The table combines Levine (2020), Haffner and colleagues (2022), Uday and Högler (2020) and da Rocha Ribas and Borba (2026); AR, autosomal recessive; AD, autosomal dominant; XLD, X-linked dominant [5, 6, 21, 22]. Elevated 1,25(OH)2D in a patient with calcipenic rickets indicates calcium deficiency or VDDR2A/2B; reduced 1,25(OH)2D indicates VDDR1A, VDDR1B or VDDR3, and in the last two 25(OH)D is also low [6]. In VDDR2A, Levine gives 1,25(OH)2D values of 50–1000 pg/mL, compared with 30–100 pg/mL in a normal child [5]. Measurement of 1,25(OH)2D is not part of the usual assessment of vitamin D status, but it is the step that distinguishes VDDR1A from nutritional rickets and from VDDR2A [12]. 1,25(OH)2D can distinguish vitamin D deficiency (low to normal, sometimes high) from calcium deficiency (high) provided that 25(OH)D is adequate, and the sample for 1,25(OH)2D should be stored before starting treatment [22]. The typical findings of nutritional rickets are decreased 25(OH)D, phosphorus, serum calcium and urinary calcium, with elevated PTH, ALP and urinary phosphorus [7].

VDDR1B is suspected with very low 25(OH)D and normal or high 1,25(OH)2D, a pattern unusual in simple nutritional deficiency, and with 25(OH)D that does not rise adequately with native vitamin D [45, 49]. VDDR3 has both 25(OH)D and 1,25(OH)2D low, with rickets and a poor response to standard vitamin D [24, 61]. If presumed nutritional rickets does not respond to native vitamin D with calcium, VDDR1B and VDDR3 should be considered [6]. VDDR2A may present with hypophosphataemia without hypocalcaemia and be confused with hypophosphataemic rickets; measurement of 1,25(OH)2D is discriminating [58]. In the FGF23-mediated forms, 1,25(OH)2D is low or inappropriately normal; in NaPi2a and NaPi2c defects it is elevated [6].

5.6. Diagnostic algorithm

Levine's algorithm starts with ALP with age- and sex-specific ranges: elevated in rickets, normal in metaphyseal dysplasia and low in hypophosphatasia, which is investigated with pyridoxal 5′-phosphate and ALPL [5]. The algorithm of Haffner and colleagues starts from the mechanism of hypophosphataemia — high PTH activity (calcipenic), inadequate intestinal phosphate absorption or renal wasting (primary tubular defect or elevated FGF23) — and was originally proposed by Penido and Alon [6]. An algorithm in a Brazilian textbook follows the same logic starting from PTH: with elevated PTH, low 25(OH)D indicates a deficiency cause or malabsorption and normal 25(OH)D indicates VDDR-I or HVDRR; with normal PTH, hypophosphataemic rickets [77]. The practical synthesis is as follows:

The table summarises Levine (2020), Haffner and colleagues (2022), Uday and Högler (2020) and the global consensus [5–7, 22]. Uday and Högler insist on correcting deficiencies before investigating alternatives and point out that, in calcium deficiency, PTH resistance with high phosphate may mimic pseudohypoparathyroidism [22]. If 25(OH)D is low in a patient with suspected XLH, vitamin D should be replaced before laboratory confirmation [11].

The French PNDS stresses three practical rules: biochemical changes precede clinical and radiological signs, so an asymptomatic sibling, especially one younger than the proband, can only be considered unaffected after laboratory tests; vitamin D metabolites are measured before any vitamin treatment; and, if there is initial vitamin D deficiency, the assessment is repeated after replacement, because nutritional rickets may be diagnosed in error when 25(OH)D is low [18]. Diagnosis often requires successive assessments and observation of the response to substantial vitamin D replacement or to active analogues, and difficult cases are discussed at the CRMR national multidisciplinary consultation meeting [18].

Table 5.6a — Initial non-emergency assessment according to the French PNDS (2024) [18]

5.7. Metabolite assays and their limitations

Vitamin D status is assessed by total 25(OH)D (25(OH)D2 plus 25(OH)D3, assumed to be equivalent) [7]. There is variability between methods; immunoassays have cross-reactivity with 25(OH)D2, 25(OH)D3 and 24,25(OH)2D and bias at extremes of concentration; the reference methods of NIST and Ghent University use isotope-dilution liquid chromatography–tandem mass spectrometry (LC-MS/MS), and the Vitamin D Standardization Program has reduced inter-laboratory variation [7]. The 2022 French consensus recommends measuring only total 25(OH)D to assess vitamin D status, measuring it in the same laboratory for each child and not routinely using, in general paediatrics, assays of 1,25(OH)2D or other metabolites [75]. This last point refers to the general paediatric population; in calcipenic rickets 1,25(OH)2D is the test that separates the VDDR forms [6, 12]. 1,25(OH)2D varies with the method, and the CALIPER paediatric reference values, obtained by automated chemiluminescence, are higher in infancy and stable after 3 years [6]. The conversion is 1 ng/mL = 2.5 nmol/L for 25(OH)D [7]. Seasonal variation of 25(OH)D is 13–24 nmol/L, PTH rises when 25(OH)D falls below 34 nmol/L and the critical threshold for rickets is 30–34 nmol/L [7].

1,25(OH)2D is elevated during calcitriol treatment, which may mimic VDDR2 if measured during treatment [15]. Its availability is limited and its cost high in some health systems: in the Brazilian case of VDDR1A in an adult woman, it was not measured for these reasons [21]. Case reports sometimes publish incorrect units ("mmol/L" for 25(OH)D, "pmol/mL" for 1,25(OH)2D, "ng/dl" for 25(OH)D), and interpretation requires checking the reference range given [15, 16]. FGF23 is used for phosphopenic rickets: assays are not standardised, reference ranges are not universal, collection should be in EDTA plasma with prompt centrifugation (values fall if centrifugation is delayed for more than one hour), and an intact FGF23 above 27 pg/mL best distinguished FGF23-dependent causes (Hartley 2022); with the Kainos assay, an FGF23 above 30 pg/mL with hypophosphataemia identified all FGF23-mediated forms, whereas in nutritional rickets and VDDR it was undetectable or below 23.9 pg/mL [6, 11, 80].

5.8. Vitamin D loading test

The oral loading test identifies forms with a defect in 25-hydroxylation or with accelerated clearance. In the protocol of Thacher and colleagues, 50,000 IU of oral vitamin D3 or D2, with serial measurements, showed a normal rise in native vitamin D on day one (normal absorption) and increments of 25(OH)D3 on day three of 9.8 ± 2.7 ng/mL in p.(Leu99Pro) homozygotes, 19.9 ± 9.6 ng/mL in heterozygotes and 30.6 ± 16.0 ng/mL in controls [43]. In VDDR3, after 50,000 IU of vitamin D3, proband 1.1 had a normal rise in colecalciferol, attenuated increments of 25(OH)D and 1,25(OH)2D and low 24,25(OH)2D, which ruled out CYP24A1 as the cause [29]. Mantoanelli and colleagues used 150,000 IU of colecalciferol, with a peak in 25(OH)D and 1,25(OH)2D on day three and a considerable fall by day thirty, faster than in controls and in children with nutritional rickets (section 10) [15]. The test provides functional support and does not replace genetic confirmation; in vitro assays of enzyme activity have the same status [45].

5.9. Genetic testing

Genetic confirmation is generally recommended, unless a non-genetic cause has been proven or there is a positive family history with a clear picture [6]. In VDDR1A, confirmation of biallelic variants in CYP27B1 is necessary because any defect at this step would produce the same biochemical profile [12]. In VDDR2A, sequencing of VDR confirms the diagnosis; failure to respond to standard doses of calcitriol and calcium is a supporting observation and not a confirmatory test [13, 55]. Molecular testing should be done early without delaying treatment; when it is not available, the response to calcitriol serves as supporting evidence, but does not replace measurement of 1,25(OH)2D [21].

Panels have limits that determine the interpretation of a negative result. In the Brazilian patient with VDDR3, a 321-gene bone disease panel with copy-number variant (CNV) analysis was normal, and the diagnosis emerged only with the exome (mean coverage 120×, 99.4% of regions above 10×) and Sanger confirmation [15]. In the Brazilian VDDR1A case, the 18-gene panel did not include HNRNPC or CYP3A4, so VDDR2B and VDDR3 were not molecularly excluded [21]. In the "VDDR1C" family, the structural variant in PHEX was not detected by the initial approaches [9]. Homozygous exon deletions, such as the microdeletion including exon 9 of VDR, require CNV analysis [57]. A negative panel result does not exclude VDDR when the gene is not included, when the variant is structural, deep intronic or a copy-number variant not analysed, or when the disease has an unknown molecular basis, as in VDDR2B [15, 21, 23].

The report should state the gene, the transcript with version (for example NM_000785.4 for CYP27B1, NM_024514.5 for CYP2R1, NM_000376.3 for VDR, NM_017460.6 for CYP3A4), the HGVS nomenclature, the zygosity and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), with the criteria applied [21, 25]. A variant of uncertain significance (VUS) requires family segregation and, where possible, a functional study. The 2026 Brazilian case illustrates the problem: NM_000785.4:c.974C>T p.(Thr325Met) in the homozygous state was classified as likely pathogenic by the laboratory, after having been described as a VUS (PM2, PP3, PP4), without published individual criteria, without segregation and without a functional study, and it is listed in ClinVar with conflicting classifications [21, 47]. A heterozygous result in CYP2R1 is not necessarily irrelevant, because heterozygotes have an attenuated response to oral vitamin D, and it should be reported with caution [43, 45]. The CYP3A4 variant p.(Ile301Thr) is the only one described in VDDR3; its absence in the parents confirms its de novo nature [15, 29].

In France, the PNDS recommends, as first line, a panel of genes of calcium-phosphate metabolism rather than gene-by-gene analysis, carried out in a laboratory linked to the CRMR and the OSCAR network (filière), and, if the panel is negative, whole-genome sequencing within the France Genomic Medicine Plan; testing can be done at any age and is indispensable for genetic counselling [18].

5.10. Prenatal diagnosis and preimplantation genetic testing

When the family variants are known, prenatal diagnosis and preimplantation genetic testing are technically possible and should be discussed in counselling for the autosomal recessive forms, according to the legal framework of each country [21]. The sources consulted do not describe fetal ultrasound markers of VDDR, and patients with VDDR1A are normal at birth [5]. In France, indications for prenatal diagnosis are discussed case by case in the multidisciplinary prenatal diagnosis centres (CPDPN), and requests for preimplantation genetic testing in the authorised centres, also case by case [18]. Congenital rickets, when it occurs, usually results from severe maternal vitamin D and calcium deficiency [7].

6. Differential Diagnosis

6.1. Comparative table

The sources of the table are the guidance of Haffner and colleagues, Levine (2020), the global consensus, the XLH GeneReviews, the skeletal dysplasia atlas and the metabolic disease texts cited in 6.2–6.5 [5–7, 11, 44, 72, 79, 82–89].

6.2. Nutritional rickets

Nutritional rickets is the main differential diagnosis of all forms of VDDR and, at the same time, the confounding factor that delays their diagnosis. Vitamin D deficiency and calcium deficiency often coexist and biochemistry may not distinguish them [7]. In countries with very low calcium intake (Nigeria, India, Bangladesh), calcium deficiency is the main cause beyond infancy, and some children had 25(OH)D above 50 nmol/L; with intake above 500 mg/day no nutritional rickets was observed [7]. Response to vitamin D with or without calcium, with normalisation of calcium, ALP and PTH and radiological healing, confirms the diagnosis; absence of response should lead to consideration of VDDR [22]. VDDR1B and VDDR3 mimic nutritional rickets in all three domains, clinical, radiological and biochemical, and VDDR1A is distinguished by normal or high 25(OH)D [5, 11]. Coexistence of a mild hereditary form with low 25(OH)D is not unusual [6]. The genetic disorders of vitamin D metabolism (CYP2R1, CYP3A4, CYP27B1, VDR) are distinguished from XLH in all three domains [11].

The comparison by da Rocha Ribas and Borba summarises the practical differences: in nutritional rickets 25(OH)D is low, calcium normal or low, PTH elevated, presentation occurs in infancy and childhood and the response to conventional vitamin D alone is favourable; in VDDR1A 25(OH)D is normal, calcium low, PTH very high, 1,25(OH)2D very low, presentation usually occurs at 6–24 months and the response to conventional vitamin D is inadequate; in XLH 25(OH)D and calcium are normal, phosphate very low, PTH normal or elevated and there is no response to vitamin D [21].

6.3. Phosphopenic rickets

The phosphopenic forms have normal or slightly altered calcium and PTH, low phosphate and TmP/GFR and low calciuria in the FGF23-mediated forms [6, 11]. The differential diagnosis of renal phosphate wasting includes CLCN5 and OCRL (Dent disease types 1 and 2, Lowe syndrome), DMP1 and ENPP1, EHHADH, GATM, HNF4A and NDUFAF6 (renal Fanconi syndromes 1–5), FAM20C, FGF23, FGFR1 (osteoglophonic dysplasia), INPPL1 (opsismodysplasia), GNAS (McCune-Albright), HRAS, KRAS and NRAS (cutaneous skeletal hypophosphataemia syndrome), KL, PTH1R and SLC34A3, as well as FGF23-mediated oncogenic osteomalacia [11]. All these entities belong to the group of X-linked hypophosphataemic rickets and hereditary hypophosphataemic rickets. Survivors of generalised arterial calcification of infancy due to ENPP1 deficiency tend to develop hypophosphataemic rickets [90]. Linear sebaceous naevus syndrome is associated with cutaneous skeletal hypophosphataemia [91]. Hypercalciuria in a patient with suspected XLH argues against starting conventional treatment or burosumab, because of the risk of nephrocalcinosis, and requires the diagnosis to be reviewed [6].

6.4. Tubulopathies and metabolic diseases

In nephropathic cystinosis, severe rickets appears at 10–18 months despite correct vitamin D supplementation, due to Fanconi syndrome with hypophosphataemia and reduced calcitriol synthesis [86]. In tyrosinaemia type 1, hypophosphataemic rickets is the most common manifestation of the proximal tubulopathy; the original patient of Sakai and Kitagawa (1957) had vitamin D-resistant rickets, and in a series of 32 patients 48% had a decreased glomerular filtration rate, 82% aminoaciduria, 67% hypercalciuria and 59% tubular acidosis [87, 92]. In Fanconi-Bickel syndrome (GLUT2, SLC2A2; more than 70% consanguineous families), presentation at 3–10 months includes hepatomegaly and severe glycosuria, and hypophosphataemic rickets is the main manifestation of tubular dysfunction [88]. Lowe syndrome combines dense congenital cataract, Fanconi tubulopathy, renal rickets, osteomalacia and fractures [72, 93]. Among the bile acid synthesis defects, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency caused rickets in 8 of 18 patients, one of them with hypocalcaemic tetany and seizures with normal liver function tests, and rickets due to malabsorption of fat-soluble vitamins may require 1α-hydroxycolecalciferol or 1,25-dihydroxycolecalciferol [89]. Rickets has also been described in transaldolase deficiency [94]. In osteopetrosis with renal tubular acidosis (CA2), the rickets of early childhood responds to vitamin D [85]. CYP24A1 deficiency, with loss of function, causes idiopathic infantile hypercalcaemia and is the biochemical opposite of VDDR3 [7, 95].

6.5. Metaphyseal dysplasias and other entities

The metaphyseal dysplasias form a group that is difficult to distinguish from rickets on radiographs alone [78]. In metaphyseal chondrodysplasia, Schmid type (OMIM 156500, COL10A1), bone structure is normal, there is coxa magna, coxa vara and short femoral necks with large femoral epiphyses until about 9 years, and the height deficit is usually greater than −3 standard deviations (SD); vitamin D given because of a misdiagnosis of rickets is contraindicated [44, 79]. In metaphyseal dysplasia, Spahr type (OMIM 250400, MMP13), rickets is excluded by normal biochemistry and vitamin D supplements are not indicated [82]. Metaphyseal anadysplasia (OMIM 602111 and 613073) is detected incidentally or because of suspected rickets, usually regresses by 6 years and has normal calcium and phosphate; vertebral changes, when present, help to exclude rickets [83]. In metaphyseal chondrodysplasia, Jansen type (OMIM 156400, constitutive activation of PTH1R), there is hypercalcaemia in the first months, low or low-normal phosphate, elevated ALP and osteocalcin and normal or low PTH, and rickets does not show involvement of the metacarpals and phalanges, skull sclerosis or elevated calcium [84]. Hypophosphatasia is distinguished by low ALP and increased urinary phosphoethanolamine, with tongue-like metaphyseal ossification defects different from rachitic fraying [44]. Blount disease and the metaphyseal dysplasias have normal ALP [6]. When abuse is suspected, 25(OH)D is similar in infants with accidental and non-accidental injuries, and the lateral and anterolateral rib fractures described in severe nutritional rickets occurred in mobile children with severe radiological rickets [7]. In adults, primary hyperparathyroidism is distinguished by elevated serum and urinary calcium, osteoporosis often coexists and prolonged osteomalacia may mimic a neoplasm [22].

7. Treatments and Risk Management Strategies

7.1. General principles

Treatment depends on the type of rickets [44]. The goal common to the calcipenic forms is to maintain serum calcium in the middle of the normal range, which normalises PTH, TRP and, consequently, phosphate; persistently elevated PTH maintains hyperparathyroid bone disease, and suppressed PTH is associated with hypercalciuria [5]. Response is assessed by clinical parameters (height, weight, annual growth velocity, head circumference in infants, degree of bowing, gait, bone pain, muscle weakness, dental changes) and biochemical parameters (phosphate, calcium, ALP, PTH, 25(OH)D); normalisation of ALP, calcium, phosphate and PTH indicates healing, and normalisation of an initially low calciuria confirms adequate calcium intake [60]. In all forms, a calcium intake of 200 mg/day (0–6 months), 260 mg/day (6–12 months) and 500 mg/day (children and adolescents) and a 25(OH)D above 50 nmol/L should be ensured [7, 60]. The conversion between vitamin D units is 1 µg = 40 IU [7, 30]. None of the drugs used in VDDR has a US Food and Drug Administration (FDA)-approved indication for these diseases, except the historical mention of "refractory rickets" in the ergocalciferol label; in the United Kingdom, the summary of product characteristics (SmPC) of alfacalcidol includes pseudodeficiency rickets (7.9) [30, 96, 97]. Maintenance doses in VDDR come from reviews and expert opinion based on small series, without randomised trials [5, 12, 60].

7.2. Symptomatic hypocalcaemia

Symptomatic hypocalcaemia is treated with intravenous calcium gluconate until calcium normalises, followed by oral calcium; dilated cardiomyopathy is treated with diuretics and angiotensin-converting enzyme (ACE) inhibitors, with paediatric cardiology [22, 60]. Uday and Högler describe a bolus of calcium gluconate followed by an infusion until normocalcaemia and only then a switch to the oral route, and point out that colecalciferol or ergocalciferol at therapeutic doses are started without waiting for the 25(OH)D result; alfacalcidol may be used for a short period in profound hypocalcaemia that responds slowly to oral calcium [22]. The US label for calcium gluconate injection (initial approval in 1941; 2026 label) is indicated in paediatric and adult patients for acute symptomatic hypocalcaemia and defines doses in milligrams of calcium gluconate [98]:

Each mL of the 10% solution contains 100 mg of calcium gluconate, corresponding to 9.3 mg (0.465 mEq) of elemental calcium [98]. For the bolus, the solution is diluted in 5% glucose or normal saline to 10–50 mg/mL and given slowly, not exceeding 100 mg/minute in paediatrics, including neonates, and 200 mg/minute in adults, with monitoring of vital signs and ECG; for continuous infusion it is diluted to 5.8–10 mg/mL [98]. Serum calcium is measured every 4–6 hours with intermittent administration and every 1–4 hours with continuous infusion; in renal impairment, the lowest dose is used first and calcium is measured every 4 hours [98]. Rapid injection may cause vasodilatation, hypotension, bradycardia, arrhythmias, syncope and cardiac arrest; calcinosis cutis and tissue necrosis may occur with or without extravasation, and administration should be through secure venous access, stopping immediately at that site if there are signs of extravasation [98]. Concomitant administration with ceftriaxone is contraindicated in neonates aged 28 days or less, because of the formation of ceftriaxone-calcium precipitates with fatal outcomes; after that age it may be sequential with line flushing, never via a Y-site; the solution is incompatible with bicarbonate, phosphate and minocycline, and contains up to 512 µg/L of aluminium, with particular risk in preterm infants [98]. Paediatric approval, including doses, is based on published literature and clinical experience, and not on controlled studies [98]. In the Birmingham series, normalisation of calcium required repeated boluses and a 72-hour infusion in one infant, and in another an early switch to oral calcium was followed by a further seizure with respiratory arrest on the third day, requiring five more days of intravenous calcium [73].

Table 7.2a — French emergency protocols for hypocalcaemia (PNDS 2024, appendices 3 and 4) [18]

The PNDS states 90 mg of elemental calcium per 10 mL ampoule of 10% calcium gluconate (2.25 mmol), and the US label 93 mg (9.3 mg/mL); the difference has no clinical impact [18] [98]. The French 1/10 dilution corresponds to 10 mg/mL of gluconate, within the label range of 5.8–10 mg/mL for continuous infusion; the rate of 1 L/m²/24 h corresponds, by calculation from the PNDS table, to about 21 mg/kg/hour of gluconate at 10 kg and 12.5 mg/kg/hour at 50 kg, above the label's initial paediatric range (8–13 mg/kg/hour) in small children, which reinforces the ionised calcium monitoring set out in the protocol [18] [98]. The adult bolus (2 g of gluconate over 10 minutes) matches the label limit of 200 mg/minute [98].

7.3. Nutritional rickets: treatment

The global consensus recommends a minimum dose of 2000 IU/day (50 µg) of vitamin D for at least 3 months and oral calcium of 500 mg/day, from diet or supplement, in combination with vitamin D, regardless of age or weight (strong recommendations, high-quality evidence); the consensus sets the minimum dose, and the daily doses by age, up to 6000 IU/day after 12 years, are given in the following table [7]. The oral route is preferred because it restores 25(OH)D faster than the intramuscular route; vitamins D2 and D3 are equivalent in daily doses, and for a single high dose D3, with a longer half-life, is preferred [7]. The treatment table of the consensus, reproduced in the guidance of Haffner and colleagues, is as follows [7, 60]:

Response is reassessed at 3 months, because treatment may need to be prolonged; daily calcium intake should be at least 500 mg; to convert IU to µg, divide by 40 [7]. Calcium, phosphate and PTH may normalise within 3 weeks, and ALP takes months [60]. Daily treatment is first line; "stoss" therapy (a single high dose) is acceptable when it is more practical and is associated with a higher risk of hypercalcaemia: in 56 Turkish children aged 3–36 months treated with 150,000, 300,000 or 600,000 IU, improvement at 30 days was similar and hypercalcaemia occurred in 8 (2 with 300,000 IU and 6 with 600,000 IU); in 76 Indian children aged 6 months to 5 years, 300,000 or 600,000 IU of D3 healed all of them radiologically by 12 weeks, with hypercalcaemia in 5 (6.5%) [7]. Sources diverge on the route of the "stoss" dose: the consensus prefers the oral route and does not specify the intramuscular route for the single dose, and the guidance of Haffner and colleagues describes it as a single intramuscular injection of 50,000 IU from 3 months up to 300,000 IU after 12 years, reserved for poor adherence [7, 60]. Uday and Högler preferably recommend D3 for the "stoss" dose, with 50,000 IU only after 3 months, and consider 60,000 IU weekly for 10 weeks orally equivalent, in efficacy and safety, to 600,000 IU intramuscularly as a single dose [7, 22]. As for calcium, Uday and Högler indicate 200–300 mg/day in infants and 500 mg/day at other ages, which differs from the formulation of the consensus ("500 mg/day regardless of age") [7, 22].

The combination of calcium and vitamin D is superior to vitamin D alone. In Nigeria, among 123 children with calcium-deficiency rickets, the combined outcome (ALP < 350 U/L and near-complete radiological healing) was achieved by 58% with calcium and vitamin D, 61% with calcium alone and 19% with vitamin D alone; in India, among 67 children with combined deficiency, complete healing at 12 weeks occurred in 50% with combined therapy, 15.7% with vitamin D alone and 11.7% with calcium alone [7]. Phosphate supplements have no role, because they worsen secondary hyperparathyroidism, and calcitriol and alfacalcidol have no role in the treatment of nutritional rickets, except short-term alfacalcidol in profound hypocalcaemia [22]. After healing, maintenance is at least 600 IU/day after 12 months [60]. The approach includes the family: mothers of infants with nutritional rickets are almost certainly deficient, the other children and symptomatic adults in the household should be screened, and at-risk members should receive supplements and information; asymptomatic relatives are not routinely tested [22]. In the Birmingham series, 5 of 9 relatives tested had 25(OH)D < 30 nmol/L, 3 had 30–50 nmol/L and 6 had elevated PTH and ALP [73].

Table 7.3a — Vitamin D replacement in insufficiency or deficiency, according to the French PNDS (appendix 2, based on the 2020 French paediatric recommendations) [18]

In adults with or at risk of osteoporosis, the PNDS reproduces the 2020 French scheme: loading with 50,000 IU of vitamin D3 per week for 8 weeks if 25(OH)D is below 20 ng/mL, or for 4 weeks between 20 and 30 ng/mL, followed by 50,000 IU per month; after 3 to 6 months, if 25(OH)D remains below 30 ng/mL, the interval is shortened (50,000 IU every 2 weeks) or the dose increased (80,000 or 100,000 IU per month), and if it exceeds 60 ng/mL the doses are spaced out (for example, every 2 months) [18]. These intermittent schemes diverge from the preference of international guidance for daily administration in the treatment of nutritional rickets, and the French text itself presents them as a stopgap until daily forms of adequate dose become available [18] [7].

7.4. Nutritional rickets: prevention and divergences between guidelines

The sources of the table are the global consensus, the AAP, ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition), the French consensus and the Endocrine Society [7, 74, 75, 99, 100]. ESPE is the European Society for Paediatric Endocrinology, and the societies of the global consensus include PES, APPES, JSPE, SLEP, APEG, ISPAE, ASPAE, CSPEM, the British Nutrition Society and ESPGHAN [7].

The guidelines diverge on four points. The first is strength: the global consensus formulates the universal 400 IU/day recommendation in the first year as strong and based on high-quality evidence, and the Endocrine Society makes a conditional suggestion, of low certainty, for ages 1–18 years, not including infants and without defining the optimal dose [7, 74]. The Endocrine Society found no randomised trials on prevention of symptomatic rickets and relies on historical data: in the study by Hess and Unger (1917), rickets occurred in 8 of 49 infants given cod liver oil and in 15 of 16 controls; in Turkey, the free 400 IU/day programme was associated with a fall in prevalence from 6% (1998) to 0.1% (2008) [74]. The second is thresholds: deficiency is defined by 25(OH)D < 30 nmol/L in the global consensus, severe deficiency by < 25 nmol/L in ESPGHAN, and the French consensus classifies deficiency as below 50 nmol/L (20 ng/mL), severe deficiency as below 25 nmol/L, sufficiency as 75–150 nmol/L, excess as above 150 nmol/L and risk of toxicity as above 200 nmol/L, recommending that 25(OH)D be kept above 50 nmol/L and suggesting above 75 nmol/L [7, 75, 100]. The third is the maximum dose and the intermittent scheme, which the French consensus limits (maximum 800 IU/day in healthy children, no 200,000 IU doses) [75]. The fourth is toxicity: the global consensus defines it as hypercalcaemia with 25(OH)D > 250 nmol/L, hypercalciuria and suppressed PTH, and notes that symptomatic toxicity in trials occurred only above 500 nmol/L [7]. All sources advise against routine measurement of 25(OH)D in healthy children [7, 74, 75]. A 2025 critical review rejected the Endocrine Society paediatric recommendations as a one-size-fits-all approach and argued for targeted screening and supplementation; this is opinion, not a guideline [101]. A 2025 French survey of 966 professionals found supplementation prescribed at more than 90% of ages and a daily dose up to 2 years in 97%, but 5% still prescribed a 200,000 IU loading dose and 10% non-pharmaceutical food supplements; only 10% assessed calcium intake with a questionnaire or tables [102].

The global consensus also recommends that pregnant women do not receive calcium above the amount recommended for non-pregnant women, that lactating women receive 600 IU/day for their own needs and not high doses to supplement the infant, that calcium-rich complementary foods be introduced by 26 weeks and that intake in childhood and adolescence be at least 500 mg/day of elemental calcium [7]. Maternal doses up to 4000 IU/day are probably safe in pregnancy and lactation, and infants of mothers taking at least 2000 IU/day have a 25(OH)D similar to that of infants given 400 IU/day; the consensus maintains 600 IU/day for the mother with 400 IU/day for the infant [7]. The French consensus recommends at least three to four servings of dairy products per day from 1 to 18 years and 500–1000 mg/day of supplemental calcium if bioavailable intake is below 300 mg/day, especially with vegan diets, and defines the diagnosis of calcium deficiency by assessment of intake, wrist and knee radiographs and measurement of ALP, PTH, 25(OH)D, calcium, phosphate and calciuria [75].

The French PNDS refers prevention to the 2022 French recommendations and summarises the intake references: in children, the calcium intakes of the European Food Safety Authority (EFSA, 2017) of 280 mg/day at 7–11 months, 450 mg/day at 1–3 years, 800 mg/day at 4–10 years and 1150 mg/day at 11–17 years; in adults, those of the French Agency for Food, Environmental and Occupational Health and Safety (ANSES), with an average requirement of 750 mg/day, an adequate intake of 950 mg/day and a tolerable upper intake level of 2500 mg/day, and the 25(OH)D targets of the French research group on osteoporosis (GRIO), above 50 nmol/L before 65 years and above 75 nmol/L after 65 years or in osteoporosis or at risk of osteoporosis [18] [75]. The paediatric emergency appendix of the same PNDS uses a different intake table (500 mg/day at 1–3 years, 700 mg/day at 4–6, 900 mg/day at 7–9 and 1200 mg/day at 10–18 years), and the values of both exceed the minimum of 500 mg/day of the international guidance for children with rickets [18] [60].

7.5. VDDR1A

Treatment is lifelong replacement of the missing hormone and not supplementation with the vitamin [12, 60]. Calcitriol (Rocaltrol® and generics) is preferred because, being the deficient hormone, it acts at physiological doses; its short half-life allows rapid onset and means that accidental hypercalcaemia resolves within a few days of stopping; it is available as capsules, oral solution and an intravenous form and is usually given twice daily [5]. Alfacalcidol (1α-hydroxycolecalciferol; One-Alpha® in the United Kingdom), which only requires hepatic 25-hydroxylation, is equally effective and, because of its longer half-life, is given once daily [5, 60]. The suggested maintenance doses are 0.3–2 µg/day of calcitriol and 0.5–3 µg/day of alfacalcidol, not adjusted for weight and similar in children and adults, titrated to keep calcium and PTH in the middle of the normal range [5, 60]. In the first 3–6 months, doses 2–5 times higher than maintenance are needed, because undermineralised bone takes up calcium ("hungry bone"), and children receive oral elemental calcium of 50 mg/kg/day during the initial phase to avoid worsening hypocalcaemia, with no maximum dose defined in the source [5, 60]. Thereafter, the fraction of calcium absorbed remains constant under treatment, so serum and urinary calcium vary with diet; supplements serve to maintain a constant calcium intake [5]. Treatment is indefinite [5].

Native vitamin D (ergocalciferol or colecalciferol) and calcifediol are marked as "not indicated" in VDDR1A: they work only at pharmacological doses, which raise 25(OH)D to 150–250 ng/mL, a concentration capable of directly activating the VDR, with 1,25(OH)2D still low and a substantially higher risk of hypercalcaemia [5, 12]. Nutritional or "stoss" doses do not correct the disease [12]. The UK SmPC for alfacalcidol states that, in pseudodeficiency rickets, high doses of native vitamin D would be needed, whereas effective doses of alfacalcidol are similar to those that heal nutritional rickets; the SmPC starting doses for all indications are 1 µg/day in adults and children over 20 kg, 0.5 µg/day in the elderly, 0.05–0.1 µg/kg/day in neonates and preterm infants and 0.05 µg/kg/day in children under 20 kg, with increments of 0.25–0.5 µg, weekly monitoring initially and every 2–4 weeks after stabilisation; most adults respond to 1–3 µg/day, maintenance is usually 0.25–1 µg/day, and the dose decreases with bone healing [97]. In the Brazilian woman diagnosed at 25 years, calcitriol 0.25 µg once daily with elemental phosphorus (500 mg/day) and calcium carbonate (1500 mg/day, about 600 mg of elemental calcium) reduced ALP from 286 to 139 U/L in about one year, but PTH remained at 532 pg/mL, reflecting incomplete control [21]. The dose used is below the maintenance range of 0.3–2 µg/day, and phosphate is not part of the guidance regimen [5, 60].

Table 7.5a — Forms of vitamin D available in France according to the PNDS (2024) [18]

In France, alfacalcidol is mainly used, as a single daily dose, with a starting dose of 2 µg/day, adjusted to the severity of hypocalcaemia and to progress; mean doses then become 0.5–1 µg/day from 4 to 9 years and 1–2 µg/day from 11 to 15 years, with no maximum dose defined in the PNDS, the practical limit being set by serum calcium and calciuria [18]. Calcitriol is given in two doses, with a starting dose of 1 µg/day and then 0.25–0.75 µg/day from 4 to 9 years and 0.5–1 µg/day from 11 to 15 years [18]. Initially calcium is added, with a total intake, including dietary intake, equal to twice the recommended amount, to avoid hungry bone, followed by dietary assessment to maintain the recommended intake for age; the usual colecalciferol supplementation is continued, because of possible residual 1α-hydroxylase activity [18]. The dose and form are adjusted to the growth curve, to signs of rickets activity and to osteopenia, and treatment continues into adulthood, because biochemical parameters become abnormal again, with a dose increase in pregnancy; the PNDS acknowledges that this recommendation rests on a low level of evidence and on the experience of the group [18]. In the French series, 23 of the 24 patients were treated with alfacalcidol and 1 with calcitriol; treatment started immediately after diagnosis in 70%, and delays were due to diagnostic uncertainty or lack of adherence [48]. The median starting dose of alfacalcidol was 1.0 µg/day (0.2–4.0), or 0.11 µg/kg/day (0.03–0.32), half the PNDS starting dose of 2 µg/day, and 74% also received a calcium supplement [18, 48]. Calcium normalised after a median of 5 months (2–20; n = 13) and ALP after about 1 year (median 12.4 months, 1.2–48; n = 8, including 3 patients with poor adherence), and DXA was normal in the 8 patients assessed; the authors consider alfacalcidol and calcitriol equivalent [48]. Nephrocalcinosis occurred under treatment in 5 of 17 patients with ultrasound, and disappeared in 3 after a reduction in the alfacalcidol dose or better adherence, with no decline in renal function at the end of follow-up [48]. Serious complications arose with late diagnosis or poor adherence: osteotomy for genu valgum at 14 years in 2 sisters with repeated admissions for hypocalcaemia and bilateral hip replacement at 37 and 38 years in a man without treatment between 20 and 45 years of age [48].

7.6. VDDR1B

Calcifediol (25-hydroxyvitamin D3, also called calcidiol) bypasses the 25-hydroxylation defect and is the preferred treatment, with supplemental calcium as in VDDR1A; it restores physiological control, because conversion to 1,25(OH)2D remains regulated by PTH [5, 60]. Molin and colleagues documented marked clinical, biochemical and densitometric improvement under calcifediol, with normal CYP24A1 activity [49]. The alternatives are vitamin D2 or D3 at pharmacological doses or calcitriol at physiological doses, with calcium and PTH kept in the middle of the normal range [5, 60]. The suggested maintenance doses are 20–50 µg/day of calcifediol, 100–200 µg/day of vitamin D3 or D2 (4000–8000 IU/day), 0.3–2 µg/day of calcitriol and 0.5–3 µg/day of alfacalcidol [5, 60]. In one French proband, alfacalcidol produced only partial improvement, with a marked rise in 1,25(OH)2D attributed to accessory 25-hydroxylases; another patient, homozygous for p.(Gly42_Leu46delinsArg), was controlled with alfacalcidol [5, 49]. In Nigeria, a homozygote with minimal response to 6 months of calcium had the radiological score reduced from 8 to 3.5 three months after 600,000 IU of intramuscular vitamin D3 and to 0.5 after a second dose, with persistent deformities; the heterozygous sisters healed with calcium, with or without 50,000 IU of vitamin D2 monthly for 6 months [43]. The Indian siblings and the Chinese twin girls were treated with titrated colecalciferol and calcium, with a good response [50, 51]. The only calcifediol with an FDA label is the extended-release formulation Rayaldee®, approved for secondary hyperparathyroidism in adults with stage 3–4 CKD and 25(OH)D < 30 ng/mL, with safety and efficacy not established in paediatrics; its use in VDDR1B is off-label and outside the approved age range, and Levine does not specify the formulation of the doses he proposes [5, 103]. Requirements decrease with age and heterozygotes have a milder phenotype [60].

The French PNDS includes calcifediol (Dedrogyl®, 1 drop = 5 µg) at a dose of 20–50 µg/day or calcitriol, and reports a French patient successfully treated with alfacalcidol [18]. In adulthood, three patients from one family who stopped treatment at the end of adolescence had, 14 to 17 years later, undetectable 25(OH)D with normal 1,25(OH)2D and normal bone mineral density at the hip and spine; the PNDS therefore accepts stopping treatment in adults, with monitoring of bone mineralisation and resumption of treatment in the event of loss of mineralisation, fracture, pregnancy or oestrogen deficiency [18]. In counselling, heterozygotes for p.(Leu99Pro) appear to have a higher risk of vitamin D deficiency than the general population, which justifies an extended family study [18].

7.7. VDDR2A and VDDR2B

The principle is to bypass the non-functional receptor in the intestine by providing enough calcium to be absorbed passively [13]. In early infancy, intestinal calcium absorption is largely independent of vitamin D, and oral elemental calcium of 5–6 g/m²/day is often sufficient in the first months; some patients need intravenous calcium until the hungry bone has healed [5, 60]. Vitamin D is then tried, preferably calcitriol or alfacalcidol, with a highly variable response [60]. In the milder forms, usually with normal hair, vitamin D at 5000–40,000 IU/day, calcifediol at 20–200 µg/day or calcitriol at 17–20 µg/day have been used, and many patients went into complete remission with very high doses; serum 1,25(OH)2D should be kept at 200–1000 pg/mL, and the maximum useful doses are not defined [5]. In patients with alopecia, about half are resistant to maximum doses and the other half respond to doses about 10 times higher than those of patients with normal hair; doses of calcitriol or alfacalcidol may reach 5–60 µg/day, limited only by cost and acceptability [5, 60]. Patients who respond only to extraordinary doses of active vitamin D also receive oral elemental calcium of 1000 mg/day [5, 60].

In non-responders, intravenous calcium is the mainstay: 1000 mg of elemental calcium per 24 hours, infused over 12 hours, for many months [5, 60]. The justification is quantitative: normal calcium balance in childhood is about 300 mg/24 h, net retention without vitamin D action is about 10% and maximum oral tolerance is around 6 g/day, so high-dose oral calcium is usually insufficient [5]. With 9.3 mg of elemental calcium per mL of 10% calcium gluconate, 1000 mg of elemental calcium corresponds to about 107 mL of this solution (calculated from the label concentration) [98]. Historically, intravenous calcium required central venous access, with the associated catheter morbidity [13, 56]. Abalı and colleagues treated four Turkish patients with total alopecia with intermittent intravenous calcium, 2–5 times per week, via a peripheral line, without infection, extravasation or arrhythmias; PTH and ALP normalised in all after 1–22 months, and maintenance with oral calcium of 200–400 mg/kg/day and calcitriol of 0.5 µg/kg/day kept PTH normal [56]. Ben Ameur and colleagues used the same route in 6 Tunisian children, with clear improvement in 5 [13, 54]. Faiyaz-Ul-Haque and colleagues corrected, with high-dose calcitriol and oral calcium, all manifestations except alopecia over 11 years [55]. Ahmad and colleagues consider high-dose intravenous calcium the currently accepted modality [13, 68].

In a Swedish girl with a homozygous microdeletion of exon 9 of VDR, high-dose oral calcium with colecalciferol and alfacalcidol gave only a partial response; with intravenous calcium infusions, bone pain resolved and rickets healed within weeks, and phosphate normalised with the fall in ALP although PTH remained very high (tertiary hyperparathyroidism), still elevated about one year after serum calcium normalised; the infusions caused mild hypercalcaemia without suppressing PTH, which eventually resolved under high-dose oral calcium with colecalciferol and alfacalcidol, without cinacalcet or surgery [57]. The authors conclude that persistent tertiary hyperparathyroidism does not prevent healing of rickets or normalisation of phosphate and that high-dose calcium, preferably intravenous, appears sufficient [57]. In the infant with a hypophosphataemic presentation without hypocalcaemia, high-dose calcitriol brought progressive biochemical improvement and catch-up growth [58].

Cinacalcet has been used off-label as an adjunct in isolated cases and in 4 of the 8 Saudi patients: none of the 4 had hypocalcaemia, there was an initial reduction in PTH, but the overall response was variable and the authors call for further research; it is not an established treatment [13, 68]. Alopecia has no effective treatment [13, 55]. Requirements decrease after puberty, which requires the regimen to be reassessed rather than kept unchanged into adulthood [5, 13]. VDDR2B is treated like VDDR2A [5, 60].

The French PNDS organises the treatment of VDDR2A by severity [18]. In moderate forms, without alopecia, it combines alfacalcidol 10 µg/day, colecalciferol 50,000 IU per month and high-dose oral calcium (three times the recommended intake for age), divided into several doses, without phosphate supplementation whatever the phosphataemia and with no maximum dose defined for the analogues; the monotherapy alternatives are those of Levine (colecalciferol 5000–40,000 IU/day, calcifediol 20–200 µg/day or calcitriol 17–20 µg/day), and the regimen is adjusted to calcium, ALP, PTH, 25(OH)D and the urinary calcium/creatinine ratio, switching to intravenous calcium if it fails [18]. In severe forms, with alopecia, about half of patients are resistant to the oral route; in these cases intravenous calcium of 1000 mg/24 h is started, infused over 12 hours overnight, usually through a central venous catheter, with a non-negligible risk of infection [18]. When PTH and ALP reach the upper limit of normal and calciuria becomes detectable, the infusions are spaced out (every other day, then one day in three) to find the minimum effective dose, with alfacalcidol 10 µg/day and colecalciferol 50,000 IU per month especially in the spacing and stopping phase; patients who stop the infusions switch to oral calcium divided throughout the day [18]. Puberty may increase requirements and make it necessary to resume the infusions; once growth is complete, doses fall considerably, with monitoring in pregnancy, and adults, even with the most severe forms, appear to be treatable for one to two decades with oral calcium of 5–6 g/m²/day [18]. The intermittent peripheral route described by Abalı and colleagues, without complications in four patients, contrasts with the central route that the PNDS considers usual [18, 56]. For the PNDS, VDDR2B may not be an entity distinct from VDDR2A and is treated in the same way [18].

7.8. VDDR3

The approach is to give high-dose vitamin D to overcome the accelerated catabolism. The two patients of Roizen and colleagues needed high-dose calcitriol or 50,000 IU/day of vitamin D3 to keep metabolites, PTH, calcium and phosphate normal [29]. In the Brazilian patient, 10,000 IU/day of colecalciferol with calcium supplementation improved growth velocity (5.9 cm in 3 months) and healed the deformities within 3 months; the lower dose was attributed to smaller body size and, possibly, to lower activity of the growth hormone pathway, which induces CYP3A4 [15]. In the Saudi patient, alfacalcidol at 1.5–4 µg/day with calcium at 30 mg/kg/day did not control the disease — PTH rose to 351 pg/mL at 8 years — and switching to colecalciferol 50,000 IU per week, with alfacalcidol stopped, improved the biochemistry (25(OH)D from 20 to 57 nmol/L at 3 months) [16]. The text and table of that report diverge on the alfacalcidol dose at 5 years (0.5 µg/day in the text, 4 µg/day in the table) [16]. The maintenance doses suggested by Levine, with no defined upper limit, are 1000 µg/day or more of vitamin D3 or D2 (40,000 IU/day), 50 µg/day or more of calcifediol, 1 µg/day or more of calcitriol and 2 µg/day or more of alfacalcidol [5, 60]. The optimal dose of colecalciferol has not yet been established [15]. No drug is labelled for VDDR3 and the evidence comes from case reports [61].

The French PNDS, with a literature search up to 2023, counts three families with VDDR3 (the two of Roizen and the Brazilian one), which needed high-dose calcitriol or vitamin D at 50,000 IU/day; the Saudi patient published in 2023 is not included [18] [16].

7.9. Suggested maintenance doses in VDDR

The table reproduces table 2 of Levine (2020), identical to table 3 of the guidance of Haffner and colleagues; doses are absolute and not weight-adjusted, and supplemental calcium is indicated in all patients [5, 60]. In the milder forms of resistance, usually with normal hair, there is a response to analogues that require 1-hydroxylation, and serum 1,25(OH)2D should be kept at 200–1000 pg/mL; in VDDR2 the maximum doses are limited by cost and acceptability, and some patients do not respond to the maximum doses tested [5]. These values come from reviews and expert consensus, not from trials, and most constitute off-label use (7.10).

Table 7.9a — Divergences between the French PNDS (2024) and the other sources of this article

7.10. Comparative regulatory status

The sources of the table are the FDA labels and the Drugs@FDA register, the UK SmPC for alfacalcidol and the EMA list of medicines for human use, consulted on 17 October 2026 [30, 75, 96–98, 103–106]. In the sources consulted, national access to these drugs in Portugal (INFARMED) and in Brazil (ANVISA and CONITEC) was not verified, so the article does not describe local reimbursement conditions. In India, of the 258 vitamin D supplements on the market, 46.5% contained calcitriol, 43% alfacalcidol and only 10.5% colecalciferol, and more than 75% of alfacalcidol preparations contained added calcium, with a risk of hypercalcaemia — a distortion of supply that is important to know when the patient is treated outside the reference centre [22].

7.11. Evidence of efficacy and its limits

The sources of the table are the series and trials cited [7, 15, 43, 49, 54–56, 68].

These data have limits that determine how they are read. None of the hereditary calcipenic forms has a randomised trial, and patient numbers do not allow comparisons between regimens; the series are retrospective, with selection of patients treated at reference centres [12, 68]. The studies are not comparable with one another, because they differ in the form of VDDR, age, severity and definition of response, and proportions obtained in series of four to eight patients do not translate into population response rates. In the ClinicalTrials.gov search of 17 October 2026 there was no interventional trial targeting VDDR, nor any new drug in development for the hereditary calcipenic forms; the vast majority of results concerned XLH and burosumab [76]. A negative search does not demonstrate non-existence. The relevant observational studies include the NIDDK protocol NCT00001242 on states of resistance to vitamin D and PTH (1997–2022, 70 participants, completed, no results posted in the registry), NCT01578824 (Israel, 26 participants), the basis of the asthma studies in patients with VDDR2A, and NCT00502866 (USA, 246 participants) on a laboratory screening test for rickets [76].

7.12. Adverse effects and their management

The adverse effect common to all vitamin D analogues is hypercalcaemia, with hypercalciuria, nephrocalcinosis and nephrolithiasis. The calcitriol label describes the hypercalcaemia syndrome with early manifestations (weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle and bone pain, metallic taste) and late manifestations (polyuria, polydipsia, weight loss, calcific conjunctivitis, pancreatitis, photophobia, ectopic calcification, nephrocalcinosis, hypertension, arrhythmias, growth arrest); in the trials in hypoparathyroidism and pseudohypoparathyroidism, about one third of patients had hypercalcaemia at least once, about one seventh hypercalciuria and about one sixth a rise in creatinine [96]. The label recommends starting with the lowest dose, ensuring a calcium intake of at least 600 mg/day, measuring serum calcium at least twice weekly during titration and then monthly, keeping the calcium × phosphate product below 70 mg²/dL², stopping pharmacological doses of vitamin D during calcitriol treatment and, if calcium exceeds the upper limit by more than 1 mg/dL, stopping the drug, withdrawing calcium supplements and reintroducing at a dose 0.25 µg/day lower, which frequently resolves the picture within 2 to 7 days; when switching from ergocalciferol to calcitriol, ergocalciferol concentrations may take months to normalise [96]. The alfacalcidol SmPC requires stopping in hypercalcaemia until normalisation, in about one week, and restarting at half the dose [97].

The ergocalciferol label describes overdose with effects persisting for two months or more after stopping: hypercalcaemia (anorexia, nausea, weakness, weight loss, constipation, anaemia, mild acidosis), polyuria, nocturia, polydipsia, hypercalciuria, reversible azotaemia, hypertension, nephrocalcinosis, vascular calcification, potentially fatal irreversible renal failure, soft tissue calcification and, in children, reduced growth velocity; treatment is withdrawal, a low-calcium diet, hydration and intravenous normal saline with or without a loop diuretic [30]. Contraindications are hypercalcaemia, malabsorption syndrome, abnormal sensitivity to the toxic effects of vitamin D and hypervitaminosis D, and hypersensitivity to vitamin D may be a factor in idiopathic hypercalcaemia of infancy, in which case vitamin D should be restricted [30]. The alfacalcidol SmPC contraindicates it in hypercalcaemia and metastatic calcification, requires regular monitoring of calcium and phosphate, especially in children, and advises caution in sarcoidosis and other granulomatous diseases; the capsule contains sesame oil [97]. In nutritional rickets, intoxication occurs mainly in infants and young children with doses of 240,000 to 4,500,000 IU, and hypercalcaemia with hypercalciuria usually occurs with 300,000 to 600,000 IU [7].

7.13. Interactions and agents to avoid

Mineral oil reduces vitamin D absorption, and thiazides in hypoparathyroidism may cause hypercalcaemia [30]. The alfacalcidol SmPC adds thiazides and calcium (increased risk of hypercalcaemia), other vitamin D analogues (avoid the combination), enzyme-inducing anticonvulsants (barbiturates, phenytoin, carbamazepine, primidone), which increase metabolism and may require higher doses, magnesium-containing antacids (hypermagnesaemia), aluminium and bile acid sequestrants, which should be taken at least one hour before or 4 to 6 hours after [97]. Digitalis drugs require caution with any vitamin D analogue, and immobilisation increases the risk of hypercalcaemia [96, 97]. CYP3A4 inducers (rifampicin, phenytoin, barbiturates, glucocorticoids) accelerate the inactivation of vitamin D metabolites and cause deficiency; this interaction is mechanistically the same as the one that defines VDDR3 and should be avoided or compensated for in these patients [15, 29]. Glucocorticoids also inhibit intestinal calcium absorption, and antiretrovirals and azole antifungals interfere with vitamin D metabolism [75]. Phosphate supplements should not be used in calcipenic rickets, because they worsen secondary hyperparathyroidism [22]. In XLH, calcium supplements are discouraged, because they may reduce phosphate absorption and increase the risk of lithiasis; this recommendation does not apply to the calcipenic forms, in which calcium is essential [11]. Vitamin D is contraindicated or not indicated in metaphyseal dysplasias misdiagnosed as rickets [79, 82].

The French adult emergency protocol adds rules for any hypocalcaemic patient: bisphosphonates, denosumab and cinacalcet are contraindicated and should be stopped immediately, with contact with the referring physician; loop diuretics are not enough to explain hypocalcaemia, thiazides reduce calciuria and not calcaemia, and corticosteroids and non-steroidal anti-inflammatory drugs may reduce intestinal calcium absorption [18]. The contraindication of cinacalcet in hypocalcaemia contrasts with its off-label adjunctive use, without hypocalcaemia, in patients with VDDR2A (7.7) [18] [68].

7.14. Pregnancy, lactation, perioperative care and transition

The only guidance consulted that addresses VDDR in pregnancy is the French PNDS, in summary form: in VDDR1A treatment continues into adulthood with a dose increase in pregnancy; in VDDR1B stopped treatment should be resumed in pregnancy; in VDDR2A pregnancy is a period of surveillance; and the follow-up schedule provides for a consultation and biochemistry every 2–3 months during pregnancy [18]. The alfacalcidol SmPC does not recommend its use in pregnancy, because of limited data and reproductive toxicity in animals at high doses, and requires monitoring for hypercalcaemia in the infant during breastfeeding; the ergocalciferol label considers safety above 400 IU/day in pregnancy not established and advises avoiding doses above the recommended daily dose unless there is a specific benefit [30, 97]. These formulations conflict with the lifelong therapeutic need of a patient with VDDR, and the decision is individual, with close monitoring of calcium; the evidence gap should be made explicit to the patient. The increased calcium requirements of pregnancy and lactation may decompensate an unrecognised VDDR1A, as in the Turkish case in which symptoms began after delivery [67]. In mice, ablation of Cyp27b1 did not disturb fetal mineral homeostasis, but pups nursed by null females had, at 21 days, about 20% lower weight, bone mineral content and ash calcium, shorter femurs and inferior microarchitecture, with recovery by 42 days; these are animal data that cannot be extrapolated to human pregnancy and lactation [107]. In the context of nutritional rickets, neonatal vitamin D deficiency is always caused by maternal deficiency, and prevention involves 600 IU/day for the mother with 400 IU/day for the infant [7].

The sources consulted do not describe specific perioperative recommendations for VDDR. Corrective orthopaedic procedures are frequent in patients diagnosed late — eight procedures in the Brazilian patient, the last at 12 years — and established deformities persist after medical treatment [21]. Metabolic correction before elective surgery is the principle implicit in the guidance, which recommends radiographs when bowing does not improve or when there is a surgical indication [60]. At transition to adulthood, the French PNDS provides for a systematic assessment: ophthalmological examination in VDDR1A (cataract), hearing assessment in VDDR2A (sensorineural deafness), bone densitometry, low-dose whole-body radiograph (EOS) and renal computed tomography [18]. At this stage, therapeutic requirements decrease in VDDR2A and VDDR1B, and the regimen should be reassessed; in VDDR1A treatment is lifelong with doses similar to those of childhood [5, 12, 13, 45].

7.15. Developments in the last twelve months

Between October 2025 and October 2026 there were no authorisations, regulatory opinions or new trials in the hereditary calcipenic forms [76, 106]. Publications in the period are of three types. At the preclinical level, Nakaya and colleagues characterised in vitro the 11α-hydroxylase activity acquired by CYP3A4 p.(Ile301Thr), with an editorial commentary pointing to the inactive metabolite 11α,25(OH)2D3 as a new direction for research; there is no immediate therapeutic implication [62, 63]. At the clinical level, series and cases were published: the Turkish national cohort of 118 patients with VDDR1A, the Saudi cohort of 45 patients from 29 families, the Vietnamese series of 19 children, a Turkish single-centre series of 16 patients with genetic rickets (6 VDDR1, 2 VDDR2, 8 hypophosphataemic), the Swedish case of tertiary hyperparathyroidism in VDDR2A, the case of VDDR2A with a hypophosphataemic presentation, the Chinese twin girls with VDDR1B and the Brazilian case of VDDR1A diagnosed in adulthood [21, 26–28, 51, 57, 58, 108]. At the epidemiological level, an analysis of NHANES (2001–2023) described a recent increase in severe 25(OH)D deficiency among African American children, pregnant women and lactating women in the USA, with implications for nutritional rickets; the exact numerical values were not read, because the available abstract truncates the less-than sign [109]. The editorial correction with the greatest practical consequence in the immediately preceding period is the retraction of "VDDR1C" (section 1.3) [9].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by inheritance pattern

VDDR1A, VDDR1B, VDDR2A and VDDR2B are autosomal recessive [5, 23, 44]. For a couple with an affected child and both parents heterozygous carriers, the recurrence risk is 25% per pregnancy, with 50% healthy carriers and 25% non-carriers among the offspring; unaffected siblings have a two-thirds probability of being carriers. In populations with high consanguinity, the probability that both members of a couple carry the same variant is greater, and the published series reflect this: 8 patients from 7 families in Tunisia, 8 patients from 4 Arab families, 45 patients from 29 Saudi families, with 13 families having 2 to 4 affected siblings [27, 54, 55]. A local allele frequency is not transferable to another population [13].

VDDR3 is autosomal dominant. In the two original patients and in the Brazilian patient, the p.(Ile301Thr) variant arose de novo, confirmed by its absence in the parents on Sanger sequencing; the risk for siblings is, in this scenario, very low, and the risk of transmission from a patient to their offspring is 50% per pregnancy [15, 29]. The Saudi patient had a suggestive family history — her father with rickets, short stature and operated genu varum —, but parental segregation was not reported in the text consulted [16]. Recurrence of the same variant on different haplotypes indicates a recurrent mutation and not a founder effect, which makes de novo occurrence plausible in any family [29].

VDDR1B requires a caveat. Thacher and colleagues described inheritance as semidominant, because heterozygotes have reduced 25(OH)D and an attenuated response to oral vitamin D, and some heterozygous girls in family 2 had rickets with bowing at 32 and 62 months, healed with calcium; OMIM, GenCC and UniProt retain the autosomal recessive classification [43, 45]. A heterozygous result should therefore be communicated with caution: it does not necessarily equate to an asymptomatic carrier, especially in a setting of low calcium intake or little sun exposure, and it warrants assessment of vitamin D status and, if necessary, supplementation [5, 43].

8.2. Cascade testing and assessment of relatives

Once the variants have been identified in the proband, cascade testing makes it possible to clarify the status of siblings, establish the reproductive risk of the parents and guide counselling of the extended family, with particular relevance in consanguineous families [21, 27]. A sibling with normal growth may not have been tested, as in the Brazilian VDDR3 case, and this should be made explicit in counselling [15]. In the recessive forms, family screening and discussion of the recurrence risk and of prenatal diagnosis, where appropriate, are part of counselling [21]. In the Brazilian case of VDDR1A in an adult woman, only the proband was tested, without a segregation study, which limits the classification of the variant [21].

Nutritional rickets has a different but equally systematic family logic. Mothers of infants with nutritional rickets are almost certainly deficient, and the other children in the household and symptomatic adults should be screened; asymptomatic individuals are not routinely tested, but are given information and supplements [22]. In the Birmingham series, 6 of 9 relatives tested had biochemical osteomalacia and all were advised to take lifelong supplementation [73]. The distinction matters in counselling: in nutritional rickets the "family risk" is environmental and is corrected with supplementation and education; in VDDR it is Mendelian.

The French PNDS recommends offering, for any diagnosis of VDDR, biochemical family screening and genetic testing; because biochemical changes precede clinical ones, an asymptomatic sibling, especially one younger than the proband, is considered unaffected only after laboratory tests; in VDDR1B the family study should be extended, because CYP2R1 heterozygotes may also have vitamin D deficiency [18].

8.3. Carriers and mosaicism

In the recessive forms, heterozygous carriers of CYP27B1 and VDR variants are clinically healthy in the published series: the heterozygous parents and siblings of the patients of Kitanaka and of Hughes had no disease, and the first-degree relatives of the patients with VDDR3 had normal vitamin D, metabolites, PTH, calcium and phosphate [29, 35, 39]. The exception is CYP2R1, discussed in 8.1. The sources consulted do not describe germline or somatic mosaicism in any of the VDDR forms; in VDDR3, de novo occurrence in two independent families means that the recurrence risk for siblings, although low, is not zero, because parental germline mosaicism is not formally excluded by the absence of the variant in the parents' blood [15, 29]. The French PNDS estimates this risk, for the parents of a proband with a de novo variant, at about 1%, and at 50% when the variant is inherited from a symptomatic parent [18].

8.4. Prenatal diagnosis and preimplantation genetic testing

When the family variants have been characterised, prenatal diagnosis by molecular analysis and preimplantation genetic testing are options to be presented to couples with a 25% risk in the recessive forms, within the applicable legal framework; da Rocha Ribas and Borba include prenatal diagnosis, where appropriate, among the elements of counselling in VDDR1A [21]. The decision should weigh the prognosis of the diseases concerned: VDDR1A treated from early childhood heals the rickets and allows normal growth, and VDDR1B may attenuate after growth, so counselling cannot present these diseases as invariably severe [5, 49]. VDDR2A with alopecia and resistance to maximum doses is the scenario with the greatest therapeutic burden, with months of intravenous calcium and alopecia without effective treatment [5, 13]. The sources consulted do not describe prenatal ultrasound markers of these diseases.

8.5. Counselling of minors and content of the consultation

Diagnosis is usually made in early childhood, and counselling is addressed to the parents, with information progressively passed on to the patient. The essential content is the nature of lifelong dependence on an active vitamin D analogue in VDDR1A, with the risk of hypercalcaemia and nephrocalcinosis associated with the doses; the importance of a constant calcium intake, because under treatment absorption is fixed and serum and urinary calcium follow the diet; the risk of relapse if treatment is interrupted, demonstrated in VDDR1B and in the Chinese twin girls; the foreseeable reduction in requirements after puberty in VDDR2A and VDDR1B, which should not be confused with cure; and, in VDDR2A with alopecia, the information that bone correction does not improve alopecia [5, 50, 51, 55, 69]. Carrier testing in asymptomatic minors that does not change management may be deferred until the individual can decide, except when the result has an immediate clinical consequence, as with CYP2R1, where a heterozygote may benefit from assessment of vitamin D status [43].

For women with VDDR, reproductive counselling includes calcium monitoring in pregnancy and lactation and the possibility of decompensation during that period, as well as the limitations of the labels regarding the use of active analogues in pregnancy (7.14) [67, 97]. The reproductive history of the patients with VDDR2A studied by Tiosano and colleagues was normal [69].

The French PNDS describes the disclosure consultation: conducted by the physician who ordered the confirmatory test, it provides information on the nature and transmission of the disease, the symptoms and warning signs requiring prompt consultation, the treatment options, the complications, the follow-up schedule and social support; it recommends offering psychological support, sending a summary letter to the physicians caring for the patient and, given the complexity of the information, scheduling a second consultation a few weeks later; where possible, multidisciplinary follow-up is organised as a day-hospital visit at the reference centre, and therapeutic education is part of the treatment objectives [18].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each number measures

None of the hereditary calcipenic forms has a validated population prevalence [12, 13, 45]. The only population-based data are Danish: in the retrospective cohort from southern Denmark (1985–2005, 0–14.9 years), with 16 hereditary cases, the mean incidence of hereditary rickets was 4.3/100,000 per year in the first year of life, and prevalences were 4.8/100,000 for hypophosphataemic rickets and 0.4/100,000 for VDDR1, from 0 to 14.9 years [14]. This number measures diagnosed cases in a European region with access to specialist care, not worldwide frequency, and VDDR1 includes forms 1A and 1B. Orphanet recorded for ORPHA:289157 a point prevalence class of "1–5/10,000" in Europe, with the status "not yet validated"; this class is incompatible with series of a few dozen patients per country and is not used in this article as an estimate [2]. For ORPHA:93160 prevalence is given as unknown, also not validated [3]. Orphanet groups OMIM numbers 277440, 600785 and 619073 under ORPHA:93160, that is, it classifies VDDR3 among the "resistant" forms despite it being autosomal dominant and catabolic in mechanism; this classification is recorded as that of the database, without correction [3, 24].

National and single-centre cohorts give the scale of accumulated experience, not rates: 118 patients with VDDR1A in Turkey through a national paediatric endocrinology network, 45 patients from 29 families in Saudi Arabia, 19 children from 17 families in a Vietnamese tertiary centre, 22 patients from 13 families and 9 patients in other Turkish and Indian series [26–28, 65, 66]. In the Turkish single-centre series of 16 patients with genetic rickets, 6 had VDDR1, 2 VDDR2 and 8 hypophosphataemic forms [108]. For VDDR1B, four families had been described before 2017, to which Molin and colleagues added seven patients from two French families; in Nigeria, missense variants were found in affected members of 2 of 12 families with more than one member with rickets and in none of the 27 children with sporadic rickets, which shows that the yield of testing depends on whether the rickets is familial [43, 49]. For VDDR2A there are only small consanguineous cohorts [54–56, 68]. For VDDR3 there are four published patients, all with the same variant, and the systematic review by Mantoanelli and colleagues, searching twelve databases including LILACS and SciELO, found no other cases up to 2022 [15, 16, 29]. For VDDR2B, the number of patients cannot be specified: there is the description of a cluster of more than 200 children in the department of Cauca, in south-western Colombia, with no additional published information, and one functionally studied patient [5, 23]. VDDR3 has no prevalence entry in Orphadata [61].

9.2. Founder populations and geography

The highest frequency of VDDR1A has been described in the French-Canadian population, in the Saguenay region of Quebec, with a founder effect documented by linkage disequilibrium [12, 36]. Genetic newborn screening of 2000 newborns in this region found a c.262del carrier frequency of 1/29, and the incidence of the disease, estimated in earlier studies and cited in the French PNDS, is about 1/2916 births, about one affected birth per year; this is a local estimate for a founder population, not a worldwide prevalence [17, 18]. In Turkey, four CYP27B1 variants account for about 81% of a national cohort of 118 patients, consistent with a mutational hotspot or founder effect [26]. In Saudi Arabia, the variant p.(Arg429Pro) is present in 51.7% of families, and two of the variants already described have been observed only in Saudis [27]. In Vietnam, the 7 bp duplication is present in 18 of 19 children [28]. In VDDR2A, the substitution described as p.Lys45Glu was found in five apparently unrelated Tunisian patients and p.(Tyr295Ter) in four unrelated Arab families [54, 55]. In VDDR3, the absence of a common haplotype between the two original patients excludes a founder [29].

Data from the Americas and Europe for the hereditary forms are mainly cases and series. In Brazil, the country's first case of VDDR3, the third worldwide, has been published from Rio de Janeiro, as well as a case of VDDR1A diagnosed at 25 years in Curitiba [15, 21]. The Brazilian literature on rickets and osteomalacia cited by a national textbook includes reviews and guidelines from Brazilian societies not read for this article [77]. In the sources consulted, no specific Brazilian guideline on the prevention of rickets was found, nor Portuguese data on the hereditary calcipenic forms; the absence of data in the sources consulted does not demonstrate the absence of published data.

9.3. Epidemiology of nutritional rickets

The incidence of nutritional rickets per 100,000 children, with differing methodologies between countries, was 2.9 in Canada, 4.9 in Australia, 7.5 in the United Kingdom and 24 in the USA; the greatest burden is in Africa, Asia and the Middle East, due to sun avoidance or calcium deficiency [7]. In high-income countries there has been a resurgence, especially in immigrants of African, Asian or Middle Eastern origin, in ethnic minorities and in refugees, while incidence in established white populations is stable or decreasing [7]. In the Danish cohort there were 112 cases of nutritional rickets, 74% of them in immigrants: the mean incidence between 1995 and 2005 was 2.9/100,000 per year (0–14.9 years) and 5.8/100,000 per year (0–2.9 years); in the children of immigrants born in Denmark it was 60/100,000 per year (0–14.9 years), and in ethnic Danish children aged 0–2.9 years it fell from 5.0 to 2.0/100,000 per year between 1985–1994 and 1995–2005 [14]. In this population, hereditary rickets was the most common cause in ethnic Danish children, and nutritional rickets the most frequent among young children as a whole [14]. In the last British prospective survey, the highest incidence (57 of 125 cases) occurred at 12–23 months, the age group with the lowest vitamin D intake in the national diet survey [22]. The incidence of the associated dilated cardiomyopathy is unknown [7]. In the USA, the analysis of NHANES 2001–2023 described a recent increase in severe 25(OH)D deficiency among African American children, pregnant women and lactating women, with African American children having the highest rate in 2021–2023; the exact percentage values were not read, because of truncation of the available abstract [109].

The risk factors, according to the global consensus and the guidance of Haffner and colleagues, are divided into maternal and child factors. On the maternal side, vitamin D deficiency (dark skin, full-covering clothing, high latitude in winter and spring, predominantly indoor life, institutionalisation, pollution, cloud cover) and a calcium-poor diet (poverty, malnutrition, special diets); on the child's side, neonatal deficiency secondary to maternal deficiency, lack of supplementation, prolonged breastfeeding without adequate complementary feeding from 6 months, high latitude, dark skin or restricted UVB radiation, and a diet poor in vitamin D or calcium [6, 7]. Individuals with more than one factor have the highest risk [6]. Exclusive breastfeeding without supplementation is the main risk factor, with abundant but low-quality evidence, and diets without milk or dairy products, soya or rice drinks not intended for infants and vegan and macrobiotic diets are predisposing [7, 75]. Sun restriction increases risk, there is no ultraviolet radiation threshold that guarantees sufficient synthesis without increasing the risk of skin cancer, and it is not practicable to give prescriptive advice on safe sun exposure [7].

In France, according to the PNDS, vitamin D supplementation was instituted by ministerial orders in 1963 and 1971 and the enrichment of infant milks in 1992, and nutritional rickets almost disappeared from the 1980s; the resurgence described in Europe and North America in the last two decades puts the incidence at about 3/100,000 children, with 6 to 7/100,000 per year before 3 and 5 years of age, and 3% of patients in a French series had severe vitamin D deficiency, with a risk of rickets; the precise incidence in France is not known [18].

9.4. Population prevention and European policies

After fortification of milk in North America and of milk, margarine and cereals in the United Kingdom, the prevalence of nutritional rickets fell until it was considered almost eradicated; where dairy products are little consumed, the consensus recommends fortifying flour, margarine, oil or soya foods [7]. Fortification of chapati flour with 6000 IU/kg raised 25(OH)D from about 12.5 to about 48 nmol/L in children over six months, and fortification of milk and margarine was estimated to raise intake at 4 years from 176 to 360 IU/day [7]. Fortification of infant formulas is recommended in all European countries, in Australia, in New Zealand and by the AAP; milk fortification is mandatory in Canada and voluntary in the USA [7].

The European survey by Uday and colleagues, sent in May 2014 to the ESPE bone and growth plate working group and to public health experts, obtained responses from 29 of the 30 countries contacted (all except Iceland), with 40 responses, two of them from Portugal [110]. A national policy existed in 28 of the 29 countries (except Italy), with universal supplementation regardless of feeding method in 23 of 29 (79%); initiation was on day 1 to 5 in 14 countries and on day 6 to 21 in another 14, and in the United Kingdom only at 6 months [110]. Adherence was good (at least 80%) in 17 countries, moderate (50–79%) in 9 and low (less than 50%) in 3, with the United Kingdom at the lowest value (5–20%); fortification beyond formulas was voluntary in 16 countries and no European country made it mandatory, unlike Israel; the medicine was paid for by patients in 18 countries and free in 8 [110]. Portugal appears with an estimated adherence of 50–70%, with a national policy, universal supplementation, financial support, a child surveillance programme and monitoring of adherence within that surveillance, totalling 5 of the 11 factors considered; the authors note that information given at discharge from neonatology was not considered, because of inconsistency in the Portuguese response [110]. For comparison, Austria and Hungary had 98%, the Czech Republic 95%, the Netherlands 90–95%, Sweden and France 90%, Finland 85%, Turkey 80%, Denmark 60–70%, Italy 50–60%, Spain 50–64%, Ireland 59%, Serbia 45% and Greece 30% [110]. Good adherence was associated with universal supplementation (p = 0.007), information at discharge (p = 0.02), financial support for families (p = 0.005), monitoring of adherence at surveillance visits (p = 0.001) and the total number of factors (p < 0.001); it was not associated with the existence of a policy, initiation on day 1 to 5, free provision or fortification [110]. The vitamin D in formulas is insufficient to protect against rickets, and the serum half-life of 25(OH)D of about two weeks justifies supplementing pregnant women and infants from birth [110]. The Turkish programme, free and monitored, reduced the prevalence of rickets from 6% in 1998 to 0.1% in 2008 [74, 110].

The global consensus recommends measuring prevalence through population samples, sentinel centres or mandatory notification, considering mandatory notification probably the most cost-effective means in low-prevalence regions, and notes that the cost-effectiveness of the programmes requires study [7].

9.5. Special populations

Preterm infants are prone to vitamin D deficiency because of incomplete transplacental transfer in the third trimester, low stores, low content in parenteral nutrition, reduced absorption and negligible sun exposure during admission; despite supplementation and nutritional support, rickets and metabolic bone disease are still observed in 8–50% of preterm infants at term-corrected age, and vitamin D intake from feeds ranges from 2 IU/day (unfortified human milk) to 250 IU/day depending on the formula or fortifier [75]. Children with chronic disease accumulate risk factors: malabsorption, maldigestion, CKD, nephrotic syndrome, cholestasis, liver failure, cystic fibrosis, secondary bone fragility, chronic inflammatory diseases, anorexia nervosa, skin diseases, anticonvulsants and prolonged corticosteroids [75]. Elemental or hypoallergenic formulas and parenteral nutrition may cause hypophosphataemic rickets due to phosphate deficiency, and gastrointestinal surgery and drugs such as valproate, cisplatin, ifosfamide, gentamicin and excess phosphate binders may cause Fanconi syndrome or interfere with calcium, vitamin D and phosphate [6]. Adults with VDDR1B may maintain normal mineral metabolism without supplementation, but the homozygous Nigerian father had a 25(OH)D of 4.9 ng/mL, elevated PTH and vertebral fractures in a context of immobility and spinal tuberculosis [43, 49]. Adults with VDDR2A have, after puberty, increased calcium absorption and normal reproduction [5, 69].

9.6. Reference networks and patient resources

The VDDR forms belong to thematic group 2 of Endo-ERN, "Disorders of Calcium & Phosphate Homeostasis", whose hypocalcaemia subgroup explicitly includes hypoparathyroidism, autosomal dominant hypocalcaemia and vitamin D-dependent rickets; coordination is in Amsterdam [19]. ERN BOND, the European Reference Network for rare bone diseases, is relevant to hypophosphataemic rickets; its home page does not present a list of diseases, so the place of VDDR in this network was not verified [20]. In France, follow-up is coordinated by the reference and competence centres for rare diseases of calcium and phosphate metabolism (CRMR/CCMR), usually by a paediatric or adult endocrinologist or nephrologist, in liaison with the general practitioner, within the OSCAR network (filière) (www.filiere-oscar.fr), which runs the national multidisciplinary consultation meeting for requests for advice; the PNDS assigns to the general practitioner suspicion in the presence of bone manifestations, hypocalcaemia or family involvement, early detection of complications, verification of adherence and psychological support [18]. The PNDS confirms that there is no patient association specific to VDDR [18]. No specific patient association was found in the other sources consulted, which does not prove that none exists; the generic resources available to families are the Orphanet pages ORPHA:289157 and ORPHA:93160 [2, 3].

10. Illustrative Clinical Case

10.1. VDDR3 in a Brazilian boy aged 2 years and 8 months

Mantoanelli and colleagues described a white boy aged 2 years and 8 months, the third published case of VDDR3 worldwide and the first in Brazil [15]. He was born at term, to non-consanguineous parents, measuring 48 cm and weighing 3.635 kg; his mother did not take prenatal vitamin D supplements. He was breastfed until 1 year and 2 months, exclusively until 6 months, without vitamin D supplementation. He crawled at 6 months and had tooth eruption at 5 months. The family lived in a sunny climate in Brazil, at a latitude between the Tropic of Capricorn and the equator. From 12 months he had bowed legs, an unsteady gait and growth arrest, with no family history of rickets or metabolic bone disease.

He was seen by an orthopaedic surgeon, who diagnosed rickets, and by a geneticist, who ordered a next-generation sequencing panel of 321 bone disease genes, with copy-number variant analysis, whose result was normal. The endocrinologist prescribed colecalciferol 3000 IU/day; three months later, without improvement, this was changed to calcitriol 0.25 µg twice daily, and at the first visit to the reference centre he was taking calcitriol 0.25 µg once daily with a calcium supplement. On examination he was 83 cm tall (−2.5 SD, with a mid-parental target of +0.7 SD), with normal weight, widened wrists and genu varum; radiographs showed active rickets, with enlargement of the costochondral junctions and widening, fraying, cupping and irregularity of the metaphyseal margin of the distal radius, ulna, femur and tibia (figure 1A, whose legend was consulted in the author manuscript deposited in PubMed Central; the image was not viewed) [15].

Initial biochemistry showed calcium 1.3 mmol/L (reference 2.2–2.77), phosphorus 1.07 mmol/L (1.45–2.1), ALP 18.45 µkat/L (< 8.3), 25(OH)D 29.45 (reference > 50; the published unit is "mmol/L", probably nmol/L), PTH 371 ng/L (12–88) and 1,25(OH)2D 252 (reference 49.7–198; published unit "pmol/mL"), a value attributed by the authors to the ongoing calcitriol. A modified loading test was performed with 150,000 IU of oral colecalciferol: 25(OH)D and 1,25(OH)2D peaked on day three and fell considerably by day thirty, with faster clearance than in the controls and in the children with nutritional rickets of the Thacher study, who received 50,000 IU (figure 2, legend consulted; image not viewed); calcium rose from 1.98 to 2.2 mmol/L and phosphorus from 1.03 to 1.64 mmol/L at 30 days [15]. On the basis of this pattern, he was treated with colecalciferol 10,000 IU/day and calcium supplements.

The exome (Twist library, NovaSeq 6000 platform, alignment to GRCh38, mean coverage of the targeted exonic regions of 120× with 99.4% above 10×) identified the heterozygous variant NM_017460.6:c.902T>C p.(Ile301Thr) in CYP3A4 (rs1815413655), absent from gnomAD and from the Brazilian database ABraOM and identical to that described by Roizen and colleagues; Sanger sequencing confirmed it in the patient and demonstrated its absence in both parents, establishing de novo occurrence. An older brother, with growth within the mid-parental target, was not tested [15].

Three months after starting 10,000 IU/day, height had risen to 91.4 cm (−1.3 SD), with a growth velocity of 5.9 cm in three months and much better gait; calcium was 2.25 mmol/L, PTH 38 ng/L and 25(OH)D 126.3, and radiographs showed marked improvement (figure 1B) [15]. The authors attribute the dose required, lower than the 50,000 IU/day of the two original cases, to smaller body size and to the possibly lower activity of the growth hormone pathway, which induces CYP3A4, in young children; and they consider that the prevalence of the disease may be underestimated, because of its similarity to nutritional deficiency and the limited availability of CYP3A4 testing, especially in sunny climates [15].

This report does not define routine management. The optimal dose of colecalciferol in VDDR3 has not been established, and the four published patients were treated in different ways, including high-dose calcitriol and 50,000 IU/day or 50,000 IU per week of colecalciferol [15, 16, 29]. The loading test with a single high dose followed by serial measurements is a diagnostic strategy described in these cases, and not a standardised procedure with a validated protocol [15, 43]. The normal 321-gene panel and the diagnosis obtained only by exome correspond to the coverage problem discussed in 5.9.

10.2. VDDR1A diagnosed in adulthood

Da Rocha Ribas and Borba described, at the Hospital de Clínicas of the Federal University of Paraná, in Curitiba, a 25-year-old woman 1.49 m tall, diagnosed at 12 months at another institution with "vitamin D-resistant rickets" because of motor delay, hypotonia, widened wrists and genu varum [21]. For 24 years she received vitamin D3 and calcium, with doses, adherence and monitoring not available, and she never received calcitriol. The deformities progressed and she underwent eight orthopaedic procedures, the last at 12 years (right medial distal femoral epiphysiodesis). There was no consanguinity or family history, and only the proband was tested.

At referral she had ALP 286 U/L (35–105), calcium 8.3 mg/dL (8.6–10.4), phosphate 1.8 mg/dL (2.5–4.5), PTH 863 pg/mL (15–65), 25(OH)D 27 ng/mL (20–50), urinary phosphate 69.7 mg/24 h (400–1300) and urinary calcium 6.5 mg/24 h (40–240); TRP, TmP/GFR, FGF23 and 1,25(OH)2D were not available, the last because of limited availability and high cost [21]. A customised 18-gene panel (ALPL, CLCN5, CTNS, CYP27B1, CYP2R1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, GNAS, KL, OCRL, PHEX, SLC34A1, SLC34A3, VDR), with 98.8% of bases at 20× or more and a mean depth of 72×, identified the homozygous variant NM_000785.4:c.974C>T p.(Thr325Met) in CYP27B1, classified by the laboratory as likely pathogenic, having previously been described as a VUS; the panel did not include HNRNPC or CYP3A4, so VDDR2B and VDDR3 were not molecularly excluded [21].

Vitamin D3 was stopped and calcitriol 0.25 µg once daily, elemental phosphorus 250 mg twice daily and calcium carbonate 500 mg three times daily were started, with no dose changes for about one year. At the end of that period, ALP was 139 U/L, calcium 8.7 mg/dL, phosphate 2.5 mg/dL, 25(OH)D 28 ng/mL, urinary calcium 42.6 mg/24 h and TRP 88% (85–95%), but PTH remained at 532 pg/mL; DXA showed a Z-score of −0.6 at the lumbar spine, −3.0 at the femoral neck and −1.9 at the total proximal femur, with no vertebral fractures on vertebral fracture assessment, and renal ultrasound showed no nephrolithiasis or nephrocalcinosis, with preserved renal function and persistent established deformities [21].

The case illustrates the cost of late diagnosis and the difference between improvement and control: the still very high PTH indicates insufficient treatment after one year. The calcitriol dose used is below the maintenance range proposed in reviews (0.3–2 µg/day), and the phosphorus supplement is not part of the regimens recommended for calcipenic rickets, in which phosphate salts worsen secondary hyperparathyroidism [5, 22, 60].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In adequately treated VDDR1A, rickets heals and growth is normal; without treatment or with late diagnosis, progressive limb deformity, short stature and bone pain set in and persist into adulthood [5, 44]. The Brazilian case diagnosed at 25 years shows the extreme outcome of this delay: a height of 1.49 m, eight orthopaedic procedures and irreversible established deformities, with partial biochemical improvement under calcitriol [21]. In the Turkish single-centre series, with a mean follow-up of 6.6 ± 4.75 years, the mean final height of the four patients who reached it was 142.07 ± 11.19 cm, in a group that included calcipenic and hypophosphataemic forms, and two patients developed nephrocalcinosis during follow-up [108]. In the French series (median follow-up 13.3 years, 1.0–52.2), the median age at walking was 1.4 years (0.8–6.0), 16 of 17 patients had normal psychomotor development, median final height was 164 cm (153–176; 160 cm in women and 167 cm in men, −1.0 SD) and 11 of the 13 patients with final height reached 160 cm or more; there was no pubertal delay, and two women had uncomplicated pregnancies [48]. There was one craniosynostosis operated on two years after diagnosis at 6 years, one Arnold-Chiari malformation without surgery and one bilateral cataract at 4 years, of uncertain relationship to the disease or the treatment [48]. Estimated glomerular filtration at the end of follow-up was 114 mL/min/1.73 m² (89–209; n = 17), but 7 of 9 children had systolic pressure above the 75th centile and 1 of 4 adults was hypertensive, which, together with data from Cyp27b1−/− mice (hypertension, hyperreninism, cardiac hypertrophy), supports blood pressure monitoring [48]. In Saguenay–Lac-Saint-Jean, the long-term benefit of neonatal diagnosis has not yet been measured [17]. In VDDR1B, the phenotype may attenuate after growth, with adults maintaining normal mineral metabolism without supplementation, but deformities acquired in childhood persist, as in the Nigerian sisters followed up to 18–20 years [43, 49].

In VDDR2A, the skeletal prognosis depends on response to treatment and on severity: Faiyaz-Ul-Haque and colleagues corrected all manifestations except alopecia over 11 years, and after puberty intestinal calcium absorption rises to above-normal values, with normocalcaemia maintained with modest oral calcium or without supplementation, PTH close to the upper limit and normal BMD despite persistently elevated 1,25(OH)2D [5, 55, 69]. Alopecia does not improve [55]. Tertiary hyperparathyroidism may persist for about one year after normalisation of calcium without preventing healing of rickets or normalisation of phosphate, and may resolve without cinacalcet or parathyroidectomy [57]. The studies of Tiosano and colleagues found no excess of infections, inflammatory diseases, asthma, hypertension or echocardiographic abnormalities, nor reproductive problems, in patients with VDDR2A [69]. In VDDR3, the Brazilian patient left the short stature range within three months of treatment, and the Saudi patient needed continuous titration to keep biochemistry and radiology normal [15, 16]. The prognosis depends on early detection; in the calcipenic forms there is no intellectual deficit attributable to the disease [77].

In nutritional rickets, the prognosis is good with treatment, but the consequences of late diagnosis or severe disease include death from cardiomyopathy or obstructed labour, myopathy, seizures, pneumonia, permanent deformity and disability, impaired growth and pain; the global consensus describes nutritional rickets as the tip of the iceberg of vitamin D deficiency [7]. Pelvic deformity with narrowing of the pelvic outlet is a sequela with obstetric consequences in adulthood [7, 22].

Table 11.1a — Time to normalisation of parameters under treatment, according to the French PNDS (2024) [18]

The late complications that the PNDS requires to be sought are growth deceleration and deformities (genu varum or valgum) until the end of growth if the disease is poorly controlled, osteomalacia in adults (bone pain, pathological fractures), dental changes, which persist because of the absence of enamel repair and the very limited repair of dentine and cementum, nephrocalcinosis and lithiasis due to iatrogenic hypercalciuria, cataracts in VDDR1A, deafness in VDDR2A and a blood pressure that tends towards high-normal values [18].

11.2. Surveillance table

Levine proposes serum (calcium, phosphorus, PTH, ALP, creatinine and the appropriate vitamin D metabolites) and urine (24-hour calcium or calcium/creatinine ratio) every 3 to 6 months, renal ultrasound every 1 to 2 years and annual wrist and knee radiographs to assess rachitic activity, with monitoring of growth and deformities [5, 12]. The guidance of Haffner and colleagues does not recommend routine radiographs in rickets under treatment, reserving them for insufficient response and for decisions affecting management, such as dose or surgery; this is the practical divergence between the two sources, and the table above follows the guidance, which is more recent and more explicit about radiation exposure [5, 60]. The intervals of 3 to 6 months for biochemistry and of 1 to 2 years for renal ultrasound are common to both sources and coincide with those given in section 7 [5, 60]. During calcitriol titration, the US label requires serum calcium at least twice weekly and then monthly, a shorter interval than that of stable follow-up [96].

11.3. What to monitor in each form

In VDDR1A, surveillance focuses on PTH and ALP as markers of dose sufficiency and on calciuria and renal ultrasound as markers of excess; treatment is lifelong and doses are similar in children and adults [5, 12]. In VDDR1B, monitoring of vitamin D status is central, and attenuation of the phenotype after growth may allow treatment to be reduced or stopped, with reassessment, because 25(OH)D falls rapidly after stopping [49, 51]. In VDDR2A and VDDR2B, requirements decrease after puberty, which requires the regimen to be reassessed; PTH and ALP are the markers of response, and mild hypercalcaemia under calcium infusions may occur without PTH suppression [5, 13, 57]. In VDDR3, continuous titration may be needed to keep biochemistry and radiology normal, and surveillance should include the risk of hypercalcaemia inherent in high doses of colecalciferol [15, 16]. In nutritional rickets, PTH is the earliest indicator of response, calcium, phosphate and PTH may normalise within three weeks, ALP takes months, and formal reassessment is done at three months [7, 60]. Monitoring 25(OH)D to keep values above 30–34 nmol/L is reasonable in prevention, although there are no studies on the best monitoring strategy [7].

12. Summary and Final Considerations

Rickets is a single syndrome with more than twenty causes, and its genetic approach begins with a simple biochemical sequence: confirm rickets by the clinical picture, by a radiograph of the metaphysis of a rapidly growing plate and by ALP elevated for age; measure PTH, ionised calcium and phosphate to separate the calcipenic from the phosphopenic forms; and, in the calcipenic forms, measure 25(OH)D and 1,25(OH)2D before starting treatment, because it is this pair of values that distinguishes nutritional rickets from the hereditary forms and the hereditary forms from one another. A low 25(OH)D with a response to vitamin D and calcium within three months identifies nutritional rickets, which remains the most frequent cause worldwide and has re-emerged in high-income countries in populations with dark skin, with skin covering, with restrictive diets or without supplementation in the first year of life. A documented lack of response is the signal that requires the diagnosis to be reconsidered, and repeating doses of vitamin D without reassessment is the main mechanism of diagnostic delay in VDDR.

The five vitamin D-dependent forms fall into three mechanisms. In failure of activation, VDDR1A (CYP27B1, autosomal recessive) presents with low or undetectable 1,25(OH)2D and normal or high 25(OH)D, and is treated with lifelong replacement with calcitriol (0.3–2 µg/day) or alfacalcidol (0.5–3 µg/day), with doses 2 to 5 times higher in the first 3 to 6 months and elemental calcium of 50 mg/kg/day in the initial phase; VDDR1B (CYP2R1) presents with very low 25(OH)D, is preferably treated with calcifediol and has the particularity that heterozygotes have an attenuated response to oral vitamin D, which requires such results to be communicated with care. In receptor resistance, VDDR2A (VDR) presents with very high 1,25(OH)2D and alopecia in about half of patients, and its treatment is high-dose calcium, oral or intravenous, because a non-functioning receptor must be bypassed; the intermittent peripheral route is an established alternative to the central catheter in small series. VDDR2B has the same phenotype with a normal VDR sequence and an unestablished molecular basis: overexpression of hnRNP C1/C2 was demonstrated in the cells of one patient, and the attribution to mutations in HNRNPC that appears in some sources is not documented. In excessive inactivation, VDDR3 (CYP3A4, autosomal dominant, recurrent de novo variant p.(Ile301Thr)) presents with both 25(OH)D and 1,25(OH)2D low and accelerated clearance after loading, and responds to high-dose vitamin D3.

Three methodological cautions run through the article. The first is nomenclature: "vitamin D-resistant rickets" historically designated XLH, and its use in old labels cannot be read as an indication for VDDR. The second is prudence in attributing causality: the proposal of a "VDDR1C" due to CYP4A22 was retracted in 2025 after a structural variant in PHEX was identified in the original family, and the implicated variant had an allele frequency of up to 4% in one population. The third is recognition of the limits of tests: a panel may not include the right gene, as happened in the Brazilian VDDR3 case diagnosed only by exome, and a negative result does not exclude a disease whose molecular basis is unknown.

The therapeutic evidence base is weak and should be presented as such. There are no randomised trials in any of the hereditary calcipenic forms, nor registered interventional trials, and the doses used come from reviews and expert consensus based on series of few patients. Most drugs are used off-label: calcitriol and calcifediol have no rickets indication in the United States, alfacalcidol has a labelled indication for pseudodeficiency rickets in the United Kingdom, and ergocalciferol retains the historical mention of "refractory rickets" with doses from another era. Follow-up therefore carries more weight than usual: PTH and ALP show whether the dose is sufficient, calciuria and renal ultrasound show whether it is excessive, and nephrocalcinosis is the iatrogenic complication to be avoided.

Prognosis depends above all on the time to diagnosis. Treated in early childhood, VDDR1A heals the rickets and allows normal growth; diagnosed in adulthood, it leaves short stature, operated deformities and hyperparathyroidism that is difficult to control. VDDR2A is corrected, except for alopecia, and improves after puberty, when the regimen should be reduced rather than maintained. VDDR1B may attenuate after growth. In all of them, calcium monitoring in pregnancy and lactation is necessary, because the increase in requirements may decompensate an unrecognised disease. On the prevention side, guidelines converge on infant supplementation, diverge on the strength of the recommendation and on deficiency thresholds, and agree on not screening 25(OH)D in healthy children; European data show that what determines adherence is the design of the programme — universal supplementation, information at discharge, financial support and monitoring at surveillance visits — and not the mere existence of a national policy.

13. References

1. Orphanet. Hypocalcemic rickets. ORPHA:289103. Available from: https://www.orpha.net/en/disease/detail/289103
2. Orphanet. Hypocalcemic vitamin D-dependent rickets. ORPHA:289157. Available from: https://www.orpha.net/en/disease/detail/289157
3. Orphanet. Hypocalcemic vitamin D-resistant rickets. ORPHA:93160. Available from: https://www.orpha.net/en/disease/detail/93160
4. Orphanet. Disorders of vitamin D metabolism. ORPHA:289098. Available from: https://www.orpha.net/en/disease/detail/289098
5. Levine MA. Diagnosis and Management of Vitamin D Dependent Rickets. Front Pediatr. 2020;8:315. doi:10.3389/fped.2020.00315. PMID: 32596195. PMC7303887.
6. Haffner D, Leifheit-Nestler M, Grund A, Schnabel D. Rickets guidance: part I-diagnostic workup. Pediatr Nephrol. 2022;37(9):2013-2036. doi:10.1007/s00467-021-05328-w. PMID: 34910242. PMC9307538.
7. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global Consensus Recommendations on Prevention and Management of Nutritional Rickets. J Clin Endocrinol Metab. 2016;101(2):394-415. doi:10.1210/jc.2015-2175. PMID: 26745253. PMC4880117.
8. Duan X, Zhang Y, Xu T. CYP4A22 loss-of-function causes a new type of vitamin D-dependent rickets (VDDR1C). J Bone Miner Res. 2024;39(7):967-979. doi:10.1093/jbmr/zjae084. PMID: 38847469.
9. [No authors listed]. Retraction of: CYP4A22 loss-of-function causes a new type of vitamin D-dependent rickets (VDDR1C). J Bone Miner Res. 2025;40(3):447. doi:10.1093/jbmr/zjaf001. PMID: 39873438.
10. Levine MA, Li D, Roizen J, Weber D. Letter to the editor regarding Duan et al, "CYP4A22 loss-of-function causes a new type of vitamin D-dependent rickets (VDDR1C)". J Bone Miner Res. 2025;40(3):445-446. doi:10.1093/jbmr/zjae203. PMID: 39714216. PMC11909730.
11. Laurent MR, Harvengt P, Mortier GR, Böckenhauer D. X-Linked Hypophosphatemia. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–. Initial posting 2012 Feb 9; last update 2023 Dec 14. Available from: https://www.ncbi.nlm.nih.gov/books/NBK83985/
12. GeneGuidance. CYP27B1 — gene record (clinical curation).
13. GeneGuidance. VDR — gene record (clinical curation; OMIM condition 277440).
14. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol. 2009;160(3):491-497. doi:10.1530/eje-08-0818. PMID: 19095780.
15. Mantoanelli L, de Almeida CM, Coelho MCA, Coutinho M, Levine MA, Collett-Solberg PF, et al. Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review. Calcif Tissue Int. 2023;112(4):512-517. doi:10.1007/s00223-022-01051-2. PMID: 36656330. PMC10393508.
16. Al-Ashwal A, Al Zahrani A, Dammas N, Aletani L, Alhuthil R. CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia. Cureus. 2023;15(12):e49976. doi:10.7759/cureus.49976. PMID: 38179381. PMC10765270.
17. Fortin CA, Girard L, Bonenfant C, Leblanc J, Cruz-Marino T, Blackburn ME, et al. Benefits of Newborn Screening for Vitamin D-Dependant Rickets Type 1A in a Founder Population. Front Endocrinol (Lausanne). 2022;13:887371. doi:10.3389/fendo.2022.887371. PMID: 35600579. PMC9120640.
18. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Rachitismes rares vitamine D-dépendants. Centre de référence maladies rares du métabolisme du calcium et du phosphate; filière OSCAR. Saint-Denis La Plaine: HAS; September 2024 (published 25 Sep 2024). Available from: https://www.has-sante.fr/jcms/p_3542916
19. Endo-ERN. Disorders of Calcium & Phosphate Homeostasis (MTG2). Available from: https://endo-ern.eu/main-thematic-groups/disorders-of-calcium-phosphate-homeostasis/
20. ERN BOND — European Reference Network on Rare Bone Diseases. Available from: https://ernbond.eu/
21. da Rocha Ribas PA, Zeghbi Cochenski Borba V. Vitamin D-dependent Rickets Type 1A: Recognizing Clinical Clues to Avoid Delayed Diagnosis. Cureus. 2026;18(9):e116126. doi:10.7759/cureus.116126. PMID: 42733725. PMC13571830.
22. Uday S, Högler W. Nutritional rickets & osteomalacia: A practical approach to management. Indian J Med Res. 2020;152(4):356-367. doi:10.4103/ijmr.ijmr_1961_19. PMID: 33380700. PMC8061584.
23. Online Mendelian Inheritance in Man, OMIM®. Vitamin D-dependent rickets, type 2B, with normal vitamin D receptor; VDDR2B. MIM number %600785. Baltimore: Johns Hopkins University. Accessed 17 October 2026. Available from: https://www.omim.org/entry/600785
24. Online Mendelian Inheritance in Man, OMIM®. Vitamin D-dependent rickets, type 3; VDDR3. MIM number #619073. Baltimore: Johns Hopkins University. Accessed 17 October 2026. Available from: https://www.omim.org/entry/619073
25. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. Available from: https://rest.variantvalidator.org/
26. Cayir A, Demirbilek H, Türkyılmaz A, Turan S, Bereket A, Darendeliler F, et al. Genotype, Phenotype Characteristics and Long-Term Follow-Up of Patients with Vitamin D-Dependent Rickets Type IA: A Nationwide Multi-Centre Retrospective Cross-Sectional Study. Horm Res Paediatr. 2025:1-9. doi:10.1159/000546497. PMID: 40602383.
27. Bin-Abbas B, Alsagheir A, Alghamdi B, Benito A, Shi Y, Alzelaye SK, et al. Molecular Genetics of 1α-Hydroxylase Deficiency in the Saudi Population. J Endocr Soc. 2026;10(2):bvaf183. doi:10.1210/jendso/bvaf183. PMID: 41623903. PMC12852950.
28. Tran TAT, Dien TM, Nguyen NL, Nguyen KN, Can TBN, Thao BP, et al. Phenotypes and Genotypes of Children with Vitamin D-Dependent Rickets Type 1A: A Single Tertiary Pediatric Center in Vietnam. Diagnostics (Basel). 2025;15(7):918. doi:10.3390/diagnostics15070918. PMID: 40218268. PMC11988750.
29. Roizen JD, Li D, O'Lear L, Javaid MK, Shaw NJ, Ebeling PR, et al. CYP3A4 mutation causes vitamin D-dependent rickets type 3. J Clin Invest. 2018;128(5):1913-1918. doi:10.1172/jci98680. PMID: 29461981. PMC5919884.
30. Torrent Pharma Inc. Ergocalciferol capsules USP 1.25 mg (50,000 IU) [prescribing information]. NDA 003444. Revised 09/2026. DailyMed set ID 4ae38744-020d-4c37-a6f1-88f55c2f1047. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4ae38744-020d-4c37-a6f1-88f55c2f1047
31. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. X-linked dominant (XLD) inheritance; p. 46–49.
32. Prader A, Illig R, Heierli E. [An unusual form of primary vitamin D-resistant rickets with hypocalcemia and autosomal-dominant hereditary transmission: hereditary pseudo-deficiency rickets]. Helv Paediatr Acta. 1961;16:452-468. PMID: 14488440.
33. Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med. 1973;289(16):817-822. doi:10.1056/nejm197310182891601. PMID: 4357855.
34. Brooks MH, Bell NH, Love L, Stern PH, Orfei E, Queener SF, et al. Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D. N Engl J Med. 1978;298(18):996-999. doi:10.1056/nejm197805042981804. PMID: 205789.
35. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science. 1988;242(4886):1702-1705. doi:10.1126/science.2849209. PMID: 2849209.
36. Labuda M, Morgan K, Glorieux FH. Mapping autosomal recessive vitamin D dependency type I to chromosome 12q14 by linkage analysis. Am J Hum Genet. 1990;47(1):28-36. PMID: 1971995. PMC1683762.
37. St-Arnaud R, Messerlian S, Moir JM, Omdahl JL, Glorieux FH. The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J Bone Miner Res. 1997;12(10):1552-1559. doi:10.1359/jbmr.1997.12.10.1552. PMID: 9333115.
38. Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL, et al. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol. 1997;11(13):1961-1970. doi:10.1210/mend.11.13.0035. PMID: 9415400.
39. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, et al. 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. doi:10.1056/nejm199803053381004. PMID: 9486994.
40. 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. doi:10.1073/pnas.1031395100. PMID: 12716975. PMC156334.
41. Chen H, Hewison M, Adams JS. Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein. J Biol Chem. 2006;281(51):39114-39120. doi:10.1074/jbc.m608006200. PMID: 17071612.
42. 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. doi:10.1073/pnas.0402490101. PMID: 15128933. PMC419671.
43. Thacher TD, Fischer PR, Singh RJ, Roizen J, Levine MA. CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency. J Clin Endocrinol Metab. 2015;100(7):E1005-13. doi:10.1210/jc.2015-1746. PMID: 25942481. PMC4490307.
44. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Hereditary rickets. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 568–574.
45. GeneGuidance. CYP2R1 — gene record (clinical curation; OMIM condition 600081).
46. [No authors listed]. Expression of Concern: CYP4A22 loss-of-function causes a new type of vitamin D-dependent rickets (VDDR1C). J Bone Miner Res. 2024;39(12):1839. doi:10.1093/jbmr/zjae168. PMID: 39569444.
47. National Center for Biotechnology Information. ClinVar. Available from: https://www.ncbi.nlm.nih.gov/clinvar/ (records 279798, 265095, 1334151, 2134, 982369, 381603, 7751, 7757, 7745, 1686293, 7746, 7747, 7754, 7756, 264696, 2137319, 7749)
48. Méaux MN, Harambat J, Rothenbuhler A, Léger J, Kamenicky P, Soskin S, et al. Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease. J Clin Endocrinol Metab. 2023;108(4):812-826. doi:10.1210/clinem/dgac639. PMID: 36321535.
49. Molin A, Wiedemann A, Demers N, Kaufmann M, Do Cao J, Mainard L, et al. Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?. J Bone Miner Res. 2017;32(9):1893-1899. doi:10.1002/jbmr.3181. PMID: 28548312.
50. Menon JC, Kumari A, Sajjan SM, Dabadghao P. Novel Mutation in CYP2R1 Causing Vitamin D-Dependent Rickets Type 1b. JCEM Case Rep. 2024;2(3):luae024. doi:10.1210/jcemcr/luae024. PMID: 38440125. PMC10911226.
51. Zhang J, Huang Y, Li J, Huai W, Li X, Qing Y, et al. Study of biallelic variants in CYP2R1 causing vitamin D hydroxylation deficiency rickets type 1B. Clin Chim Acta. 2026;594:122882. doi:10.1016/j.cca.2026.122882. PMID: 42838446.
52. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376(9736):180-188. doi:10.1016/s0140-6736(10)60588-0. PMID: 20541252. PMC3086761.
53. National Center for Biotechnology Information. Protein NP_000367.1: vitamin D3 receptor isoform VDRA [Homo sapiens]. Available from: https://www.ncbi.nlm.nih.gov/protein/NP_000367.1
54. Ben Ameur S, Silve C, Chabchoub I, Damak F, Kamoun F, Toussaint A, et al. Clinical and Genetic Characterization of Tunisian Children with Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets. Horm Res Paediatr. 2017;87(1):23-29. doi:10.1159/000452886. PMID: 28013309.
55. Faiyaz-Ul-Haque M, AlDhalaan W, AlAshwal A, Bin-Abbas BS, AlSagheir A, Alotaiby M, et al. Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR): clinical heterogeneity and long-term efficacious management of eight patients from four unrelated Arab families with a loss of function VDR mutation. J Pediatr Endocrinol Metab. 2018;31(8):861-868. doi:10.1515/jpem-2017-0312. PMID: 29949513.
56. Abalı S, Tamura M, Turan S, Atay Z, Isguven P, Güran T, et al. Hereditary vitamin D-resistant rickets: a report of four cases with two novel variants in the VDR gene and successful use of intermittent intravenous calcium via a peripheral route. J Pediatr Endocrinol Metab. 2020;33(4):557-562. doi:10.1515/jpem-2019-0466. PMID: 32049653.
57. Lodefalk M, Nilsson O. Persistent Hyperparathyroidism in Vitamin D-Dependent Rickets Type 2A Does Not Prevent Normalization of Hypophosphatemia or Healing of the Rickets. Horm Res Paediatr. 2026;99(6):824-833. doi:10.1159/000546444. PMID: 40383122. PMC12187100.
58. Tantivit N, Jacobsen CM. A case of vitamin D-dependent rickets type 2A presenting with hypophosphatemia without hypocalcemia. JCEM Case Rep. 2026;4(8):luag189. doi:10.1210/jcemcr/luag189. PMID: 42438800. PMC13356965.
59. Uitterlinden AG, Ralston SH, Brandi ML, Carey AH, Grinberg D, Langdahl BL, et al. The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann Intern Med. 2006;145(4):255-264. doi:10.7326/0003-4819-145-4-200608150-00005. PMID: 16908916.
60. Haffner D, Leifheit-Nestler M, Grund A, Schnabel D. Rickets guidance: part II-management. Pediatr Nephrol. 2022;37(10):2289-2302. doi:10.1007/s00467-022-05505-5. PMID: 35352187. PMC9395459.
61. GeneGuidance. CYP3A4 — gene record (clinical curation; VDDR3 and pharmacogenetics).
62. Nakaya N, Sakamoto R, Mano H, Mikami B, Imaishi H, Nagasawa K, et al. Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets. FEBS J. 2026;293(3):660-676. doi:10.1111/febs.70277. PMID: 41046353.
63. Senda T, Hirota Y. A new metabolic path in type 3 rickets. FEBS J. 2026;293(3):656-659. doi:10.1111/febs.70382. PMID: 41467305. PMC12871899.
64. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, Clinical approach to inborn errors of metabolism in paediatrics, section 1.4.10.
65. Tahir S, Demirbilek H, Ozbek MN, Baran RT, Tanriverdi S, Hussain K. Genotype and Phenotype Characteristics in 22 Patients with Vitamin D-Dependent Rickets Type I. Horm Res Paediatr. 2016;85(5):309-317. doi:10.1159/000444483. PMID: 26982175.
66. Dodamani MH, Sehemby M, Memon SS, Sarathi V, Lila AR, Chapla A, et al. Genotype and phenotypic spectrum of vitamin D dependent rickets type 1A: our experience and systematic review. J Pediatr Endocrinol Metab. 2021;34(12):1505-1513. doi:10.1515/jpem-2021-0403. PMID: 34492747.
67. [No authors listed]. O-16 A case of vitamin D-dependent rickets diagnosed in adulthood following pregnancy. JCEM Case Rep. 2025;3(Suppl). PMC11771411. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11771411/
68. Ahmad N, Ansari SA, Aleysae NA, Heaphy ELG, Sobaihi MM, Alghamdi BA, et al. Hereditary vitamin D resistant rickets (HVDRR) case series: phenotype, genotype, conventional treatment, and adjunctive cinacalcet therapy. Pediatr Endocrinol Diabetes Metab. 2024;30(2):74-80. doi:10.5114/pedm.2024.139367. PMID: 39026484. PMC11249798.
69. Tiosano D, Abrams SA, Weisman Y. Lessons Learned from Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets Patients on Vitamin D Functions. J Nutr. 2021;151(3):473-481. doi:10.1093/jn/nxaa380. PMID: 33438017.
70. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Large fontanelle; p. 204–205.
71. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Suspected non-accidental injury; p. 326–327.
72. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Cataract; p. 88–91.
73. Uday S, Fratzl-Zelman N, Roschger P, Klaushofer K, Chikermane A, Saraff V, et al. Cardiac, bone and growth plate manifestations in hypocalcemic infants: revealing the hidden body of the vitamin D deficiency iceberg. BMC Pediatr. 2018;18(1):183. doi:10.1186/s12887-018-1159-y. PMID: 29940979. PMC6019205.
74. Demay MB, Pittas AG, Bikle DD, Diab DL, Kiely ME, Lazaretti-Castro M, et al. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2024;109(8):1907-1947. doi:10.1210/clinem/dgae290. PMID: 38828931.
75. Bacchetta J, Edouard T, Laverny G, Bernardor J, Bertholet-Thomas A, Castanet M, et al. Vitamin D and calcium intakes in general pediatric populations: A French expert consensus paper. Arch Pediatr. 2022;29(4):312-325. doi:10.1016/j.arcped.2022.02.008. PMID: 35305879.
76. ClinicalTrials.gov. Search by condition: vitamin D dependent rickets; hereditary vitamin D resistant rickets; 1-alpha hydroxylase deficiency; nutritional rickets; calcipenic rickets. Available from: https://clinicaltrials.gov/ (API v2)
77. Ribeiro LO, Ribeiro EM. Raquitismo hipofosfatêmico. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 116–117.
78. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Skeletal dysplasias; p. 316–319.
79. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Metaphyseal chondrodysplasia, Schmid type. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 33–36.
80. Hartley IR, Gafni RI, Roszko KL, Brown SM, de Castro LF, Saikali A, et al. Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia. J Bone Miner Res. 2022;37(11):2174-2185. doi:10.1002/jbmr.4702. PMID: 36093861. PMC9712269.
81. Pereira DL, Carvalho EDF, Ribeiro EM. Osteogênese imperfeita. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 269–272.
82. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Metaphyseal dysplasia, Spahr type. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 41–43.
83. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Metaphyseal anadysplasia. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 44–49.
84. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Metaphyseal chondrodysplasia, Jansen type. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 54–57.
85. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Osteopetrosis with renal tubular acidosis. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 591–595.
86. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 26, Cystinosis, sections 26.1.1 and 26.1.5.
87. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 17, section 17.1 Hereditary tyrosinaemia type I.
88. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 8, section 8.5 Fanconi-Bickel syndrome.
89. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 38, Disorders of bile acid synthesis, sections 38.1, 38.2 and 38.5.
90. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 39, section 39.1.1 Disorders of ectonucleotide metabolism.
91. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Linear sebaceous nevus syndrome; p. 702–705.
92. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. Hepatorenal tyrosinemia/fumarylacetoacetate hydrolase deficiency; p. 183–191.
93. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 44, Disorders of cellular trafficking, section 44.3.2.
94. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 7, section 7.10 Transaldolase deficiency.
95. Lainis V, Katsouli O, Gazi S, Kassi E, Chronopoulos E, Tournis S. Hereditary disorders of vitamin-D metabolism and its receptor. Hormones (Athens). 2025;24(2):335-346. doi:10.1007/s42000-025-00630-w. PMID: 39893280.
96. Rising Pharma Holdings, Inc. Calcitriol oral solution 1 mcg/mL [prescribing information]. ANDA 209798. Revised 02/2025. DailyMed set ID 1bd717a4-5fdf-4697-a6b2-9df55c6517bb. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1bd717a4-5fdf-4697-a6b2-9df55c6517bb
97. Neon Healthcare Ltd. One-Alpha 0.25 microgram, 0.5 microgram and 1 microgram soft capsules — Summary of Product Characteristics. Date of revision of the text 12/04/2022. Available from: https://www.medicines.org.uk/emc/product/12653/smpc
98. Fresenius Kabi USA, LLC. Calcium Gluconate injection, for intravenous use [prescribing information]. NDA 208418. DailyMed set ID 8b77c3d2-992d-4261-8421-9cfd07328fbf, version 7, of 18 May 2026. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8b77c3d2-992d-4261-8421-9cfd07328fbf
99. Wagner CL, Greer FR; American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122(5):1142-1152. doi:10.1542/peds.2008-1862. PMID: 18977996.
100. Braegger C, Campoy C, Colomb V, Decsi T, Domellof M, Fewtrell M, et al. Vitamin D in the healthy European paediatric population. J Pediatr Gastroenterol Nutr. 2013;56(6):692-701. doi:10.1097/mpg.0b013e31828f3c05. PMID: 23708639.
101. Nwosu BU. Vitamin D for the prevention of diseases in children: A rebuttal to the 2024 Endocrine Society Clinical Practice Guideline. Front Endocrinol (Lausanne). 2025;16:1578609. doi:10.3389/fendo.2025.1578609. PMID: 40510464. PMC12158689.
102. Pechabrier ML, Bacchetta J, Tounian P, Eddiry S, Linglart A, Edouard T. Survey on vitamin D supplementation in children in France: Evaluation of real-life practices following the new 2022 French recommendations. Arch Pediatr. 2025;32(1):4-11. doi:10.1016/j.arcped.2024.09.006. PMID: 39567315.
103. OPKO Pharmaceuticals/EirGen. RAYALDEE (calcifediol) extended-release capsules [prescribing information]. NDA 208010. DailyMed set ID 6a95effd-32a5-46b6-a30e-7f4f9bf8cc77. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6a95effd-32a5-46b6-a30e-7f4f9bf8cc77
104. U.S. Food and Drug Administration. Drugs@FDA: NDA 003444 (Drisdol, ergocalciferol). Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=003444
105. U.S. Food and Drug Administration. Drugs@FDA: NDA 018044 (Rocaltrol, calcitriol capsules). Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018044
106. European Medicines Agency. Download medicine data: medicines for human use. Available from: https://www.ema.europa.eu/en/medicines/download-medicine-data
107. Hartery SA, Kirby BJ, Walker EC, Kaufmann M, Jones G, St-Arnaud R, et al. Loss of maternal calcitriol reversibly alters early offspring growth and skeletal development in mice. J Bone Miner Res. 2024;39(5):595-610. doi:10.1093/jbmr/zjae035. PMID: 38477809. PMC11206081.
108. Köprülü Ö, Özer G, Erbaş IM, Nalbantoğlu Ö, Gürsoy S, Özkan B. Clinical and Laboratory Characteristics of Patients with Genetic Rickets: A Single-Center Experience with Long-Term Outcomes. Turk Arch Pediatr. 2025;60(5):483-490. doi:10.5152/turkarchpediatr.2025.25140. PMID: 40959932. PMC12432106.
109. Sun H. Recent Surge in Severe 25-hydroxyvitamin D Deficiency Among African American Children and Pregnant Women: Implications for Rickets. J Racial Ethn Health Disparities. 2026;13(4):3061-3068. doi:10.1007/s40615-025-02480-z. PMID: 40372599.
110. Uday S, Kongjonaj A, Aguiar M, Tulchinsky T, Högler W. Variations in infant and childhood vitamin D supplementation programmes across Europe and factors influencing adherence. Endocr Connect. 2017;6(8):667-675. doi:10.1530/ec-17-0193. PMID: 28924002. PMC5655685.