Vitamin D-Dependent Rickets Type 1B

Mendelian MONDO:0010810 Pathograph 20 Show in embeddings browser Metabolic Bone Disorders Inborn Error of Metabolism

Vitamin D-dependent rickets type 1B is caused by variants in CYP2R1, the principal hepatic vitamin D 25-hydroxylase. The block sits one step earlier in the activation pathway than in type 1A: reduced hepatic 25-hydroxylation causes very low 25-hydroxyvitamin D. Calcitriol is variable: normal or high values are well documented and do not exclude the diagnosis, but low values can also occur. The presentation can therefore mimic nutritional vitamin D deficiency, but persistence despite ordinary replacement, relapse when pharmacological parent-vitamin-D doses are reduced, and molecular testing can reveal the inherited defect. Severe classic disease is usually associated with biallelic variants. Some cohorts show intermediate biochemical or clinical effects in heterozygotes, whereas other families have clinically normal heterozygous parents; semidominant behavior is reported but is not uniform. Treatment is individualized: calcifediol bypasses the blocked step, high-dose parent vitamin D has produced responses compatible with residual or alternative hydroxylation, and selected nonresponders receive calcitriol.

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1
Inheritance
3
Pathophys.
12
Phenotypes
1
Gaps
20
Pathograph
1
Genes
3
Medical Actions
6
Differentials
1
Models
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Homozygous and compound heterozygous CYP2R1 genotypes produce the classic, severe disorder. A Nigerian study found a dosage-dependent biochemical effect and described semidominant inheritance, and a Saudi cohort reported symptomatic heterozygotes. This is not universal: other pedigrees have clinically normal heterozygous parents, and phenotype severity can vary independently of gene dosage. Autosomal recessive inheritance therefore remains the primary label, with reported semidominant behavior and variable heterozygote penetrance.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:25942481 SUPPORT Human Clinical
"CYP2R1 mutations cause a novel form of genetic vitamin D deficiency with semidominant inheritance."
Demonstrates a dosage-dependent biochemical effect and describes semidominant inheritance in the studied Nigerian families.
PMID:28548312 SUPPORT Human Clinical
"Heterozygous mutations were present in their normal parents."
Shows that heterozygosity was clinically silent in two other families, limiting generalization of semidominant inheritance.
PMID:33715104 SUPPORT Human Clinical
"The findings of both the current and the previous studies suggest that VDDR1b is a more complex disorder than the known autosomal recessive inheritance model and the phenotype may show an extensive variation regardless of the mutation type and the gene dosage."
Supports recording variable expression without treating either a simple recessive or a uniformly semidominant model as complete.
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Discussions and Knowledge Gaps

1
Do Cyp2r1-null mice develop a skeletal mineralization defect under the studied conditions, or were the relevant skeletal endpoints simply not assessed?
HUMAN MODEL MISMATCH OPEN cyp2r1_mouse_human_severity_mismatch
Attached to
pathophysiology#Hepatic 25-Hydroxylase Deficiency pathophysiology#Defective Skeletal Mineralization
The mouse establishes that CYP2R1 is a major 25-hydroxylase, but its residual metabolite production and preserved calcitriol coexist with a report of no overt health issues. That abstract-level statement is not a skeletal assessment and cannot support a negative mineralization result. Humans can develop a mineralization defect despite retaining normal or high calcitriol; whether mice differ because of stronger alternative 25-hydroxylation, dietary rescue, developmental timing, or merely unmeasured skeletal endpoints remains open.
Proposed experiments
Cross-species mapping of residual vitamin D 25-hydroxylation
exp_cyp2r1_cross_species_hydroxylase_flux
Compare isotope-traced vitamin D-to-25-hydroxyvitamin D flux and expression of candidate alternative hydroxylases in Cyp2r1-null mouse hepatocytes and CYP2R1-deficient patient-derived hepatocyte models under matched substrate concentrations.
Decision criterion
Greater residual flux in mouse cells, reversible by perturbing a candidate alternative hydroxylase, would support species-specific enzymatic compensation; similar flux would shift attention to diet and mineral homeostasis.
Show evidence (1 reference)
PMID:24019477 SUPPORT Model Organism
"Our results support the idea that the CYP2R1 is the major enzyme responsible for 25-hydroxylation of vitamin D, but clearly a second, as-yet unknown, enzyme is another contributor to this important step in vitamin D activation."
Grounds the proposed cross-species flux experiment in the demonstrated residual, unidentified hydroxylase activity.
Longitudinal skeletal phenotyping under controlled vitamin D and calcium intake
exp_cyp2r1_mouse_skeletal_stress_test
Phenotype Cyp2r1-null and wild-type mice across growth using matched, controlled vitamin D and calcium diets, serial mineral biochemistry, radiography and growth-plate histomorphometry.
Decision criterion
Emergence of rickets only under restricted substrate or mineral intake would identify dietary rescue in the original model; persistently normal skeletons despite low 25-hydroxyvitamin D would support species-specific compensation.
Show evidence (2 references)
PMID:24019477 SUPPORT Model Organism
"These mice presented no health issues."
Grounds the need for sensitive skeletal phenotyping beyond the reported absence of overt illness.
PMID:28548312 SUPPORT Human Clinical
"Siblings exhibited the three stages of rickets based on biochemical and radiographic findings."
Supplies the human skeletal endpoint that the proposed mouse experiment must test under controlled conditions.
Show evidence (2 references)
PMID:24019477 SUPPORT Model Organism
"These mice had greater than 50% reduction in serum 25-hydroxyvitamin D3. Curiously, the 1α,25-dihydroxyvitamin D3 level in the serum remained unchanged. These mice presented no health issues."
Defines the murine biochemical phenotype and the abstract's broad report of no health issues; it does not establish a negative skeletal endpoint.
PMID:28548312 SUPPORT Human Clinical
"Siblings exhibited the three stages of rickets based on biochemical and radiographic findings."
Provides the contrasting human skeletal phenotype that makes translation from the knockout uncertain.
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Pathophysiology

3
Hepatic 25-Hydroxylase Deficiency
CYP2R1 is the principal microsomal enzyme that hydroxylates carbon 25 of vitamin D in the liver, the first of the two activation steps. Disease variants reduce or abolish CYP2R1-dependent activity, so ingested or cutaneously synthesized vitamin D is converted inefficiently to 25-hydroxyvitamin D. Partially active alleles retain some conversion in vitro, while alternative 25-hydroxylases are a proposed additional source; consequently 25-hydroxyvitamin D is markedly reduced but calcitriol need not be.
CYP2R1 hgnc:20580 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYP2R1 (hgnc:20580). hgnc:20580 is a gene from the HUGO Gene Nomenclature Committee.
Vitamin D 25-Hydroxylase Activity GO:0030343 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves Vitamin D 25-Hydroxylase Activity (GO:0030343), qualified as loss of function. GO:0030343 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Animal models
Cyp2r1-null mouse Mouse partially recapitulates Recapitulates reduced circulating 25-hydroxyvitamin D while showing that the pathway is not abolished and that calcitriol can remain regulated.
Downstream
Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling Reduced 25-hydroxylation depletes the circulating intermediate and limits vitamin-D-dependent calcium homeostasis even though calcitriol is variable and can remain normal or high.
Low circulating 25-hydroxyvitamin D Loss of the principal hepatic 25-hydroxylase directly lowers its circulating product.
Show evidence (2 references)
PMID:15128933 SUPPORT In Vitro
"The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity."
Shows the disease allele abolishing the enzymatic activity that defines this node.
PMID:25942481 SUPPORT In Vitro
"in vitro studies showed that K242N and L99P had markedly reduced or complete loss of 25-hydroxylase activity, respectively"
Confirms loss of 25-hydroxylase activity for a second independent allele.
Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling
Very low 25-hydroxyvitamin D limits substrate availability for renal 1-alpha-hydroxylation. General vitamin-D-dependent-rickets physiology predicts that effective intestinal calcium and phosphate absorption can then become inadequate relative to mineral demand, but absorption has not been measured directly in the cited VDDR1B cohorts. Renal regulation and residual 25-hydroxylation can preserve or increase circulating calcitriol, while other reports support lower values; calcitriol is therefore variable rather than a defining deficiency. When effective vitamin D and calcium supply is inadequate, the calciopenic cascade of hypocalcemia, secondary hyperparathyroidism and phosphaturia follows. This is an evidence-calibrated mechanistic inference that places the disorder in the module's calciopenic trigger arm.
Vitamin D Metabolic Process GO:0042359 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Vitamin D Metabolic Process (GO:0042359). GO:0042359 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Skeletal Mineralization Reduced calcium and phosphate supply lowers the calcium-phosphate product at the mineralization front.
Hypocalcemia Inadequate calciotropic support can lower serum calcium or produce hypocalcemic manifestations, particularly in severe disease.
Hypophosphatemia The calciopenic response promotes renal phosphate loss, reducing serum phosphate available for mineralization.
Secondary hyperparathyroidism Compensatory parathyroid-hormone elevation is part of the calciopenic response to inadequate effective vitamin D and mineral supply.
Show evidence (3 references)
PMID:15128933 SUPPORT Human Clinical
"With regard to human inborn errors, selective 25-hydroxyvitamin D3deficiency is a rare autosomal recessive disorder characterized by impaired synthesis of an intermediate in the vitamin D biosynthetic pathway that results in endocrine defects in vitamin D signaling."
Directly links deficient intermediate synthesis to endocrine vitamin D signaling defects.
PMID:28548312 SUPPORT Human Clinical
"We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)2 D."
Establishes that loss of the circulating intermediate does not imply low calcitriol and directly supports the corrected metabolic state.
PMID:37074534 SUPPORT Other
"VDDR refers to a group of conditions characterised by abnormalities in the pathway of vitamin D metabolism resulting in the reduced action of vitamin D (primarily intestinal calcium and phosphate absorption), which causes hypocalcemia, rickets and secondary hyperparathyroidism."
Supports the group-level calciopenic mechanism while leaving intestinal absorption in VDDR1B itself explicitly unmeasured and inferential.
Defective Skeletal Mineralization
Failure to mineralize newly formed osteoid and the growing metaphysis, presenting as rickets with the radiographic and clinical features indistinguishable from nutritional rickets.
Osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
Bone Mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Bone Mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↓ DECREASED
Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bone, annotated with bone element (UBERON:0001474). UBERON:0001474 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Rickets Failure to mineralize growing osteoid and metaphyses produces the defining rachitic phenotype.
Bone pain Poorly mineralized bone and deformity commonly produce skeletal pain.
Short stature Chronic growth-plate mineralization failure can impair linear growth.
Limitation of physical activity Bone pain and skeletal deformity can limit physical activity in affected individuals.
Bone deformity Persistent failure of growth-plate and osteoid mineralization can deform weight-bearing bone.
Gait abnormality Pain and lower-limb deformity can disturb gait.
Genu valgum Rachitic mineralization failure at weight-bearing growth plates can produce valgus knee deformity.
Show evidence (1 reference)
PMID:28548312 SUPPORT Human Clinical
"Siblings exhibited the three stages of rickets based on biochemical and radiographic findings."
Reports observed biochemical and radiographic rickets rather than merely a study objective.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Vitamin D-Dependent Rickets Type 1B Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Endocrine 1
Secondary hyperparathyroidism HP:0000867 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary hyperparathyroidism (HP:0000867). HP:0000867 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32596195 SUPPORT Other
"VDDR1b is associated with hypocalcemia, secondary hyperparathyroidism and low plasma concentrations of 25(OH)D, with reduced clinical and biochemical responsiveness to conventional doses of vitamin D."
Directly identifies the compensatory parathyroid response in VDDR1B.
PMID:34137732 SUPPORT Human Clinical
"Table 3Comparison between the heterozygous and homozygous (presenting symptoms, biochemical, and radiological abnormalities).Heterozygous (n = 9)Homozygous (n = 18)Presenting symptoms: Bone pain7/918/18 Short stature3/99/18 Limitation of activity5/913/18 Bone deformity1/97/18 Gait..."
The table reports a composite abnormal profile in 20 of 27 participants. It does not permit assigning that count to PTH, calcium, or alkaline phosphatase individually, so no frequency is inferred here.
Limbs 1
Genu valgum HP:0002857 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu valgum (HP:0002857). HP:0002857 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18 Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18"
Summing heterozygous and homozygous subgroups gives 8 of 27 participants; the exact count is retained without assigning a categorical frequency.
Metabolism 2
Hypocalcemia HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15128933 SUPPORT Human Clinical
"Before treatment, he had low normal serum calcium levels (2.00–2.32 mM; normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM; normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels (2,360–3,000 units/liter; normal range 100–320 units/liter), serum..."
The reported calcium interval includes values below the stated lower reference limit in the index case; no population frequency is inferred.
PMID:34137732 SUPPORT Human Clinical
"Some patients had a severe presentation in the form of bone deformity (8/27) and hypocalcemic manifestations (5/27)"
Supports clinically attributed hypocalcemic manifestations in a subset of the cohort. Frequency is deliberately not inferred because the reported count is for manifestations rather than measured biochemical hypocalcemia.
Hypophosphatemia HP:0002148 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypophosphatemia (HP:0002148). HP:0002148 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15128933 SUPPORT Human Clinical
"Before treatment, he had low normal serum calcium levels (2.00–2.32 mM; normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM; normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels (2,360–3,000 units/liter; normal range 100–320 units/liter), serum..."
Low serum phosphate against the stated reference range in the index case. No frequency is asserted: this is a single-patient report.
Musculoskeletal 1
Rickets HP:0002748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"All patients described in our study presented with classical clinical, biochemical, and radiological features of vitamin D deficiency and associated rickets."
Directly documents rickets across the 27-person cohort.
Nervous System 1
Gait abnormality OCCASIONAL Gait disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Table 3Comparison between the heterozygous and homozygous (presenting symptoms, biochemical, and radiological abnormalities).Heterozygous (n = 9)Homozygous (n = 18)Presenting symptoms: Bone pain7/918/18 Short stature3/99/18 Limitation of activity5/913/18 Bone deformity1/97/18 Gait..."
Summing heterozygous and homozygous subgroups gives 7 of 27 participants (26%), mapping to OCCASIONAL (5-29%).
Constitutional 1
Bone pain VERY_FREQUENT HP:0002653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone pain (HP:0002653). HP:0002653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Our patients presented with variable symptoms: 25/27 had bone pain, 18 out of 27 had limitations of physical activity, and 12 out of 27 presented with short stature."
Bone pain in 25 of 27 patients (93%) in the largest reported CYP2R1 cohort, a derived count that maps to VERY_FREQUENT (80-100%).
Growth 1
Short stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Our patients presented with variable symptoms: 25/27 had bone pain, 18 out of 27 had limitations of physical activity, and 12 out of 27 presented with short stature."
Short stature in 12 of 27 patients (44%), a derived count that maps to FREQUENT (30-79%).
Other 4
Low circulating 25-hydroxyvitamin D Decreased circulating vitamin D concentration HP:0100512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating 25-hydroxyvitamin D concentration, annotated with Decreased circulating vitamin D concentration (HP:0100512). HP:0100512 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28548312 SUPPORT Human Clinical
"We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)2 D."
Directly reports the very low circulating 25-hydroxyvitamin D that defines the phenotype while distinguishing it from the active metabolite.
PMID:25942481 SUPPORT Human Clinical
"Heterozygous subjects were less affected than homozygous subjects, and oral administration of vitamin D led to significantly lower increases in serum 25-hydroxyvitamin D in heterozygous than in control subjects, whereas homozygous subjects showed negligible increases."
Quantifies the failure to raise 25-hydroxyvitamin D on vitamin D administration, in a genotype-dependent manner.
Limitation of physical activity FREQUENT
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Our patients presented with variable symptoms: 25/27 had bone pain, 18 out of 27 had limitations of physical activity, and 12 out of 27 presented with short stature."
Activity limitation in 18 of 27 participants (67%) maps to FREQUENT (30-79%).
Bone deformity
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Some patients had a severe presentation in the form of bone deformity (8/27) and hypocalcemic manifestations (5/27)"
Bone deformity occurred in 8 of 27 participants; the exact count is retained without assigning a categorical frequency.
Elevated circulating alkaline phosphatase Elevated circulating alkaline phosphatase concentration HP:0003155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating alkaline phosphatase concentration (HP:0003155). HP:0003155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15128933 SUPPORT Human Clinical
"Before treatment, he had low normal serum calcium levels (2.00–2.32 mM; normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM; normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels (2,360–3,000 units/liter; normal range 100–320 units/liter), serum..."
Alkaline phosphatase roughly tenfold above the stated upper limit in the index case. No frequency is asserted: this is a single-patient report.
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Genetic Associations

1
CYP2R1 loss-of-function variants (Causative)
Gene: CYP2R1 hgnc:20580 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYP2R1 (hgnc:20580). hgnc:20580 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:15128933 SUPPORT Human Clinical
"This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2."
The index case establishing CYP2R1 as the disease gene.
PMID:34137732 SUPPORT Human Clinical
"Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous."
Documents recurrent CYP2R1 alleles across the largest reported cohort.
💊

Medical Actions

3
Calcifediol Replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcidiol CHEBI:17933 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcidiol (CHEBI:17933). CHEBI:17933 is a therapeutic agent from Chemical Entities of Biological Interest.
Calcifediol (25-hydroxyvitamin D3) supplies the product of the blocked reaction directly. It is the most specific biochemical bypass when available. A seven-patient study reported clinical, biochemical and densitometric improvement, while long-term comparative data remain limited.
Mechanism Target:
BYPASSES Hepatic 25-Hydroxylase Deficiency — Supplying 25-hydroxyvitamin D downstream of CYP2R1 bypasses the deficient hepatic reaction rather than attempting to restore the mutant enzyme.
Show evidence (1 reference)
PMID:28548312 SUPPORT Human Clinical
"For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry)."
Direct product replacement provides clinical evidence for bypassing the 25-hydroxylase defect.
Show evidence (1 reference)
PMID:28548312 SUPPORT Human Clinical
"For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry)."
Reports improvement after direct replacement with the missing 25-hydroxylated metabolite.
High-Dose Parent Vitamin D with Calcium Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cholecalciferol CHEBI:28940 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cholecalciferol, annotated with calciol (CHEBI:28940). CHEBI:28940 is a therapeutic agent from Chemical Entities of Biological Interest. ergocalciferol CHEBI:28934 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ergocalciferol, annotated with vitamin D2 (CHEBI:28934). CHEBI:28934 is a therapeutic agent from Chemical Entities of Biological Interest. calcium(2+) CHEBI:29108 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcium(2+) (CHEBI:29108). CHEBI:29108 is a therapeutic agent from Chemical Entities of Biological Interest.
Pharmacological cholecalciferol or ergocalciferol can produce clinical and biochemical responses. Increased flux through partially active CYP2R1 and/or alternative 25-hydroxylases is a plausible interpretation of that response, not a directly measured patient mechanism. Response and maintenance dose vary by genotype and age: a Saudi cohort commonly relapsed when doses were reduced, whereas other adults maintained mineral homeostasis without ongoing supplementation. Calcium is co-administered or optimized according to mineral status; monitoring guides the dose and guards against overtreatment.
Mechanism Target:
RESTORES Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling — High-dose parent vitamin D produced clinical and biochemical responses in most of this cohort, while calcium supplementation supports mineral supply. Increased flux through residual CYP2R1 and/or alternative 25-hydroxylases is a plausible explanation, not a pathway measurement in these patients.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Thirteen out of 18 homozygous patients and all the heterozygous patients responded to high doses of vitamin D treatment, but they regressed after decreasing the dose, requiring lifelong therapy."
Supports the observed restoration by high-dose parent vitamin D while showing that maintenance requirements were cohort- and genotype-dependent; it does not identify which hydroxylase carried the increased flux.
Show evidence (3 references)
PMID:38440125 SUPPORT Human Clinical
"The children were treated with oral calcium and cholecalciferol, dose titrated to maintain serum alkaline phosphatase, 25 hydroxy vitamin D, and parathyroid hormone levels in the normal range, with good clinical and radiological response."
Documents monitored cholecalciferol-plus-calcium therapy with clinical and radiological improvement in affected siblings.
PMID:28548312 SUPPORT Human Clinical
"Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation."
Qualifies the Saudi cohort's lifelong-maintenance observation by documenting age-related improvement without supplementation in another family series.
PMID:34137732 SUPPORT Human Clinical
"We noticed a symptomatic and biochemical improvement in all heterozygous patients after treatment with supra-therapeutic doses of vitamin D (i.e. 50,000–100,000 IU of vitamin D2 weekly) for 8–12 weeks, regardless of their mutation, and none of them required calcitriol (1,25-[OH]2 vitamin D),..."
Documents ergocalciferol response and genotype-dependent maintenance needs in the Saudi cohort.
Calcitriol for Selected Parent-Vitamin-D Nonresponders
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcitriol CHEBI:17823 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcitriol (CHEBI:17823). CHEBI:17823 is a therapeutic agent from Chemical Entities of Biological Interest.
Calcitriol is not routine replacement for an obligatorily low calcitriol concentration: the biomarker is variable in VDDR1B, and normal or high values do not exclude the disorder. It can bypass both activation steps in selected patients whose biochemical abnormalities do not improve with high-dose parent vitamin D. The Saudi cohort used closer follow-up and annual renal ultrasonography to watch for calcification or nephrolithiasis during treatment.
Mechanism Target:
BYPASSES Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling — Active hormone replacement bypasses both hepatic 25-hydroxylation and renal 1-alpha-hydroxylation to restore downstream receptor signaling.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Five out of 18 homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment."
Improvement in parent-vitamin-D nonresponders supports use of calcitriol as a downstream bypass in selected patients.
Show evidence (2 references)
PMID:34137732 SUPPORT Human Clinical
"Five out of 18 homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment."
Restricts calcitriol to the documented nonresponding subgroup rather than presenting it as universal therapy.
PMID:34137732 SUPPORT Human Clinical
"These patients required closer follow-up and renal ultrasonography every year to check for signs of calcifications or nephrolithiasis, which was negative in all patients receiving calcitriol."
Supports renal surveillance during calcitriol therapy while noting that no calcification was observed in this cohort.
🔬

Biochemical Markers

2
25-hydroxyvitamin D (calcifediol) (Decreased)
Context: Low, because the hepatic 25-hydroxylation that produces it is the blocked step. This is the measurement type 1B shares with nutritional deficiency and the one that separates it from type 1A, where 25-hydroxyvitamin D is normal or high because the substrate accumulates behind a later block.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"We analyzed 27 patients from nine different families who presented with low 25-OH vitamin D and not responding to usual treatment."
Low 25-hydroxyvitamin D together with non-response to usual treatment is the presenting biochemical signature of the cohort.
1,25-dihydroxyvitamin D (calcitriol) (Variable)
Context: Published guidance classifies calcitriol as variable, so lower values can occur. Normal calcitriol was reported in the index case and untreated adults, and another series describes normal or high concentrations despite very low 25-hydroxyvitamin D. Residual 25-hydroxylation and renal regulation may preserve active hormone despite the upstream block. Normal or elevated calcitriol therefore does not exclude this disorder, and measuring it alone would be misleading.
Show evidence (4 references)
PMID:15128933 SUPPORT Human Clinical
"Before treatment, he had low normal serum calcium levels (2.00–2.32 mM; normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM; normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels (2,360–3,000 units/liter; normal range 100–320 units/liter), serum..."
Reports calcitriol within the stated normal range alongside low 25-hydroxyvitamin D in the index case.
PMID:28548312 SUPPORT Human Clinical
"We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)2 D."
Directly supports the normal-or-high range and corrects the prior assertion that calcitriol is necessarily deficient.
PMID:32430692 SUPPORT Human Clinical
"These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH)2 vitamin D."
Extends the normal-calcitriol observation to three untreated adults with undetectable 25-hydroxyvitamin D.
+ 1 more reference
🔬

Diagnosis

2
Clinical and biochemical evaluation of refractory calciopenic rickets
Consider VDDR1B when clinical or radiographic rickets and very low 25-hydroxyvitamin D persist despite an adequate, adhered-to calcium and vitamin D regimen, or when severe vitamin D deficiency clusters in a family. Interpret calcium, phosphate, age-adjusted alkaline phosphatase, PTH, 25-hydroxyvitamin D, calcitriol, and renal phosphate handling together; normal or high calcitriol does not exclude VDDR1B.
Clinical Evaluation NCIT:C124351 NCI Thesaurus (NCIT)
Results: Persistent very low 25-hydroxyvitamin D with a calciopenic rachitic profile and inadequate response to ordinary replacement supports CYP2R1 testing but is not independently specific for VDDR1B.
Show evidence (2 references)
PMID:37074534 SUPPORT Other
"If rickets fails to heal and/or if there is a family history of rickets, then refractory rickets should be considered as a differential diagnosis."
Establishes adequate-treatment nonhealing and family history as triggers for a refractory-rickets evaluation.
PMID:32596195 SUPPORT Other
"Subjects with calciopenic rickets will have elevated serum levels of PTH, which depress the TRP and cause hypophosphatemia. These subjects have either inadequate intake of calcium and/or vitamin D or genetic defects that impair vitamin D activation or responses (i.e., VDDR)."
Supports combined biochemical interpretation rather than diagnosis from an isolated vitamin D metabolite.
CYP2R1 molecular genetic confirmation
Molecular analysis of CYP2R1 provides confirmation after the clinical, biochemical, exposure, and acquired-cause assessment. Biallelic pathogenic variants support classic severe VDDR1B; a single variant requires phenotype-aware interpretation because heterozygote penetrance and severity are variable.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Pathogenic CYP2R1 variant(s) consistent with the individual's phenotype and inheritance establish the molecular diagnosis.
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Confirmation of the diagnosis should be pursued by performing molecular analysis of the CYP2R1 gene in the patients and their families."
Directly recommends CYP2R1 molecular analysis for confirmation in patients and relatives.
🩻

Imaging Findings

2
Generalized osteopenia on radiographs FREQUENT
Generalized radiographic osteopenia was the most common individual imaging abnormality in the 27-person cohort.
Xray
Osteopenia HP:0000938 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18 Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18"
Summing the two zygosity strata gives generalized osteopenia in 15 of 27 participants (56%), mapping to FREQUENT (30-79%).
Metaphyseal cupping on radiographs OCCASIONAL
Metaphyseal cupping was present in a minority of the cohort and is an imaging sign of active rickets rather than a VDDR1B-specific discriminator.
Xray
Metaphyseal cupping HP:0003021 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:34137732 SUPPORT Human Clinical
"Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18 Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18"
Summing the two zygosity strata gives cupping in 4 of 27 participants (15%), mapping to OCCASIONAL (5-29%).
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Vitamin D-Dependent Rickets Type 1B:

Nutritional calcium or vitamin D deficiency rickets
Overlapping Features Nutritional rickets is the commonest mimic and can share very low 25-hydroxyvitamin D and a calciopenic biochemical profile. Adequate calcium and vitamin D with adherence should heal ordinary nutritional disease; persistence or recurrent dose dependence warrants refractory-rickets evaluation.
Distinguishing Features
  • Dietary calcium/vitamin D intake, sunlight exposure, and adherence explain most nutritional cases.
  • Failure to heal despite adequate calcium and vitamin D or a strong family history favors a refractory cause such as VDDR1B.
Show evidence (1 reference)
PMID:37074534 SUPPORT Other
"By far the commonest cause of rickets is nutritional rickets, due to dietary deficiency in calcium and/or vitamin D intake. Therefore, it would be common practice, particularly in resource-deprived settings, to treat cases of rickets presenting clinically empirically with oral calcium and..."
Defines the common nutritional mimic and the response-to-adequate-repletion boundary for escalating the differential.
Vitamin D-dependent rickets type 1A MONDO:0020723
Overlapping Features VDDR1A shares calciopenic rickets but reflects CYP27B1 deficiency at the second activation step. Its usual profile is normal or elevated 25-hydroxyvitamin D with very low calcitriol, unlike the markedly low 25-hydroxyvitamin D and variable calcitriol of VDDR1B.
Distinguishing Features
  • CYP27B1 rather than CYP2R1 pathogenic variants establish VDDR1A.
  • Normal or elevated 25-hydroxyvitamin D with very low calcitriol favors VDDR1A.
Show evidence (1 reference)
PMID:37074534 SUPPORT Other
"The typical biochemical findings are of hypocalcemia, hypophosphatemia, hyperphosphatasia, secondary hyperparathyroidism, and normal or elevated 25OHD with extremely low 1,25(OH)2D."
Defines the metabolite profile that separates the downstream CYP27B1 block from CYP2R1 deficiency.
Vitamin D-dependent rickets type 2A MONDO:0010186
Overlapping Features VDDR2A can share severe rickets and hypocalcemia but is caused by VDR dysfunction. Elevated calcitriol and partial or complete alopecia favor VDDR2A, whereas CYP2R1-related VDDR1B has very low 25-hydroxyvitamin D and no defining alopecia phenotype.
Distinguishing Features
  • Biallelic pathogenic VDR variants establish VDDR2A.
  • Markedly elevated calcitriol and alopecia favor receptor resistance rather than CYP2R1 deficiency.
Show evidence (3 references)
PMID:37074534 SUPPORT Other
"The clinical features and presentation of VDDR2a are similar to forms of VDDR1, except for the presence of partial or complete alopecia that develops within the first year of life."
Identifies the principal clinical discriminator for VDR-mediated disease.
PMID:37074534 SUPPORT Other
"VDDR2a is due to biallelic mutations in VDR, the gene that encodes for the vitamin D receptor (VDR), located on chromosome 12q13.11. This results in resistance to 1,25(OH)2D."
Establishes the VDR cause and receptor-resistance mechanism.
PMID:37074534 SUPPORT Other
"The biochemistry of VDDR2a is similar to VDDR1a, except for elevated 1,25(OH)2D."
Supports elevated calcitriol as a biochemical discriminator.
Vitamin D-dependent rickets type 3 MONDO:0033640
Overlapping Features VDDR3 is caused by gain-of-function CYP3A4-mediated acceleration of vitamin D metabolite inactivation. Both 25-hydroxyvitamin D and calcitriol can be low, and molecular testing distinguishes it from deficient CYP2R1 25-hydroxylation.
Distinguishing Features
  • A pathogenic gain-of-function CYP3A4 variant supports VDDR3 rather than VDDR1B.
  • Low 25-hydroxyvitamin D together with low calcitriol and rapid loss after dosing favors excessive catabolism.
Show evidence (2 references)
PMID:37074534 SUPPORT Other
"This has only been recently described as a form of VDDR due to gain-of-function mutations in CYP3A4 (located on chromosome 7q22.1), encoding a cytochrome P450 enzyme, resulting in increased inactivation of vitamin D metabolites."
Establishes the accelerated-catabolism mechanism that distinguishes VDDR3.
PMID:32596195 SUPPORT Other
"Both affected individuals had detectable serum concentrations of vitamin D3 but low serum concentrations of 25(OH)D and 1,25(OH)2D that increased after administration of very large doses of vitamin D or calcitriol and which decreased rapidly thereafter."
Supports the paired low-metabolite and rapid-loss pattern that distinguishes excessive catabolism from the VDDR1B pattern.
Phosphopenic rickets from renal phosphate wasting
Overlapping Features FGF23-mediated disorders and proximal renal tubulopathies can cause rickets through primary phosphate loss. Age-adjusted phosphate, PTH, calcium, 25-hydroxyvitamin D, and tubular phosphate reabsorption separate this branch from calciopenic VDDR1B.
Distinguishing Features
  • Normal PTH and calcium with low phosphate favors primary phosphopenic rickets.
  • Reduced tubular phosphate reabsorption identifies genetic or acquired renal phosphate wasting.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"Subjects who have hypophosphatemia and normal serum levels of PTH, calcium, and 25(OH)D are likely to have phosphopenic rickets; a normal or elevated tubular reabsorption of phosphorus (TRP) will be found in subjects with inadequate intake or absorption of phosphorus. By contrast, patients with..."
Provides the biochemical and renal-handling distinction from calciopenic vitamin D-dependent rickets.
🐁

Animal Models

1
Cyp2r1-null mouse
A whole-animal test of CYP2R1's contribution to vitamin D activation. The knockout lowers serum 25-hydroxyvitamin D3 by more than half but leaves calcitriol unchanged, demonstrating both CYP2R1's major role and substantial CYP2R1-independent 25-hydroxylation. The abstract reports no overt health issues, but it does not establish whether skeletal endpoints were assessed.
Species
Mouse
Genotype
Homozygous Cyp2r1 knockout
Publication
PMID:24019477
Pathograph links
Hepatic 25-Hydroxylase Deficiency partially recapitulates fidelity: moderate Recapitulates reduced circulating 25-hydroxyvitamin D while showing that the pathway is not abolished and that calcitriol can remain regulated.
Limitations: The null mouse retains a substantial residual fraction of circulating 25-hydroxyvitamin D3 and has no reported overt illness, whereas humans with severe biallelic CYP2R1 variants can develop rickets. Diet, species-specific alternative hydroxylases and unreported skeletal phenotyping in the abstract leave skeletal fidelity unassessed.
Readouts
Serum 25-hydroxyvitamin D3 concentration
Direction: DECREASED
Interpretation: A greater-than-50% reduction demonstrates that CYP2R1 is a major, but not exclusive, source of circulating 25-hydroxyvitamin D3 in mice.
Show evidence (1 reference)
PMID:24019477 SUPPORT Model Organism
"These mice had greater than 50% reduction in serum 25-hydroxyvitamin D3."
Reports the direction and magnitude of the metabolite readout.
Serum 1-alpha,25-dihydroxyvitamin D3 concentration
Direction: UNCHANGED
Interpretation: Preserved active hormone despite loss of Cyp2r1 argues against treating calcitriol deficiency as an obligatory consequence of this lesion.
Show evidence (1 reference)
PMID:24019477 SUPPORT Model Organism
"Curiously, the 1α,25-dihydroxyvitamin D3 level in the serum remained unchanged."
Directly reports the unchanged active-hormone readout.
Show evidence (1 reference)
PMID:24019477 SUPPORT Model Organism
"Our results support the idea that the CYP2R1 is the major enzyme responsible for 25-hydroxylation of vitamin D, but clearly a second, as-yet unknown, enzyme is another contributor to this important step in vitamin D activation."
Supports partial rather than complete recapitulation of the human 25-hydroxylase lesion.
Show evidence (1 reference)
PMID:24019477 SUPPORT Model Organism
"We have now produced Cyp2r1 (-/-) mice."
Establishes the whole-animal knockout used to test CYP2R1 function.
{ }

Source YAML

click to show 
name: Vitamin D-Dependent Rickets Type 1B
synonyms:
- VDDR1B
- Vitamin D hydroxylation-deficient rickets, type 1B
- Vitamin D 25-hydroxylase deficiency
- Selective 25-hydroxyvitamin D deficiency
creation_date: "2026-08-19T00:00:00Z"
category: Mendelian
description: >-
  Vitamin D-dependent rickets type 1B is caused by variants in CYP2R1, the
  principal hepatic vitamin D 25-hydroxylase. The block sits one step earlier in
  the activation pathway than in type 1A: reduced hepatic 25-hydroxylation causes
  very low 25-hydroxyvitamin D. Calcitriol is variable: normal or high values are
  well documented and do not exclude the diagnosis, but low values can also
  occur. The presentation can therefore mimic
  nutritional vitamin D deficiency, but persistence despite ordinary replacement,
  relapse when pharmacological parent-vitamin-D doses are reduced, and molecular
  testing can reveal the inherited defect. Severe classic disease is usually
  associated with biallelic variants. Some cohorts show intermediate biochemical
  or clinical effects in heterozygotes, whereas other families have clinically
  normal heterozygous parents; semidominant behavior is reported but is not
  uniform. Treatment is individualized: calcifediol bypasses the blocked step,
  high-dose parent vitamin D has produced responses compatible with residual or
  alternative hydroxylation, and selected nonresponders receive calcitriol.
disease_term:
  preferred_term: vitamin D hydroxylation-deficient rickets, type 1B
  term:
    id: MONDO:0010810
    label: vitamin D hydroxylation-deficient rickets, type 1B
parents:
- Metabolic Bone Disorders
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous and compound heterozygous CYP2R1 genotypes produce the classic,
    severe disorder. A Nigerian study found a dosage-dependent biochemical effect
    and described semidominant inheritance, and a Saudi cohort reported symptomatic
    heterozygotes. This is not universal: other pedigrees have clinically normal
    heterozygous parents, and phenotype severity can vary independently of gene
    dosage. Autosomal recessive inheritance therefore remains the primary label,
    with reported semidominant behavior and variable heterozygote penetrance.
  evidence:
  - reference: PMID:25942481
    reference_title: CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CYP2R1 mutations cause a novel form of genetic vitamin D deficiency with
      semidominant inheritance.
    explanation: >-
      Demonstrates a dosage-dependent biochemical effect and describes
      semidominant inheritance in the studied Nigerian families.
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous mutations were present in their normal parents.
    explanation: >-
      Shows that heterozygosity was clinically silent in two other families,
      limiting generalization of semidominant inheritance.
  - reference: PMID:33715104
    reference_title: Two novel CYP2R1 mutations in a family with vitamin D-dependent rickets type 1b.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings of both the current and the previous studies suggest that
      VDDR1b is a more complex disorder than the known autosomal recessive
      inheritance model and the phenotype may show an extensive variation
      regardless of the mutation type and the gene dosage.
    explanation: >-
      Supports recording variable expression without treating either a simple
      recessive or a uniformly semidominant model as complete.
genetic:
- name: CYP2R1 loss-of-function variants
  gene_term:
    preferred_term: CYP2R1
    term:
      id: hgnc:20580
      label: CYP2R1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Reported alleles include the original p.Leu99Pro missense variant, p.Lys242Asn,
    and the splice and duplication variants c.367+1G>A and c.768dupT that recur in
    Saudi families.
  evidence:
  - reference: PMID:15128933
    reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This individual was found to be homozygous for a transition mutation in
      exon 2 of the CYP2R1 gene on chromosome 11p15.2.
    explanation: >-
      The index case establishing CYP2R1 as the disease gene.
  - reference: PMID:34137732
    reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and
      c.768dupT (15/27 patients), where 18 patients were homozygous for their
      identified mutation and 9 patients were heterozygous.
    explanation: >-
      Documents recurrent CYP2R1 alleles across the largest reported cohort.
pathophysiology:
- name: Hepatic 25-Hydroxylase Deficiency
  description: >-
    CYP2R1 is the principal microsomal enzyme that hydroxylates carbon 25 of
    vitamin D in the liver, the first of the two activation steps. Disease variants
    reduce or abolish CYP2R1-dependent activity, so ingested or cutaneously
    synthesized vitamin D is converted inefficiently to 25-hydroxyvitamin D.
    Partially active alleles retain some conversion in vitro, while alternative
    25-hydroxylases are a proposed additional source; consequently
    25-hydroxyvitamin D is markedly reduced but calcitriol need not be.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CYP2R1
    term:
      id: hgnc:20580
      label: CYP2R1
  molecular_functions:
  - preferred_term: Vitamin D 25-Hydroxylase Activity
    term:
      id: GO:0030343
      label: vitamin D 25-hydroxylase activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:15128933
    reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The inherited mutation caused the substitution of a proline for an
      evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and
      eliminated vitamin D 25-hydroxylase enzyme activity.
    explanation: >-
      Shows the disease allele abolishing the enzymatic activity that defines
      this node.
  - reference: PMID:25942481
    reference_title: CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in vitro studies showed that K242N and L99P had markedly reduced or complete
      loss of 25-hydroxylase activity, respectively
    explanation: >-
      Confirms loss of 25-hydroxylase activity for a second independent allele.
  downstream:
  - target: Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling
    causal_link_type: DIRECT
    description: >-
      Reduced 25-hydroxylation depletes the circulating intermediate and limits
      vitamin-D-dependent calcium homeostasis even though calcitriol is variable
      and can remain normal or high.
    evidence:
    - reference: PMID:28548312
      reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We discuss the difficulties in establishing the correct diagnosis and the
        specific biochemical pattern, namely, very low 25-OH-D suggestive of
        classical vitamin D deficiency, in the face of normal/high concentrations
        of 1,25-(OH)2 D.
      explanation: >-
        Links the CYP2R1 disorder to depleted 25-hydroxyvitamin D while preserving
        the explicitly non-obligatory calcitriol response.
  - target: Low circulating 25-hydroxyvitamin D
    causal_link_type: DIRECT
    description: >-
      Loss of the principal hepatic 25-hydroxylase directly lowers its circulating
      product.
    evidence:
    - reference: PMID:28548312
      reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We discuss the difficulties in establishing the correct diagnosis and the
        specific biochemical pattern, namely, very low 25-OH-D suggestive of
        classical vitamin D deficiency, in the face of normal/high concentrations
        of 1,25-(OH)2 D.
      explanation: >-
        Directly supports the low circulating product as a causal consequence of
        the inherited enzyme defect.
- name: Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling
  description: >-
    Very low 25-hydroxyvitamin D limits substrate availability for renal
    1-alpha-hydroxylation. General vitamin-D-dependent-rickets physiology predicts
    that effective intestinal calcium and phosphate absorption can then become
    inadequate relative to mineral demand, but absorption has not been measured
    directly in the cited VDDR1B cohorts. Renal regulation and residual
    25-hydroxylation can preserve or increase circulating calcitriol, while other
    reports support lower values; calcitriol is therefore variable rather than a
    defining deficiency. When effective vitamin D and calcium supply is inadequate,
    the calciopenic cascade of hypocalcemia, secondary hyperparathyroidism and
    phosphaturia follows. This is an evidence-calibrated mechanistic inference that
    places the disorder in the module's calciopenic trigger arm.
  role: central_effector
  biological_scale: ORGANISM
  conforms_to: "defective_skeletal_mineralization#Calciopenic Substrate Deficiency"
  biological_processes:
  - preferred_term: Vitamin D Metabolic Process
    term:
      id: GO:0042359
      label: vitamin D metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:15128933
    reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With regard to human inborn errors, selective 25-hydroxyvitamin D3deficiency
      is a rare autosomal recessive disorder characterized by impaired synthesis
      of an intermediate in the vitamin D biosynthetic pathway that results in
      endocrine defects in vitamin D signaling.
    explanation: >-
      Directly links deficient intermediate synthesis to endocrine vitamin D
      signaling defects.
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discuss the difficulties in establishing the correct diagnosis and the
      specific biochemical pattern, namely, very low 25-OH-D suggestive of
      classical vitamin D deficiency, in the face of normal/high concentrations
      of 1,25-(OH)2 D.
    explanation: >-
      Establishes that loss of the circulating intermediate does not imply low
      calcitriol and directly supports the corrected metabolic state.
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR refers to a group of conditions characterised by abnormalities in the
      pathway of vitamin D metabolism resulting in the reduced action of vitamin D
      (primarily intestinal calcium and phosphate absorption), which causes
      hypocalcemia, rickets and secondary hyperparathyroidism.
    explanation: >-
      Supports the group-level calciopenic mechanism while leaving intestinal
      absorption in VDDR1B itself explicitly unmeasured and inferential.
  downstream:
  - target: Defective Skeletal Mineralization
    causal_link_type: DIRECT
    description: >-
      Reduced calcium and phosphate supply lowers the calcium-phosphate product at
      the mineralization front.
    evidence:
    - reference: PMID:28548312
      reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We discuss the difficulties in establishing the correct diagnosis and the
        specific biochemical pattern, namely, very low 25-OH-D suggestive of
        classical vitamin D deficiency, in the face of normal/high concentrations
        of 1,25-(OH)2 D. Siblings exhibited the three stages of rickets based on
        biochemical and radiographic findings.
      explanation: >-
        Co-locates the corrected metabolic pattern with biochemical and
        radiographic rickets in the affected siblings.
  - target: Hypocalcemia
    causal_link_type: DIRECT
    description: >-
      Inadequate calciotropic support can lower serum calcium or produce
      hypocalcemic manifestations, particularly in severe disease.
    evidence:
    - reference: PMID:15128933
      reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Before treatment, he had low normal serum calcium levels (2.00–2.32 mM;
        normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM;
        normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels
        (2,360–3,000 units/liter; normal range 100–320 units/liter), serum
        1α,25-dihydroxyvitamin D levels (137–142 pM) that were in the normal range
        (48–182 pM), and low 25-hydroxyvitamin D levels (10–12 nM; normal 25–137 nM).
      explanation: >-
        Documents calcium values extending below the stated reference interval in
        the index case with the corrected metabolite pattern.
  - target: Hypophosphatemia
    causal_link_type: DIRECT
    description: >-
      The calciopenic response promotes renal phosphate loss, reducing serum
      phosphate available for mineralization.
    evidence:
    - reference: PMID:15128933
      reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Before treatment, he had low normal serum calcium levels (2.00–2.32 mM;
        normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM;
        normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels
        (2,360–3,000 units/liter; normal range 100–320 units/liter), serum
        1α,25-dihydroxyvitamin D levels (137–142 pM) that were in the normal range
        (48–182 pM), and low 25-hydroxyvitamin D levels (10–12 nM; normal 25–137 nM).
      explanation: >-
        Documents serum phosphate below the stated reference interval in the
        index case.
  - target: Secondary hyperparathyroidism
    causal_link_type: DIRECT
    description: >-
      Compensatory parathyroid-hormone elevation is part of the calciopenic
      response to inadequate effective vitamin D and mineral supply.
    evidence:
    - reference: PMID:32596195
      reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        VDDR1b is associated with hypocalcemia, secondary hyperparathyroidism and
        low plasma concentrations of 25(OH)D, with reduced clinical and biochemical
        responsiveness to conventional doses of vitamin D.
      explanation: >-
        Directly identifies secondary hyperparathyroidism in VDDR1B without
        assigning it a cohort frequency.
- name: Defective Skeletal Mineralization
  description: >-
    Failure to mineralize newly formed osteoid and the growing metaphysis,
    presenting as rickets with the radiographic and clinical features
    indistinguishable from nutritional rickets.
  role: effector
  biological_scale: TISSUE
  conforms_to: "defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front"
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Bone Mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  locations:
  - preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  evidence:
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Siblings exhibited the three stages of rickets based on biochemical and
      radiographic findings.
    explanation: >-
      Reports observed biochemical and radiographic rickets rather than merely a
      study objective.
  downstream:
  - target: Rickets
    causal_link_type: DIRECT
    description: >-
      Failure to mineralize growing osteoid and metaphyses produces the defining
      rachitic phenotype.
    evidence:
    - reference: PMID:28548312
      reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Siblings exhibited the three stages of rickets based on biochemical and
        radiographic findings.
      explanation: >-
        Directly documents the skeletal phenotype downstream of the
        mineralization defect.
  - target: Bone pain
    causal_link_type: DIRECT
    description: >-
      Poorly mineralized bone and deformity commonly produce skeletal pain.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our patients presented with variable symptoms: 25/27 had bone pain, 18 out
        of 27 had limitations of physical activity, and 12 out of 27 presented
        with short stature.
      explanation: >-
        Documents bone pain in the cohort with CYP2R1-related mineralization
        disease.
  - target: Short stature
    causal_link_type: DIRECT
    description: >-
      Chronic growth-plate mineralization failure can impair linear growth.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our patients presented with variable symptoms: 25/27 had bone pain, 18 out
        of 27 had limitations of physical activity, and 12 out of 27 presented
        with short stature.
      explanation: >-
        Documents short stature in the cohort with CYP2R1-related rickets.
  - target: Limitation of physical activity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Bone pain and skeletal deformity can limit physical activity in affected
      individuals.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our patients presented with variable symptoms: 25/27 had bone pain, 18 out
        of 27 had limitations of physical activity, and 12 out of 27 presented
        with short stature.
      explanation: >-
        Documents activity limitation in the CYP2R1 cohort; the edge is indirect
        through pain and deformity rather than a direct cellular effect.
  - target: Bone deformity
    causal_link_type: DIRECT
    description: >-
      Persistent failure of growth-plate and osteoid mineralization can deform
      weight-bearing bone.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Some patients had a severe presentation in the form of bone deformity
        (8/27) and hypocalcemic manifestations (5/27)
      explanation: >-
        Directly reports bone deformity in 8 of 27 affected individuals.
  - target: Gait abnormality
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Pain and lower-limb deformity can disturb gait.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Table 3Comparison between the heterozygous and homozygous (presenting symptoms, biochemical, and radiological abnormalities).Heterozygous (n = 9)Homozygous (n = 18)Presenting symptoms: Bone pain7/918/18 Short stature3/99/18 Limitation of activity5/913/18 Bone deformity1/97/18 Gait abnormality1/96/18Hypocalcemia manifestation (Seizure, carpopedal spasm, muscle cramps, and twitching)0/95/1825-OH vitamin D levels range, nmol/L6–25<6Abnormal bone profile (high parathyroid hormone, low calcium, high alkaline phosphatase)4/916/18Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18 Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18
      explanation: >-
        The subgroup counts sum to gait abnormality in 7 of 27 participants.
  - target: Genu valgum
    causal_link_type: DIRECT
    description: >-
      Rachitic mineralization failure at weight-bearing growth plates can produce
      valgus knee deformity.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18
        Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18
      explanation: >-
        The subgroup counts sum to genu valgum in 8 of 27 participants.
phenotypes:
- category: Skeletal
  name: Rickets
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: PMID:34137732
    reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients described in our study presented with classical clinical,
      biochemical, and radiological features of vitamin D deficiency and
      associated rickets.
    explanation: >-
      Directly documents rickets across the 27-person cohort.
- category: Biochemical
  name: Low circulating 25-hydroxyvitamin D
  description: >-
    The defining biochemical finding; it is shared with nutritional deficiency,
    which is why the disorder is easy to miss.
  phenotype_term:
    preferred_term: Decreased circulating 25-hydroxyvitamin D concentration
    term:
      id: HP:0100512
      label: Decreased circulating vitamin D concentration
  reports_on:
  - target: Hepatic 25-Hydroxylase Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Persistently low 25-hydroxyvitamin D despite adequate exposure or ordinary
      replacement is the circulating readout of impaired 25-hydroxylation.
    evidence:
    - reference: PMID:25942481
      reference_title: CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Heterozygous subjects were less affected than homozygous subjects, and oral
        administration of vitamin D led to significantly lower increases in serum
        25-hydroxyvitamin D in heterozygous than in control subjects, whereas
        homozygous subjects showed negligible increases.
      explanation: >-
        The genotype-dependent failure to raise the measured metabolite links this
        biochemical readout to loss of CYP2R1 activity.
  evidence:
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discuss the difficulties in establishing the correct diagnosis and the
      specific biochemical pattern, namely, very low 25-OH-D suggestive of
      classical vitamin D deficiency, in the face of normal/high concentrations
      of 1,25-(OH)2 D.
    explanation: >-
      Directly reports the very low circulating 25-hydroxyvitamin D that defines
      the phenotype while distinguishing it from the active metabolite.
  - reference: PMID:25942481
    reference_title: CYP2R1 Mutations Impair Generation of 25-hydroxyvitamin D and Cause an Atypical Form of Vitamin D Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous subjects were less affected than homozygous subjects, and oral
      administration of vitamin D led to significantly lower increases in serum
      25-hydroxyvitamin D in heterozygous than in control subjects, whereas
      homozygous subjects showed negligible increases.
    explanation: >-
      Quantifies the failure to raise 25-hydroxyvitamin D on vitamin D
      administration, in a genotype-dependent manner.
- category: Musculoskeletal
  name: Bone pain
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients presented with variable symptoms: 25/27 had bone pain, 18 out
      of 27 had limitations of physical activity, and 12 out of 27 presented
      with short stature.
    explanation: >-
      Bone pain in 25 of 27 patients (93%) in the largest reported CYP2R1
      cohort, a derived count that maps to VERY_FREQUENT (80-100%).
- category: Growth
  name: Short stature
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients presented with variable symptoms: 25/27 had bone pain, 18 out
      of 27 had limitations of physical activity, and 12 out of 27 presented
      with short stature.
    explanation: >-
      Short stature in 12 of 27 patients (44%), a derived count that maps to
      FREQUENT (30-79%).
- category: Functional
  name: Limitation of physical activity
  frequency: FREQUENT
  description: >-
    Reduced ability to perform usual physical activity was reported in 18 of 27
    cohort participants.
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients presented with variable symptoms: 25/27 had bone pain, 18 out
      of 27 had limitations of physical activity, and 12 out of 27 presented
      with short stature.
    explanation: >-
      Activity limitation in 18 of 27 participants (67%) maps to FREQUENT
      (30-79%).
- category: Skeletal
  name: Bone deformity
  description: >-
    Clinically apparent bone deformity was reported in 8 of 27 cohort participants.
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some patients had a severe presentation in the form of bone deformity
      (8/27) and hypocalcemic manifestations (5/27)
    explanation: >-
      Bone deformity occurred in 8 of 27 participants; the exact count is retained
      without assigning a categorical frequency.
- category: Neuromuscular
  name: Gait abnormality
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Table 3Comparison between the heterozygous and homozygous (presenting symptoms, biochemical, and radiological abnormalities).Heterozygous (n = 9)Homozygous (n = 18)Presenting symptoms: Bone pain7/918/18 Short stature3/99/18 Limitation of activity5/913/18 Bone deformity1/97/18 Gait abnormality1/96/18Hypocalcemia manifestation (Seizure, carpopedal spasm, muscle cramps, and twitching)0/95/1825-OH vitamin D levels range, nmol/L6–25<6Abnormal bone profile (high parathyroid hormone, low calcium, high alkaline phosphatase)4/916/18Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18 Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18
    explanation: >-
      Summing heterozygous and homozygous subgroups gives 7 of 27 participants
      (26%), mapping to OCCASIONAL (5-29%).
- category: Skeletal
  name: Genu valgum
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18
      Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18
    explanation: >-
      Summing heterozygous and homozygous subgroups gives 8 of 27 participants;
      the exact count is retained without assigning a categorical frequency.
- category: Biochemical
  name: Secondary hyperparathyroidism
  phenotype_term:
    preferred_term: Secondary hyperparathyroidism
    term:
      id: HP:0000867
      label: Secondary hyperparathyroidism
  evidence:
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR1b is associated with hypocalcemia, secondary hyperparathyroidism and
      low plasma concentrations of 25(OH)D, with reduced clinical and biochemical
      responsiveness to conventional doses of vitamin D.
    explanation: >-
      Directly identifies the compensatory parathyroid response in VDDR1B.
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Table 3Comparison between the heterozygous and homozygous (presenting symptoms, biochemical, and radiological abnormalities).Heterozygous (n = 9)Homozygous (n = 18)Presenting symptoms: Bone pain7/918/18 Short stature3/99/18 Limitation of activity5/913/18 Bone deformity1/97/18 Gait abnormality1/96/18Hypocalcemia manifestation (Seizure, carpopedal spasm, muscle cramps, and twitching)0/95/1825-OH vitamin D levels range, nmol/L6–25<6Abnormal bone profile (high parathyroid hormone, low calcium, high alkaline phosphatase)4/916/18Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18 Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18
    explanation: >-
      The table reports a composite abnormal profile in 20 of 27 participants.
      It does not permit assigning that count to PTH, calcium, or alkaline
      phosphatase individually, so no frequency is inferred here.
- category: Biochemical
  name: Hypocalcemia
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  evidence:
  - reference: PMID:15128933
    reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Before treatment, he had low normal serum calcium levels (2.00–2.32 mM;
      normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM;
      normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels
      (2,360–3,000 units/liter; normal range 100–320 units/liter), serum
      1α,25-dihydroxyvitamin D levels (137–142 pM) that were in the normal range
      (48–182 pM), and low 25-hydroxyvitamin D levels (10–12 nM; normal 25–137 nM).
    explanation: >-
      The reported calcium interval includes values below the stated lower
      reference limit in the index case; no population frequency is inferred.
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some patients had a severe presentation in the form of bone deformity
      (8/27) and hypocalcemic manifestations (5/27)
    explanation: >-
      Supports clinically attributed hypocalcemic manifestations in a subset of
      the cohort. Frequency is deliberately not inferred because the reported
      count is for manifestations rather than measured biochemical hypocalcemia.
- category: Biochemical
  name: Hypophosphatemia
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  evidence:
  - reference: PMID:15128933
    reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Before treatment, he had low normal serum calcium levels (2.00–2.32 mM;
      normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM;
      normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels
      (2,360–3,000 units/liter; normal range 100–320 units/liter), serum
      1α,25-dihydroxyvitamin D levels (137–142 pM) that were in the normal range
      (48–182 pM), and low 25-hydroxyvitamin D levels (10–12 nM; normal 25–137 nM).
    explanation: >-
      Low serum phosphate against the stated reference range in the index case.
      No frequency is asserted: this is a single-patient report.
- category: Biochemical
  name: Elevated circulating alkaline phosphatase
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  reports_on:
  - target: Defective Skeletal Mineralization
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated alkaline phosphatase is a biochemical readout of active rachitic
      bone turnover and impaired mineralization, not a cause of the skeletal lesion.
    evidence:
    - reference: PMID:15128933
      reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Before treatment, he had low normal serum calcium levels (2.00–2.32 mM;
        normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM;
        normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels
        (2,360–3,000 units/liter; normal range 100–320 units/liter), serum
        1α,25-dihydroxyvitamin D levels (137–142 pM) that were in the normal range
        (48–182 pM), and low 25-hydroxyvitamin D levels (10–12 nM; normal 25–137 nM).
      explanation: >-
        Grounds the alkaline-phosphatase readout in the index case's measured
        biochemical and mineral phenotype.
  evidence:
  - reference: PMID:15128933
    reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Before treatment, he had low normal serum calcium levels (2.00–2.32 mM;
      normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM;
      normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels
      (2,360–3,000 units/liter; normal range 100–320 units/liter), serum
      1α,25-dihydroxyvitamin D levels (137–142 pM) that were in the normal range
      (48–182 pM), and low 25-hydroxyvitamin D levels (10–12 nM; normal 25–137 nM).
    explanation: >-
      Alkaline phosphatase roughly tenfold above the stated upper limit in the
      index case. No frequency is asserted: this is a single-patient report.
imaging_findings:
- name: Generalized osteopenia on radiographs
  modality: XRAY
  frequency: FREQUENT
  imaging_finding_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  diagnostic: false
  description: >-
    Generalized radiographic osteopenia was the most common individual imaging
    abnormality in the 27-person cohort.
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18
      Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18
    explanation: >-
      Summing the two zygosity strata gives generalized osteopenia in 15 of 27
      participants (56%), mapping to FREQUENT (30-79%).
- name: Metaphyseal cupping on radiographs
  modality: XRAY
  frequency: OCCASIONAL
  imaging_finding_term:
    preferred_term: Metaphyseal cupping
    term:
      id: HP:0003021
      label: Metaphyseal cupping
  diagnostic: false
  description: >-
    Metaphyseal cupping was present in a minority of the cohort and is an imaging
    sign of active rickets rather than a VDDR1B-specific discriminator.
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological manifestations: Generalized osteopenia2/913/18 Cupping0/94/18
      Geno-valgus1/97/18 Rachitic rosary01/18 Normal7/95/18
    explanation: >-
      Summing the two zygosity strata gives cupping in 4 of 27 participants
      (15%), mapping to OCCASIONAL (5-29%).
diagnosis:
- name: Clinical and biochemical evaluation of refractory calciopenic rickets
  diagnosis_term:
    preferred_term: Clinical Evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >-
    Consider VDDR1B when clinical or radiographic rickets and very low
    25-hydroxyvitamin D persist despite an adequate, adhered-to calcium and vitamin
    D regimen, or when severe vitamin D deficiency clusters in a family. Interpret
    calcium, phosphate, age-adjusted alkaline phosphatase, PTH, 25-hydroxyvitamin D,
    calcitriol, and renal phosphate handling together; normal or high calcitriol
    does not exclude VDDR1B.
  results: >-
    Persistent very low 25-hydroxyvitamin D with a calciopenic rachitic profile and
    inadequate response to ordinary replacement supports CYP2R1 testing but is not
    independently specific for VDDR1B.
  evidence:
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If rickets fails to heal and/or if there is a family history of rickets, then
      refractory rickets should be considered as a differential diagnosis.
    explanation: >-
      Establishes adequate-treatment nonhealing and family history as triggers for
      a refractory-rickets evaluation.
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subjects with calciopenic rickets will have elevated serum levels of PTH,
      which depress the TRP and cause hypophosphatemia. These subjects have either
      inadequate intake of calcium and/or vitamin D or genetic defects that impair
      vitamin D activation or responses (i.e., VDDR).
    explanation: >-
      Supports combined biochemical interpretation rather than diagnosis from an
      isolated vitamin D metabolite.
- name: CYP2R1 molecular genetic confirmation
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: CYP2R1
        term:
          id: hgnc:20580
          label: CYP2R1
  description: >-
    Molecular analysis of CYP2R1 provides confirmation after the clinical,
    biochemical, exposure, and acquired-cause assessment.
    Biallelic pathogenic variants support classic severe VDDR1B; a single variant
    requires phenotype-aware interpretation because heterozygote penetrance and
    severity are variable.
  results: >-
    Pathogenic CYP2R1 variant(s) consistent with the individual's phenotype and
    inheritance establish the molecular diagnosis.
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Confirmation of the diagnosis should be pursued by performing molecular
      analysis of the CYP2R1 gene in the patients and their families.
    explanation: >-
      Directly recommends CYP2R1 molecular analysis for confirmation in patients
      and relatives.
differential_diagnoses:
- name: Nutritional calcium or vitamin D deficiency rickets
  description: >-
    Nutritional rickets is the commonest mimic and can share very low
    25-hydroxyvitamin D and a calciopenic biochemical profile. Adequate calcium and
    vitamin D with adherence should heal ordinary nutritional disease; persistence
    or recurrent dose dependence warrants refractory-rickets evaluation.
  distinguishing_features:
  - Dietary calcium/vitamin D intake, sunlight exposure, and adherence explain most nutritional cases.
  - Failure to heal despite adequate calcium and vitamin D or a strong family history favors a refractory cause such as VDDR1B.
  evidence:
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      By far the commonest cause of rickets is nutritional rickets, due to dietary
      deficiency in calcium and/or vitamin D intake. Therefore, it would be common
      practice, particularly in resource-deprived settings, to treat cases of
      rickets presenting clinically empirically with oral calcium and vitamin D
      supplementation. However, if despite adequate compliance to these regimes,
      rickets persists, then ‘refractory’ causes of rickets must be considered.
    explanation: >-
      Defines the common nutritional mimic and the response-to-adequate-repletion
      boundary for escalating the differential.
- name: Vitamin D-dependent rickets type 1A
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 1A
    term:
      id: MONDO:0020723
      label: vitamin D-dependent rickets, type 1A
  description: >-
    VDDR1A shares calciopenic rickets but reflects CYP27B1 deficiency at the second
    activation step. Its usual profile is normal or elevated 25-hydroxyvitamin D
    with very low calcitriol, unlike the markedly low 25-hydroxyvitamin D and
    variable calcitriol of VDDR1B.
  distinguishing_features:
  - CYP27B1 rather than CYP2R1 pathogenic variants establish VDDR1A.
  - Normal or elevated 25-hydroxyvitamin D with very low calcitriol favors VDDR1A.
  evidence:
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The typical biochemical findings are of hypocalcemia, hypophosphatemia,
      hyperphosphatasia, secondary hyperparathyroidism, and normal or elevated
      25OHD with extremely low 1,25(OH)2D.
    explanation: >-
      Defines the metabolite profile that separates the downstream CYP27B1 block
      from CYP2R1 deficiency.
- name: Vitamin D-dependent rickets type 2A
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 2A
    term:
      id: MONDO:0010186
      label: vitamin D-dependent rickets, type 2A
  description: >-
    VDDR2A can share severe rickets and hypocalcemia but is caused by VDR
    dysfunction. Elevated calcitriol and partial or complete alopecia favor VDDR2A,
    whereas CYP2R1-related VDDR1B has very low 25-hydroxyvitamin D and no defining
    alopecia phenotype.
  distinguishing_features:
  - Biallelic pathogenic VDR variants establish VDDR2A.
  - Markedly elevated calcitriol and alopecia favor receptor resistance rather than CYP2R1 deficiency.
  evidence:
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical features and presentation of VDDR2a are similar to forms of
      VDDR1, except for the presence of partial or complete alopecia that develops
      within the first year of life.
    explanation: >-
      Identifies the principal clinical discriminator for VDR-mediated disease.
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR2a is due to biallelic mutations in VDR, the gene that encodes for the
      vitamin D receptor (VDR), located on chromosome 12q13.11. This results in
      resistance to 1,25(OH)2D.
    explanation: >-
      Establishes the VDR cause and receptor-resistance mechanism.
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The biochemistry of VDDR2a is similar to VDDR1a, except for elevated
      1,25(OH)2D.
    explanation: >-
      Supports elevated calcitriol as a biochemical discriminator.
- name: Vitamin D-dependent rickets type 3
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 3
    term:
      id: MONDO:0033640
      label: vitamin D-dependent rickets, type 3
  description: >-
    VDDR3 is caused by gain-of-function CYP3A4-mediated acceleration of vitamin D
    metabolite inactivation. Both 25-hydroxyvitamin D and calcitriol can be low,
    and molecular testing distinguishes it from deficient CYP2R1 25-hydroxylation.
  distinguishing_features:
  - A pathogenic gain-of-function CYP3A4 variant supports VDDR3 rather than VDDR1B.
  - Low 25-hydroxyvitamin D together with low calcitriol and rapid loss after dosing favors excessive catabolism.
  evidence:
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This has only been recently described as a form of VDDR due to gain-of-function
      mutations in CYP3A4 (located on chromosome 7q22.1), encoding a cytochrome P450
      enzyme, resulting in increased inactivation of vitamin D metabolites.
    explanation: >-
      Establishes the accelerated-catabolism mechanism that distinguishes VDDR3.
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Both affected individuals had detectable serum concentrations of vitamin D3
      but low serum concentrations of 25(OH)D and 1,25(OH)2D that increased after
      administration of very large doses of vitamin D or calcitriol and which
      decreased rapidly thereafter.
    explanation: >-
      Supports the paired low-metabolite and rapid-loss pattern that distinguishes
      excessive catabolism from the VDDR1B pattern.
- name: Phosphopenic rickets from renal phosphate wasting
  description: >-
    FGF23-mediated disorders and proximal renal tubulopathies can cause rickets
    through primary phosphate loss. Age-adjusted phosphate, PTH, calcium,
    25-hydroxyvitamin D, and tubular phosphate reabsorption separate this branch
    from calciopenic VDDR1B.
  distinguishing_features:
  - Normal PTH and calcium with low phosphate favors primary phosphopenic rickets.
  - Reduced tubular phosphate reabsorption identifies genetic or acquired renal phosphate wasting.
  evidence:
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subjects who have hypophosphatemia and normal serum levels of PTH, calcium,
      and 25(OH)D are likely to have phosphopenic rickets; a normal or elevated
      tubular reabsorption of phosphorus (TRP) will be found in subjects with
      inadequate intake or absorption of phosphorus. By contrast, patients with
      XLH and other genetic or acquired causes of renal phosphate wasting will have
      reduced TRP values.
    explanation: >-
      Provides the biochemical and renal-handling distinction from calciopenic
      vitamin D-dependent rickets.
- name: Acquired malabsorption, liver disease, or medication-related rickets and osteomalacia
  description: >-
    Celiac or other malabsorption, liver disease, renal comorbidity, and medications
    affecting vitamin D metabolism or renal phosphate handling can produce acquired
    low-vitamin-D or mineral disease. History and directed testing should exclude
    these causes before attributing nonresponse to inherited CYP2R1 deficiency.
  distinguishing_features:
  - Gastrointestinal, hepatic, or renal disease provides an acquired explanation for the biochemical pattern.
  - Antiepileptic or other enzyme-inducing medication exposure favors drug-associated osteomalacia.
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We excluded patients who had nutritional, malabsorption, or comorbidity
      factors (i.e. celiac disease, liver disease, or renal failure), and patients
      who were on anti-epileptic medications.
    explanation: >-
      Shows the acquired and exposure-related causes excluded in the molecular
      CYP2R1 cohort.
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CYP3A4 has also been shown in in vitro studies to be the enzyme induced by
      P450-inducing drugs (such as rifampicin, carbamazepine and phenobarbital) to
      result in drug-induced osteomalacia.
    explanation: >-
      Directly identifies common enzyme-inducing medications as an acquired
      vitamin D catabolism differential.
treatments:
- name: Calcifediol Replacement
  description: >-
    Calcifediol (25-hydroxyvitamin D3) supplies the product of the blocked
    reaction directly. It is the most specific biochemical bypass when available.
    A seven-patient study reported clinical, biochemical and densitometric
    improvement, while long-term comparative data remain limited.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcidiol
      term:
        id: CHEBI:17933
        label: calcidiol
  evidence:
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For the first time, and according to the concept of personalized medicine,
      we demonstrate dramatic improvements in patients who were given 25-OH-D
      therapy (clinical symptoms, biochemical data, and bone densitometry).
    explanation: >-
      Reports improvement after direct replacement with the missing
      25-hydroxylated metabolite.
  target_mechanisms:
  - target: Hepatic 25-Hydroxylase Deficiency
    treatment_effect: BYPASSES
    description: >-
      Supplying 25-hydroxyvitamin D downstream of CYP2R1 bypasses the deficient
      hepatic reaction rather than attempting to restore the mutant enzyme.
    evidence:
    - reference: PMID:28548312
      reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        For the first time, and according to the concept of personalized medicine,
        we demonstrate dramatic improvements in patients who were given 25-OH-D
        therapy (clinical symptoms, biochemical data, and bone densitometry).
      explanation: >-
        Direct product replacement provides clinical evidence for bypassing the
        25-hydroxylase defect.
- name: High-Dose Parent Vitamin D with Calcium Supplementation
  description: >-
    Pharmacological cholecalciferol or ergocalciferol can produce clinical and
    biochemical responses. Increased flux through partially active CYP2R1 and/or
    alternative 25-hydroxylases is a plausible interpretation of that response,
    not a directly measured patient mechanism. Response and maintenance dose vary
    by genotype and age: a Saudi cohort commonly relapsed when doses were reduced,
    whereas other adults maintained mineral homeostasis without ongoing
    supplementation. Calcium is co-administered or optimized according to mineral
    status; monitoring guides the dose and guards against overtreatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholecalciferol
      term:
        id: CHEBI:28940
        label: calciol
    - preferred_term: ergocalciferol
      term:
        id: CHEBI:28934
        label: vitamin D2
    - preferred_term: calcium(2+)
      term:
        id: CHEBI:29108
        label: calcium(2+)
  evidence:
  - reference: PMID:38440125
    reference_title: Novel Mutation in CYP2R1 Causing Vitamin D-Dependent Rickets Type 1b.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The children were treated with oral calcium and cholecalciferol, dose
      titrated to maintain serum alkaline phosphatase, 25 hydroxy vitamin D, and
      parathyroid hormone levels in the normal range, with good clinical and
      radiological response.
    explanation: >-
      Documents monitored cholecalciferol-plus-calcium therapy with clinical and
      radiological improvement in affected siblings.
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, adult patients were able to maintain normal mineral
      metabolism without vitamin D supplementation.
    explanation: >-
      Qualifies the Saudi cohort's lifelong-maintenance observation by documenting
      age-related improvement without supplementation in another family series.
  - reference: PMID:34137732
    reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We noticed a symptomatic and biochemical improvement in all heterozygous
      patients after treatment with supra-therapeutic doses of vitamin D (i.e.
      50,000–100,000 IU of vitamin D2 weekly) for 8–12 weeks, regardless of their
      mutation, and none of them required calcitriol (1,25-[OH]2 vitamin D),
      whereas the homozygous group required more frequent therapy in the form of
      weekly to twice monthly maintenance high-dose vitamin D therapy, and some of
      them needed calcitriol for a lifetime.
    explanation: >-
      Documents ergocalciferol response and genotype-dependent maintenance needs
      in the Saudi cohort.
  target_mechanisms:
  - target: Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling
    treatment_effect: RESTORES
    description: >-
      High-dose parent vitamin D produced clinical and biochemical responses in
      most of this cohort, while calcium supplementation supports mineral supply.
      Increased flux through residual CYP2R1 and/or alternative 25-hydroxylases is
      a plausible explanation, not a pathway measurement in these patients.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thirteen out of 18 homozygous patients and all the heterozygous patients
        responded to high doses of vitamin D treatment, but they regressed after
        decreasing the dose, requiring lifelong therapy.
      explanation: >-
        Supports the observed restoration by high-dose parent vitamin D while
        showing that maintenance requirements were cohort- and genotype-dependent;
        it does not identify which hydroxylase carried the increased flux.
- name: Calcitriol for Selected Parent-Vitamin-D Nonresponders
  description: >-
    Calcitriol is not routine replacement for an obligatorily low calcitriol
    concentration: the biomarker is variable in VDDR1B, and normal or high values
    do not exclude the disorder. It can bypass both activation steps in selected
    patients whose biochemical abnormalities do not improve with high-dose parent
    vitamin D. The Saudi cohort used closer follow-up and annual renal
    ultrasonography to watch for calcification or nephrolithiasis during treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
  evidence:
  - reference: PMID:34137732
    reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five out of 18 homozygous patients required calcitriol to improve their
      biochemical data, whereas none of the heterozygous patients and patients who
      carried the c.367+1G>A mutation required calcitriol treatment.
    explanation: >-
      Restricts calcitriol to the documented nonresponding subgroup rather than
      presenting it as universal therapy.
  - reference: PMID:34137732
    reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients required closer follow-up and renal ultrasonography every
      year to check for signs of calcifications or nephrolithiasis, which was
      negative in all patients receiving calcitriol.
    explanation: >-
      Supports renal surveillance during calcitriol therapy while noting that no
      calcification was observed in this cohort.
  target_mechanisms:
  - target: Reduced 25-Hydroxyvitamin D Availability and Calciopenic Signaling
    treatment_effect: BYPASSES
    description: >-
      Active hormone replacement bypasses both hepatic 25-hydroxylation and renal
      1-alpha-hydroxylation to restore downstream receptor signaling.
    evidence:
    - reference: PMID:34137732
      reference_title: '25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Five out of 18 homozygous patients required calcitriol to improve their
        biochemical data, whereas none of the heterozygous patients and patients who
        carried the c.367+1G>A mutation required calcitriol treatment.
      explanation: >-
        Improvement in parent-vitamin-D nonresponders supports use of calcitriol as
        a downstream bypass in selected patients.
animal_models:
- name: Cyp2r1-null mouse
  species: Mouse
  genotype: Homozygous Cyp2r1 knockout
  publication: PMID:24019477
  description: >-
    A whole-animal test of CYP2R1's contribution to vitamin D activation. The
    knockout lowers serum 25-hydroxyvitamin D3 by more than half but leaves
    calcitriol unchanged, demonstrating both CYP2R1's major role and substantial
    CYP2R1-independent 25-hydroxylation. The abstract reports no overt health
    issues, but it does not establish whether skeletal endpoints were assessed.
  evidence:
  - reference: PMID:24019477
    reference_title: CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We have now produced Cyp2r1 (-/-) mice.
    explanation: >-
      Establishes the whole-animal knockout used to test CYP2R1 function.
  modeled_mechanisms:
  - target: Hepatic 25-Hydroxylase Deficiency
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Recapitulates reduced circulating 25-hydroxyvitamin D while showing that the
      pathway is not abolished and that calcitriol can remain regulated.
    limitations: >-
      The null mouse retains a substantial residual fraction of circulating
      25-hydroxyvitamin D3 and has no reported overt illness, whereas humans with
      severe biallelic CYP2R1 variants can develop rickets. Diet, species-specific
      alternative hydroxylases and unreported skeletal phenotyping in the abstract
      leave skeletal fidelity unassessed.
    readouts:
    - name: Serum 25-hydroxyvitamin D3 concentration
      target: Hepatic 25-Hydroxylase Deficiency
      direction: DECREASED
      interpretation: >-
        A greater-than-50% reduction demonstrates that CYP2R1 is a major, but not
        exclusive, source of circulating 25-hydroxyvitamin D3 in mice.
      evidence:
      - reference: PMID:24019477
        reference_title: CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          These mice had greater than 50% reduction in serum 25-hydroxyvitamin D3.
        explanation: >-
          Reports the direction and magnitude of the metabolite readout.
    - name: Serum 1-alpha,25-dihydroxyvitamin D3 concentration
      target: Hepatic 25-Hydroxylase Deficiency
      direction: UNCHANGED
      interpretation: >-
        Preserved active hormone despite loss of Cyp2r1 argues against treating
        calcitriol deficiency as an obligatory consequence of this lesion.
      evidence:
      - reference: PMID:24019477
        reference_title: CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Curiously, the 1α,25-dihydroxyvitamin D3 level in the serum remained
          unchanged.
        explanation: >-
          Directly reports the unchanged active-hormone readout.
    evidence:
    - reference: PMID:24019477
      reference_title: CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results support the idea that the CYP2R1 is the major enzyme
        responsible for 25-hydroxylation of vitamin D, but clearly a second,
        as-yet unknown, enzyme is another contributor to this important step in
        vitamin D activation.
      explanation: >-
        Supports partial rather than complete recapitulation of the human
        25-hydroxylase lesion.
discussions:
- discussion_id: cyp2r1_mouse_human_severity_mismatch
  prompt: >-
    Do Cyp2r1-null mice develop a skeletal mineralization defect under the studied
    conditions, or were the relevant skeletal endpoints simply not assessed?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Hepatic 25-Hydroxylase Deficiency
  - pathophysiology#Defective Skeletal Mineralization
  rationale: >-
    The mouse establishes that CYP2R1 is a major 25-hydroxylase, but its residual
    metabolite production and preserved calcitriol coexist with a report of no
    overt health issues. That abstract-level statement is not a skeletal
    assessment and cannot support a negative mineralization result. Humans can
    develop a mineralization defect despite retaining normal or high calcitriol;
    whether mice differ because of stronger alternative 25-hydroxylation, dietary
    rescue, developmental timing, or merely unmeasured skeletal endpoints remains
    open.
  proposed_experiments:
  - experiment_id: exp_cyp2r1_cross_species_hydroxylase_flux
    name: Cross-species mapping of residual vitamin D 25-hydroxylation
    description: >-
      Compare isotope-traced vitamin D-to-25-hydroxyvitamin D flux and expression
      of candidate alternative hydroxylases in Cyp2r1-null mouse hepatocytes and
      CYP2R1-deficient patient-derived hepatocyte models under matched substrate
      concentrations.
    decision_criterion: >-
      Greater residual flux in mouse cells, reversible by perturbing a candidate
      alternative hydroxylase, would support species-specific enzymatic
      compensation; similar flux would shift attention to diet and mineral
      homeostasis.
    evidence:
    - reference: PMID:24019477
      reference_title: CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results support the idea that the CYP2R1 is the major enzyme
        responsible for 25-hydroxylation of vitamin D, but clearly a second,
        as-yet unknown, enzyme is another contributor to this important step in
        vitamin D activation.
      explanation: >-
        Grounds the proposed cross-species flux experiment in the demonstrated
        residual, unidentified hydroxylase activity.
  - experiment_id: exp_cyp2r1_mouse_skeletal_stress_test
    name: Longitudinal skeletal phenotyping under controlled vitamin D and calcium intake
    description: >-
      Phenotype Cyp2r1-null and wild-type mice across growth using matched,
      controlled vitamin D and calcium diets, serial mineral biochemistry,
      radiography and growth-plate histomorphometry.
    decision_criterion: >-
      Emergence of rickets only under restricted substrate or mineral intake would
      identify dietary rescue in the original model; persistently normal skeletons
      despite low 25-hydroxyvitamin D would support species-specific compensation.
    evidence:
    - reference: PMID:24019477
      reference_title: CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These mice presented no health issues.
      explanation: >-
        Grounds the need for sensitive skeletal phenotyping beyond the reported
        absence of overt illness.
    - reference: PMID:28548312
      reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Siblings exhibited the three stages of rickets based on biochemical and
        radiographic findings.
      explanation: >-
        Supplies the human skeletal endpoint that the proposed mouse experiment
        must test under controlled conditions.
  evidence:
  - reference: PMID:24019477
    reference_title: CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These mice had greater than 50% reduction in serum 25-hydroxyvitamin D3.
      Curiously, the 1α,25-dihydroxyvitamin D3 level in the serum remained
      unchanged. These mice presented no health issues.
    explanation: >-
      Defines the murine biochemical phenotype and the abstract's broad report of
      no health issues; it does not establish a negative skeletal endpoint.
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Siblings exhibited the three stages of rickets based on biochemical and
      radiographic findings.
    explanation: >-
      Provides the contrasting human skeletal phenotype that makes translation
      from the knockout uncertain.
biochemical:
- name: 25-hydroxyvitamin D (calcifediol)
  presence: Decreased
  biomarker_term:
    preferred_term: 25-Hydroxyvitamin D Measurement
    term:
      id: NCIT:C92268
      label: 25-Hydroxyvitamin D Measurement
  context: >-
    Low, because the hepatic 25-hydroxylation that produces it is the blocked
    step. This is the measurement type 1B shares with nutritional deficiency and
    the one that separates it from type 1A, where 25-hydroxyvitamin D is normal
    or high because the substrate accumulates behind a later block.
  evidence:
  - reference: PMID:34137732
    reference_title: "25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We analyzed 27 patients from nine different families who presented with
      low 25-OH vitamin D and not responding to usual treatment.
    explanation: >-
      Low 25-hydroxyvitamin D together with non-response to usual treatment is
      the presenting biochemical signature of the cohort.
- name: 1,25-dihydroxyvitamin D (calcitriol)
  presence: Variable
  biomarker_term:
    preferred_term: 1,25-Dihydroxyvitamin D3 Measurement
    term:
      id: NCIT:C179754
      label: 1,25-Dihydroxyvitamin D3 Measurement
  context: >-
    Published guidance classifies calcitriol as variable, so lower values can
    occur. Normal calcitriol was reported in the index case and untreated adults,
    and another series describes normal or high concentrations despite very low
    25-hydroxyvitamin D. Residual 25-hydroxylation and renal regulation may
    preserve active hormone despite the upstream block. Normal or elevated
    calcitriol therefore does not exclude this disorder, and measuring it alone
    would be misleading.
  evidence:
  - reference: PMID:15128933
    reference_title: Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Before treatment, he had low normal serum calcium levels (2.00–2.32 mM;
      normal range 2.12–2.62 mM), low serum phosphate levels (0.84–0.87 mM;
      normal range 0.97–1.45 mM), elevated serum alkaline phosphatase levels
      (2,360–3,000 units/liter; normal range 100–320 units/liter), serum
      1α,25-dihydroxyvitamin D levels (137–142 pM) that were in the normal range
      (48–182 pM), and low 25-hydroxyvitamin D levels (10–12 nM; normal 25–137 nM).
    explanation: >-
      Reports calcitriol within the stated normal range alongside low
      25-hydroxyvitamin D in the index case.
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discuss the difficulties in establishing the correct diagnosis and the
      specific biochemical pattern, namely, very low 25-OH-D suggestive of
      classical vitamin D deficiency, in the face of normal/high concentrations
      of 1,25-(OH)2 D.
    explanation: >-
      Directly supports the normal-or-high range and corrects the prior assertion
      that calcitriol is necessarily deficient.
  - reference: PMID:32430692
    reference_title: Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With Vitamin D 25-Hydroxylase Deficiency (CYP2R1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These three patients had undetectable 25-OH vitamin D, but normal levels of
      plasma 1-25(OH)2 vitamin D.
    explanation: >-
      Extends the normal-calcitriol observation to three untreated adults with
      undetectable 25-hydroxyvitamin D.
  - reference: PMID:37074534
    reference_title: Refractory Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Table 3Summary of genotype, biochemical differences and treatment options for each form of vitamin D-dependent ricketsInheritanceGene25OHD*1,25(OH)2DTreatmentVDDR1a (OMIM 264700)AR
      CYP27B1
      Variable↓ (occasionally normal)Preferably calcitriol/alfacalcidolHigh doses of D2/D3 can be used insteadCalcium supplementationVDDR1b (OMIM 600081)AR
      CYP2R1
      ↓↓VariableCalcitriol of very high doses of D2/D3More recently, calcifediolCalcium supplementationVDDR2a (OMIM 277440)AR
      VDR
      Normal/↑↑↑Very high doses of calcitriol/alfacalcidolHigh doses of calcium supplementation (may be required intravenously)VDDR2b (OMIM 600785)ARUnknownNormal/↑↑↑Very high doses of calcitriol/alfacalcidolHigh doses of calcium supplementation (may be required intravenously)VDDR3 (OMIM 619073)AD
      CYP3A4
      ↓↓Very high doses of calcitriol/alfacalcidol or D2/D3Calcium supplementation*Can also be affected by vitamin D intake1,25(OH)2D 1,25-dihydroxyvitamin D, 25OHD 25-hydroxyvitamin D, AD Autosomal dominant, AR Autosomal recessive, D2/D3 Ergocalciferol/Cholecalciferol, VDDR Vitamin D-dependent rickets↓ Reduced, ↑ Elevated, ↓↓ Markedly reduced, ↑↑ Markedly elevated
    explanation: >-
      The review's VDDR1B comparison table explicitly classifies 1,25(OH)2D as
      variable, preventing normal/high case series from becoming an exclusive
      biochemical rule and allowing lower reported values.
notes: >-
  Nomenclature caution: MONDO carries "vitamin D hydroxylation-deficient rickets"
  as an EXACT synonym of the rickets umbrella MONDO:0005520 as well as being the
  label stem of this term, MONDO:0010810. Curators resolving that string must
  disambiguate before binding it.
📚

References & Deep Research

Deep Research

1
Claude Code ▸
Vitamin D-Dependent Rickets Type 1B (VDDR1B) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-08-19T18:06:41.208544

Vitamin D-Dependent Rickets Type 1B (VDDR1B) — Comprehensive Research Report

1. Disease Information

Overview. Vitamin D-dependent rickets type 1B (VDDR1B), also called vitamin D 25-hydroxylase deficiency or "selective 25-hydroxyvitamin D deficiency," is an autosomal recessive inborn error of vitamin D metabolism caused by loss-of-function variants in CYP2R1, which encodes the principal hepatic microsomal vitamin D 25-hydroxylase (Cheng et al., PNAS 2004, PMID:15128933). Loss of this enzyme activity blocks the first obligatory activation step of vitamin D — hydroxylation of vitamin D3/D2 at carbon-25 to form 25-hydroxyvitamin D [25(OH)D] — producing a phenotype that is clinically and radiographically indistinguishable from nutritional vitamin D deficiency rickets but that fails to respond, or responds only poorly, to conventional-dose vitamin D3 supplementation (Molin et al., J Bone Miner Res 2017, PMID:28548312).

Key identifiers: - OMIM: #600081 (VDDR1B, phenotype); 608713 (CYP2R1, gene) - MONDO: MONDO:0010810 - Gene: CYP2R1 (HGNC:20586), chromosome 11p15.2 - Orphanet: ORPHA:289320 (Vitamin D-dependent rickets type 1B) - ICD-10: E55.0 (Rickets, active) is used generically; no VDDR1B-specific code exists - MeSH:* Rickets (D012279); Vitamin D Deficiency (D014808)

Synonyms: 25-hydroxylase deficiency rickets; vitamin D 25-hydroxylase deficiency; selective 25-hydroxyvitamin D deficiency; CYP2R1 deficiency rickets; hereditary vitamin D-resistant rickets type 1B (this last term is discouraged since VDDR1B is not a vitamin-D-resistant disorder but a synthesis defect).

Data provenance: Essentially all published knowledge derives from individual patient/family case reports and small case series (the largest being 27 subjects from 9 Saudi families; Alzahrani et al. 2021, PMID:34137732), rather than population/aggregate registries — VDDR1B is exceedingly rare, with fewer than 40 molecularly confirmed patients reported worldwide as of 2024.

2. Etiology

Disease Causal Factors

VDDR1B is monogenic: biallelic (homozygous or compound heterozygous) loss-of-function variants in CYP2R1 abolish or severely reduce hepatic 25-hydroxylase activity (Cheng et al. 2004, PMID:15128933; Thacher et al., JCEM 2015, PMID:25942481). A subset of reported heterozygous carriers also show a milder, incompletely penetrant biochemical phenotype (blunted 25(OH)D response to vitamin D3 loading), suggesting semi-dominant/haploinsufficiency effects for some alleles (Thacher et al. 2015, PMID:25942481).

Genetic Risk Factors

Reported pathogenic variants (all in CYP2R1, NM_024514): - p.Leu99Pro (L99P, c.296T>C) — the most recurrent pathogenic allele, first reported homozygous in a Nigerian child (Cheng et al. 2004) and subsequently in Moroccan and additional Nigerian families (homozygous in 3, heterozygous in 6, across 2 generations of 2 Nigerian families; Thacher et al. 2015, PMID:25942481; Molin et al. 2017, PMID:28548312). In vitro expression shows normal protein levels but essentially abolished 25-hydroxylase activity. - p.Lys242Asn (K242N) — identified in a second Nigerian family; markedly reduced (not abolished) enzymatic activity in vitro (Thacher et al. 2015, PMID:25942481). - c.367+1G>A (splice donor) and c.768dupT (frameshift) — the two founder-like alleles accounting for the majority of the 27 Saudi Arabian patients from 9 families (12/27 and 15/27 patients respectively; 18 homozygous, 9 heterozygous carriers with biochemical abnormalities) (Alzahrani et al. 2021, PMID:34137732; earlier reported by Al Mutair et al., JCEM 2012, PMID:22855339, as compound heterozygous splice-site + frameshift mutations in a Saudi sibship). - Deletion/insertion (indel) mutation — homozygous in a French family reported by Molin et al. 2017 (PMID:28548312), alongside the recurrent L99P allele in a Moroccan family (7 patients, 2 families total). - c.50_51insTCGGCGGCGC (p.Leu18ArgfsTer79) — a novel frameshift variant, homozygous, reported in two siblings from India — the first molecularly confirmed VDDR1B case from Asia (JCEM Case Reports 2024, PMID:38440125). - Additional novel missense and truncating variants have been reported in isolated case reports through 2021 ("New Variants of the CYP2R1 Gene…", PMC8699237).

Population/allele frequency: Because reported alleles are private or regionally clustered (Nigeria, Saudi Arabia/Gulf, Morocco, France, India), none reach appreciable frequency in gnomAD; most pathogenic alleles are absent or present only as rare heterozygotes in population reference databases, consistent with a fully penetrant recessive Mendelian disease.

Environmental Risk Factors

No independent environmental cause exists for VDDR1B itself (it is monogenic), but the biochemical/clinical severity is strongly modulated by cutaneous vitamin D3 synthesis (sun exposure) and dietary vitamin D intake — because CYP2R1-null patients still retain a minor, CYP2R1-independent route of 25-hydroxylation (via CYP27A1 and other hepatic/extrahepatic P450s), higher substrate (vitamin D3) availability can partially compensate. This is the biochemical rationale for supraphysiologic vitamin D3 dosing as first-line therapy, and it is also why the phenotype can be misdiagnosed as ordinary nutritional rickets when a family history or lack of vitamin D3-dose response is not recognized (Molin et al. 2017, PMID:28548312 — explicitly framed as "a rare condition or a misdiagnosed condition").

Protective Factors

No specific genetic protective alleles have been described for VDDR1B. High cutaneous/dietary vitamin D3 substrate supply is the main modifiable factor mitigating severity, since residual (non-CYP2R1) 25-hydroxylase activity is substrate-driven.

Gene-Environment Interactions

The core gene-environment interaction is substrate-dependent enzymatic bypass: because a second, lower-affinity/lower-capacity 25-hydroxylation pathway exists (demonstrated definitively in Cyp2r1-knockout mice, which retain ~50% of normal serum 25(OH)D3 rather than none; Zhu et al., PNAS 2013, PMID:24019477), increasing vitamin D3 intake to supraphysiologic levels can drive meaningful 25(OH)D production even in the near-total absence of CYP2R1 activity. Homozygous L99P patients show a markedly blunted (but not entirely absent) rise in 25(OH)D after oral vitamin D3 loading compared with heterozygotes (Thacher et al. 2015, PMID:25942481), directly demonstrating gene-dose/substrate interaction.

3. Phenotypes

Phenotype Type HPO term Onset/Notes
Rickets (radiographic) Sign/imaging HP:0002748 (Rickets) Typically infancy–early childhood; metaphyseal fraying/cupping
Tibial bowing Sign HP:0002979 (Bowing of the legs) Reported as early as age 2 y in the Nigerian kindred, symptomatic by 12.5 y (Thacher 2015)
Leg pain Symptom HP:0002829 (Arthralgia)/HP:0030836 (limb pain, if available) Presenting complaint in several reports
Rachitic rosary (rib beading) Sign HP:0000895 (Beading of ribs) Classic rachitic finding
Wrist/metaphyseal enlargement Sign HP:0003037 (Metaphyseal widening)/HP:0005034 (wide wrist)
Failure to thrive Sign HP:0001508 More prominent in infantile-onset/severe cases
Hypotonia / muscle weakness Sign HP:0001324 (Muscle weakness), HP:0001252 (Hypotonia)
Hypocalcemic seizures Sign HP:0002917 (Hypocalcemia) → HP:0032669 or HP:0001250 (Seizure) Reported in severe/early presentations, more typical of VDDR1A but described in VDDR1B too
Low serum 25(OH)D Lab abnormality HP:0100511 (Abnormality of vitamin D metabolism) — closest available; consider a custom biochemical descriptor Hallmark, disproportionately low relative to sun/diet exposure and unresponsive to standard-dose vitamin D3
Hypocalcemia Lab abnormality HP:0002901
Hypophosphatemia Lab abnormality HP:0002148 Secondary to hyperparathyroidism-driven renal phosphate wasting
Elevated alkaline phosphatase Lab abnormality HP:0003155
Secondary hyperparathyroidism (elevated PTH) Lab abnormality HP:0000870 Compensatory response to hypocalcemia
Normal-to-low 1,25(OH)2D Lab abnormality (distinguishing) — Distinguishes from VDDR1A, where 1,25(OH)2D is disproportionately low/undetectable despite normal CYP27B1 substrate

Characteristics: - Onset: Predominantly infantile/early childhood, though several reported cases (Nigerian kindred, Molin et al. 2017 French/Moroccan families) presented in later childhood/adolescence with milder or slowly progressive disease, and at least one adult cohort has been studied for long-term skeletal consequences (Wiedemann et al., Calcif Tissue Int 2020, PMID:32430692). - Severity/course: Variable — homozygotes for null alleles (e.g., L99P homozygotes) show more severe biochemical deficiency and more blunted treatment response than heterozygotes; disease is generally described as progressive if untreated, but non-progressive/stable once adequately treated with high-dose vitamin D3. - Frequency of individual phenotypes: Given the very small published cohorts (n≤27), only qualitative/case-count frequencies are available rather than validated percentage estimates; rickets, bowing, and biochemical hypovitaminosis D are near-universal among reported homozygotes, while seizures are less consistently reported. - Quality of life: Not systematically studied with validated instruments (no EQ-5D/SF-36/PROMIS data identified in the literature); qualitatively, adequately treated patients show good clinical/radiographic recovery ("rickets heal" — Thacher et al. 2015), and Wiedemann et al. 2020 (PMID:32430692) specifically found that prolonged 25-OH-vitamin D deficiency in treated adults did not impair bone mineral density, suggesting a favorable long-term skeletal prognosis with treatment.

4. Genetic/Molecular Information

Causal gene: CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1), HGNC:20586, OMIM *608713, chromosome 11p15.2. Encodes a microsomal (endoplasmic-reticulum-anchored) cytochrome P450 monooxygenase expressed predominantly in liver, with lower expression in numerous extrahepatic tissues (skin, testis, adipose, etc.).

Variant classification/type (per ACMG/AMP, as reported in the literature and ClinVar): - Missense: p.Leu99Pro (ClinVar RCV000002216, pathogenic), p.Lys242Asn - Frameshift: c.768dupT (p.Leu257Serfs*6; ClinVar VCV000977185), c.50_51insTCGGCGGCGC (p.Leu18ArgfsTer79) - Splice-site: c.367+1G>A (canonical splice-donor loss) - Indel: the French-family deletion/insertion reported by Molin et al. 2017

Functional consequences: In vitro heterologous expression studies (COS-7/HEK293 systems) show that pathogenic missense alleles (L99P) can retain normal protein expression levels while exhibiting complete loss of 25-hydroxylase catalytic activity, whereas K242N shows markedly reduced but not abolished activity — consistent with the somewhat milder phenotype variability seen clinically (Thacher et al. 2015, PMID:25942481). Frameshift/splice alleles are predicted to cause nonsense-mediated decay or truncated, non-functional protein (Al Mutair et al. 2012, PMID:22855339).

Allele frequency/population data: No pathogenic CYP2R1 allele associated with VDDR1B reaches polymorphic frequency in gnomAD/1000 Genomes/TOPMed; each is essentially private to the reporting family or regional cluster (Nigeria: L99P, K242N; Saudi Arabia: c.367+1G>A, c.768dupT; Morocco: L99P; France: indel; India: p.Leu18ArgfsTer79). This contrasts with common regulatory/coding CYP2R1 SNPs (e.g., rs10741657, rs2060793) that are well-studied GWAS hits for population variation in circulating 25(OH)D and are unrelated to the Mendelian disease.

Somatic vs. germline: Germline only; VDDR1B is not associated with somatic mosaicism or malignancy.

Modifier genes: None formally established; residual 25-hydroxylation via CYP27A1 and other minor hepatic/extrahepatic hydroxylases (demonstrated in the Cyp2r1/Cyp27a1 double-knockout mouse model — Zhu et al. 2013, PMID:24019477) functionally modifies phenotype severity but is not itself a defined "modifier gene" locus in humans.

Epigenetic information: Not disease-specific for VDDR1B; general regulatory studies show hepatic CYP2R1 expression is repressed by obesity/metabolic stress and streptozotocin-induced diabetes in mouse models (unrelated to the Mendelian disorder but relevant to acquired/relative 25(OH)D deficiency).

Chromosomal abnormalities: None reported; VDDR1B is caused by intragenic point/small indel variants, not large structural rearrangements.

Protein structure: The crystal structure of CYP2R1 in complex with vitamin D3 (Strushkevich et al., J Mol Biol 2008, PMID:18511070) shows the canonical CYP fold (12 core α-helices, β-sheet subdomains, heme buried centrally), a closed conformation with the substrate-access channel gated by the B′-helix, and vitamin D3 bound in an elongated pose with its aliphatic side chain oriented toward the heme iron for regiospecific C25 hydroxylation — explaining the enzyme's narrow substrate specificity and the structural basis by which active-site missense variants (e.g., L99P, which lies near a substrate-contacting region) abolish catalysis.

Suggested ontology terms: HGNC:20586 (CYP2R1); GO:0034653 (retinoic acid catabolic process — off-target; correct term: GO:0042359, vitamin D metabolic process); GO:0034644 (cellular response to UV); molecular function GO:0004497 (monooxygenase activity), GO:0070576 (vitamin D 25-hydroxylase activity, if available as a specific GO term); UniProt Q6VVW9 (mouse) / Q9UF56 (human CYP2R1); CHEBI:28934 (cholecalciferol/vitamin D3), CHEBI:17933 (25-hydroxyvitamin D3, calcifediol).

5. Environmental Information

  • Environmental factors: Not disease-causing (VDDR1B is monogenic), but sunlight (UVB) exposure and dietary vitamin D intake determine substrate availability for the minor CYP2R1-independent 25-hydroxylation pathway and are the basis of the high-dose vitamin D3 treatment strategy.
  • Lifestyle factors: Reduced sun exposure or low dietary vitamin D intake would be expected to unmask/worsen the phenotype in genetically predisposed individuals, though this has not been rigorously quantified for VDDR1B specifically (unlike common nutritional rickets).
  • Infectious agents: None implicated.

6. Mechanism / Pathophysiology

Causal chain: 1. Initial defect (molecular/enzymatic): Biallelic loss-of-function CYP2R1 variants abolish or severely impair hepatic microsomal vitamin D 25-hydroxylase activity (GO:0004497 monooxygenase activity; the enzyme catalyzes NADPH-cytochrome P450 reductase-dependent hydroxylation at C25 of the vitamin D side chain). 2. Biochemical consequence: Failure to convert vitamin D3 (cholecalciferol, from skin/diet) to 25-hydroxyvitamin D3 [25(OH)D3, calcifediol] — the major circulating vitamin D metabolite and substrate for renal 1α-hydroxylase (CYP27B1). Serum 25(OH)D falls to deficient/near-undetectable levels despite normal or even excess vitamin D3 precursor availability (Cheng et al. 2004, PMID:15128933). 3. Downstream hormonal consequence: Reduced 25(OH)D substrate limits renal CYP27B1-mediated production of the active hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, calcitriol], though residual (non-CYP2R1) 25-hydroxylation and compensatory renal 1α-hydroxylase upregulation can partially buffer 1,25(OH)2D3 levels — hence 1,25(OH)2D3 may be low-normal rather than undetectable (distinguishing VDDR1B biochemically from the more profound calcitriol deficiency of VDDR1A/CYP27B1 deficiency). 4. Cellular/tissue consequence: Reduced calcitriol-VDR (vitamin D receptor, NR1I1) signaling in intestinal enterocytes decreases active transcellular calcium (and secondarily phosphate) absorption (biological process: GO:0070508, cholesterol import; more relevantly GO:0006816 calcium ion transport and GO:0030299 intestinal cholesterol absorption analogs — the specific relevant GO term is GO:0033280, response to vitamin D). 5. Systemic consequence — mineral homeostasis: Reduced intestinal calcium absorption → hypocalcemia → compensatory secondary hyperparathyroidism (elevated PTH) → renal phosphate wasting → hypophosphatemia, and PTH-driven increased bone turnover contributing to elevated serum alkaline phosphatase. 6. Tissue-level outcome — impaired mineralization: Combined hypocalcemia/hypophosphatemia impair hydroxyapatite deposition at the growth-plate mineralization front, producing the rachitic growth-plate histology (widened, disorganized hypertrophic chondrocyte zone) and osteomalacic changes in cortical/trabecular bone, manifesting clinically as rickets, bowing, rachitic rosary, and growth-plate widening.

Cell types involved (CL terms): hepatocyte (CL:0000182, site of primary enzymatic defect), enterocyte/intestinal absorptive cell (CL:0000584, target of reduced calcitriol signaling), chondrocyte — growth plate hypertrophic chondrocyte (CL:0000138, site of impaired mineralization), osteoblast (CL:0000062) and osteoclast (CL:0000092, bone remodeling/turnover), chief cell of parathyroid gland (CL:1000398, source of compensatory PTH secretion), and renal proximal tubule epithelial cell (CL:1001016, site of CYP27B1 1α-hydroxylation and, secondarily, PTH-driven phosphate wasting).

Anatomical/organ correlate: This causal chain maps directly onto dismech's defective_skeletal_mineralization module (the calciopenic arm — nutritional-vitamin-D-deficiency-analogous mechanism, converging on "Impaired Hydroxyapatite Deposition at the Mineralization Front") — VDDR1B is a strong candidate conformer to that module's calciopenic trigger arm, entering via a primary hepatic 25-hydroxylation defect rather than dietary/sunlight deficiency, but converging on the same rate-limiting mineralization node.

Molecular pathways (KEGG/Reactome): Vitamin D metabolism/activation pathway (Reactome R-HSA-5579022, "Defective CYP2R1 causes vitamin D 25-hydroxylase deficiency" — Reactome has a specific disease pathway entry for this defect); KEGG hsa00140 (Steroid hormone biosynthesis, vitamin D branch).

Immune involvement: Not a primary disease mechanism; VDR/calcitriol signaling has broader immunomodulatory roles described in the general vitamin D literature, but no VDDR1B-specific immune phenotype has been reported.

Molecular profiling / omics: No transcriptomic, proteomic, or single-cell studies specific to VDDR1B patient tissue have been published (the disease is studied almost exclusively via targeted Sanger/exome sequencing and biochemical phenotyping, not omics).

7. Anatomical Structures Affected

  • Organ level (primary): Liver (site of CYP2R1 deficiency; UBERON:0002107); skeletal system broadly (rickets/osteomalacia).
  • Organ level (secondary): Kidney (compensatory 1α-hydroxylase activity, renal phosphate wasting; UBERON:0002113); parathyroid glands (compensatory hyperplasia/hypersecretion; UBERON:0001132); small intestine (reduced calcium/phosphate absorption; UBERON:0002108).
  • Body systems: Skeletal system, endocrine system (calcium-PTH-vitamin D axis), digestive system (hepatic and intestinal components).
  • Tissue/cell level: Growth plate cartilage (UBERON:0002514) — hypertrophic chondrocyte zone; long bone cortical/trabecular bone (UBERON:0002481); hepatocyte microsomal/ER compartment (site of CYP2R1 localization).
  • Subcellular level: Endoplasmic reticulum (GO:0005783) — CYP2R1 is an ER-membrane-anchored microsomal P450.
  • Localization/laterality: Systemic/bilateral — rickets and bowing are bilateral, symmetric skeletal findings (unlike unilateral focal bone lesions).

8. Temporal Development

  • Onset: Typically infancy to early childhood (as young as 2 years for radiographic bowing in the index Nigerian family), though later-childhood/adolescent presentation is also reported; onset pattern is insidious/chronic rather than acute.
  • Progression: Untreated disease is progressive (worsening rachitic deformity, growth impairment); with high-dose vitamin D3 treatment, radiographic healing of rickets is documented (Thacher et al. 2015, PMID:25942481), and adult follow-up (Wiedemann et al. 2020, PMID:32430692) shows preserved bone mineral density despite persistent biochemical 25(OH)D deficiency — suggesting good long-term prognosis with adequate calcium/vitamin D3 management even if full biochemical normalization of 25(OH)D is not achieved.
  • Disease course pattern: Chronic, lifelong biochemical defect (enzyme deficiency is permanent), but clinically manageable/stable with treatment; relapse on treatment discontinuation has been specifically described as a diagnostic clue distinguishing VDDR1B from self-limited nutritional rickets (JCEM Case Reports 2024, PMID:38440125).
  • Critical periods: Growth-plate-open childhood/adolescence is the period of clinical vulnerability for rachitic skeletal deformity; after growth-plate closure, the primary residual risk shifts to osteomalacia/bone mineral density, which appears to be less severely affected in treated adults.

9. Inheritance and Population

  • Epidemiology: No formal prevalence/incidence estimate exists; VDDR1B is classified as ultra-rare, with the world literature comprising fewer than ~40 molecularly confirmed cases across scattered case reports/small series as of 2024. This maps to prevalence_class: NOT_YET_DOCUMENTED or ULTRA_RARE in dismech terms, sourced from Orphanet (ORPHA:289320).
  • Inheritance pattern: Autosomal recessive (biallelic homozygous or compound heterozygous variants). Notably, several reports describe heterozygous carriers with a milder, incompletely penetrant biochemical phenotype (subnormal 25(OH)D response to vitamin D3 challenge) — this is a semi-dominant/haploinsufficiency signal worth capturing explicitly (e.g., an Inheritance block noting incomplete penetrance in heterozygotes, distinct from the fully penetrant recessive homozygous/compound-heterozygous disease).
  • Penetrance/expressivity: Homozygous null genotypes show high penetrance for biochemical and clinical rickets; expressivity is variable in severity and age of clinical recognition, likely modulated by sun exposure/diet (substrate availability) as discussed above.
  • Consanguinity: Multiple reported kindreds (Nigerian, Saudi Arabian, Moroccan) are from populations/family structures with elevated consanguinity, consistent with recessive inheritance and founder alleles; the Saudi cohort (Alzahrani et al. 2021) specifically comprises 9 families with two recurrent founder-like alleles.
  • Founder effects: L99P recurs across Nigerian and Moroccan families (possibly a mutational hotspot rather than a single founder haplotype, given geographic spread); c.367+1G>A and c.768dupT appear to function as regional founder/recurrent alleles within the Saudi Arabian cohort.
  • Affected populations/geography: Cases reported from Nigeria, Saudi Arabia (largest series), Morocco, France, and — as of 2024 — India (first Asian case, JCEM Case Reports 2024, PMID:38440125), suggesting global but sporadic distribution rather than strict geographic restriction, with ascertainment likely biased toward regions/populations with active clinical genetics programs and higher consanguinity rates.
  • Sex ratio / age distribution: No sex predilection has been reported; case series span pediatric through adult ages (Wiedemann et al. 2020 specifically studied adult outcomes).

10. Diagnostics

Clinical/laboratory tests: - Serum 25-hydroxyvitamin D (25(OH)D) — markedly low/undetectable despite adequate sun/dietary exposure (the key discriminating lab finding); LOINC 62292-8 (25-Hydroxyvitamin D3). - Serum calcium (low/low-normal), phosphate (low), alkaline phosphatase (elevated), intact PTH (elevated) — the classic secondary-hyperparathyroid rachitic biochemical panel. - Serum 1,25-dihydroxyvitamin D — typically low-normal (distinguishing from the profoundly low/undetectable 1,25(OH)2D of VDDR1A/CYP27B1 deficiency, where 25(OH)D is normal-to-high but 1α-hydroxylation is blocked). - Radiographic imaging (long bones, wrists, chest) — classic rachitic metaphyseal fraying/cupping, rib beading, bowing.

Genetic testing: - Targeted CYP2R1 Sanger sequencing or a rickets/metabolic-bone-disease gene panel is the recommended diagnostic approach once biochemical findings (low 25(OH)D unresponsive to standard vitamin D3 dosing, especially with a positive family history or parental consanguinity) raise suspicion. - Whole-exome sequencing has been used in several reported cases when the phenotype was initially misattributed to nutritional deficiency.

Clinical criteria / differential diagnosis: - Nutritional vitamin D deficiency rickets: distinguished by response to standard-dose vitamin D3 and correction of 25(OH)D; VDDR1B does not normalize 25(OH)D with usual doses and requires supraphysiologic dosing or fails to respond to repeated conventional courses (this non-response is the single most important clinical clue prompting genetic testing — emphasized in JCEM Case Reports 2024, PMID:38440125). - VDDR type 1A (CYP27B1 deficiency, OMIM #264700): 25(OH)D is normal-to-elevated but 1,25(OH)2D is low/undetectable (blocked renal 1α-hydroxylation), the inverse biochemical pattern from VDDR1B. - VDDR type 2A (VDR mutations, hereditary vitamin D-resistant rickets, OMIM #277440): elevated 1,25(OH)2D with target-organ resistance (often with alopecia). - VDDR type 3 (CYP3A4-mediated accelerated vitamin D inactivation, OMIM #619073): a distinct hypercatabolic mechanism. - Hypophosphatemic rickets (e.g., X-linked, PHEX/FGF23-mediated): distinguished by normal PTH and normal/high 1,25(OH)2D with isolated renal phosphate wasting, versus the secondary-hyperparathyroid picture of VDDR1B.

Screening: No population newborn or carrier screening program exists for VDDR1B given its extreme rarity; case-finding is clinical (family history of rickets, consanguinity, treatment non-response) followed by targeted sequencing.

11. Outcome/Prognosis

  • Mortality: No disease-specific mortality has been reported; VDDR1B is not considered a life-limiting condition when diagnosed and treated.
  • Morbidity: Untreated/undiagnosed disease carries morbidity from progressive skeletal deformity (bowing), growth impairment, and potentially hypocalcemic seizures in severe infantile presentations.
  • Functional/skeletal outcome with treatment: Radiographic healing of rickets is well documented with high-dose vitamin D3 (Thacher et al. 2015, PMID:25942481; JCEM Case Reports 2024, PMID:38440125). Long-term adult follow-up (Wiedemann et al. 2020, PMID:32430692) found that persistent biochemical 25(OH)D deficiency, once patients are past the growth-plate-vulnerable period and on adequate calcium/vitamin D management, does not translate into reduced bone mineral density — a reassuring prognostic finding.
  • Complications: Growth deformity/bowing if diagnosis is delayed; recurrence/relapse of rachitic biochemistry on treatment discontinuation is a recognized pattern used diagnostically.
  • Prognostic factors: Genotype severity (null/frameshift/splice vs. hypomorphic missense such as K242N) correlates with degree of biochemical deficiency and blunting of treatment response; early diagnosis and sustained supraphysiologic vitamin D3/calcium therapy are the main modifiable prognostic levers.

12. Treatment

Pharmacotherapy (first-line): - High-dose (supraphysiologic) oral cholecalciferol (vitamin D3) plus calcium supplementation is the mainstay, with dose titrated against serum alkaline phosphatase, 25(OH)D, and PTH to achieve normalization and radiographic healing (JCEM Case Reports 2024, PMID:38440125; Thacher et al. 2015, PMID:25942481). NCIT term: NCIT:C15986 (Pharmacotherapy) as treatment_term, with therapeutic_agent CHEBI:28934 (cholecalciferol). - Calcifediol [25(OH)D3] supplementation is mechanistically attractive (it bypasses the defective hydroxylation step entirely) and has been used/discussed in the literature, though most published cases relied on high-dose native vitamin D3 with clinical/biochemical response, implying that some residual (CYP2R1-independent) 25-hydroxylation capacity is exploitable at high substrate doses. Where used, calcifediol would map to therapeutic_agent CHEBI:17933 (calcifediol/25-hydroxyvitamin D3) under the same NCIT:C15986 Pharmacotherapy treatment_term. - Calcitriol [1,25(OH)2D3] is a theoretical option (bypassing both defective hydroxylation steps) but is not the standard reported approach for VDDR1B specifically (contrast with VDDR1A, where calcitriol is first-line because the defect is downstream at the 1α-hydroxylation step).

Advanced therapeutics: No gene therapy, cell therapy, or RNA-based therapeutics have been developed or trialed for VDDR1B — the condition is effectively manageable with vitamin D3/calcium supplementation, which has limited the impetus for advanced modality development.

Surgical: Orthopedic correction (e.g., osteotomy) may be considered for severe, fixed bowing deformity that does not remodel after biochemical correction, as in other rachitic conditions, though this is not specifically documented in the VDDR1B literature reviewed.

Supportive care: Physical therapy/rehabilitation for gait or deformity-related functional impairment (NCIT:C15302, Physical Therapy) may be used adjunctively, per general rachitic-disease management, though not specifically reported for VDDR1B.

Monitoring/treatment strategy: Dose titration is driven by serial serum alkaline phosphatase, 25(OH)D, calcium, phosphate, and PTH, aiming for normalization of all markers and radiographic healing; because relapse occurs on treatment discontinuation, long-term/indefinite supplementation is implied rather than a time-limited course (JCEM Case Reports 2024, PMID:38440125).

Experimental treatments: No registered clinical trials (ClinicalTrials.gov) specific to VDDR1B were identified — consistent with its extreme rarity and effective management via existing vitamin D formulations.

Adverse events: Because supraphysiologic vitamin D3 dosing is used, monitoring for hypercalcemia/hypercalciuria and vitamin D toxicity is an implied but not separately quantified risk in the literature reviewed.

13. Prevention

  • Primary prevention: Not applicable in the classic sense (monogenic recessive disease); genetic counseling for consanguineous families or those with an affected child is the relevant preventive intervention.
  • Screening/early detection: Prenatal or carrier testing could theoretically be offered in families with a known pathogenic CYP2R1 variant, though no formal ACMG/professional-society screening recommendation specific to VDDR1B exists given its rarity.
  • Genetic counseling: Recommended for identified families to inform recurrence risk (25% for future affected offspring of two carrier parents) and to guide early biochemical monitoring/prophylactic vitamin D3 dosing in at-risk siblings.
  • Behavioral/public health: General population-level vitamin D sufficiency campaigns (sunlight exposure, dietary/supplement fortification) do not prevent VDDR1B itself, but adequate substrate availability mitigates severity in affected individuals and could plausibly delay/reduce clinical presentation.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring VDDR1B-equivalent disease has been reported in companion animals or wildlife (unlike some other Mendelian metabolic bone diseases with veterinary correlates). NCBITaxon:9606 (Homo sapiens) is the sole natural-disease species.
  • Orthologous gene: Mouse Cyp2r1 (NCBI Gene: 74790) is the well-characterized ortholog used for functional/model studies (see below); Uniprot Q6VVW9 (mouse Cyp2r1).
  • Comparative biology: CYP2R1's role as the principal vitamin D 25-hydroxylase is evolutionarily conserved across mammals, supporting cross-species mechanistic relevance of the mouse knockout data to human pathophysiology, though as detailed below the mouse model's phenotype is notably milder than the human disease (a HUMAN_MODEL_MISMATCH-relevant point for dismech curation).

15. Model Organisms

Mouse — Cyp2r1 knockout (global): Zhu, Ochalek, Kaufmann, Jones & DeLuca, PNAS 2013 (PMID:24019477), "CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo." Cyp2r1⁻/⁻ mice show >50% reduction (not complete loss) in serum 25(OH)D3, with unchanged serum 1,25(OH)2D3 and no overt health/skeletal phenotype reported in the paper — i.e., the mouse model partially, not fully, recapitulates the human biochemical defect and does not reproduce the rachitic phenotype seen in human null patients. This is an important HUMAN_MODEL_MISMATCH/FAILS_TO_RECAPITULATE-relevant finding for dismech curation: the residual 25-hydroxylation capacity is proportionally much greater in mouse than appears to be the case in the most severely affected human homozygotes (e.g., L99P homozygotes with profound, blunted-response deficiency). - A double knockout of Cyp2r1 and Cyp27a1 (the latter encoding a mitochondrial P450 with minor 25-hydroxylase side activity) was also generated in the same study; circulating 25(OH)D3 and 1,25(OH)2D levels remained similar to the single Cyp2r1 knockout, indicating that additional, still-unidentified 25-hydroxylase(s) contribute to the residual activity — an open mechanistic gap explicitly flagged by the authors and relevant for a KNOWLEDGE_GAP discussion node in a dismech pathophysiology model (the identity of the "other" enzyme(s) responsible for the residual ~50% activity in Cyp2r1-null mice remains unresolved as of the cited literature). - Model limitations: The mild mouse phenotype (no overt rachitic bone disease reported) limits its use for studying skeletal/clinical endpoints of VDDR1B and suggests either species differences in the relative contribution of alternative hydroxylases, in dietary/husbandry vitamin D substrate availability, or in downstream calcium-handling compensation — none of which have been fully dissected in the literature reviewed. - Applications: The knockout mouse remains the primary tool for studying CYP2R1's biochemical/enzymological role in whole-organism vitamin D activation and for testing alternative-pathway hypotheses (e.g., candidate secondary 25-hydroxylases), but is not an adequate model for the severe/complete human null phenotype or its skeletal consequences. - Resources: MGI accession for Cyp2r1 (MGI:1919338); IMPC/KOMP repositories may hold additional Cyp2r1 allele lines beyond the specific knockout described by Zhu et al.

In vitro models: Heterologous expression systems (COS-7, HEK293, or yeast/insect-cell expression of recombinant CYP2R1) have been used extensively to functionally characterize individual patient variants (e.g., L99P, K242N) for residual enzymatic activity, as cited above (Thacher et al. 2015, PMID:25942481) — these represent the most direct and best-characterized "model" evidence linking specific human genotypes to loss/reduction of 25-hydroxylase catalytic function, complementing the whole-organism mouse data.

Summary Table of Key Evidence

Claim PMID Evidence type
CYP2R1 identified as key human vitamin D 25-hydroxylase; first patient variant 15128933 (Cheng et al., PNAS 2004) HUMAN_CLINICAL + IN_VITRO
Compound heterozygous splice + frameshift CYP2R1 variants, Saudi sibship 22855339 (Al Mutair et al. 2012) HUMAN_CLINICAL
L99P and K242N functional characterization, 2 Nigerian families, blunted vitamin D3 response 25942481 (Thacher et al., JCEM 2015) HUMAN_CLINICAL + IN_VITRO
CYP2R1 review of mutations causing vitamin D-deficiency rickets 27473561 (Thacher & Levine 2017) Review
7 patients/2 families (Moroccan L99P, French indel); "rare or misdiagnosed" 28548312 (Molin et al., JBMR 2017) HUMAN_CLINICAL
27 Saudi patients/9 families; two founder-like alleles 34137732 (Alzahrani et al. 2021) HUMAN_CLINICAL
Adult BMD preserved despite persistent 25(OH)D deficiency 32430692 (Wiedemann et al. 2020) HUMAN_CLINICAL
First Asian (Indian) case; novel frameshift variant 38440125 (JCEM Case Reports 2024) HUMAN_CLINICAL
Cyp2r1 knockout mouse; partial, not full, biochemical recapitulation 24019477 (Zhu et al., PNAS 2013) MODEL_ORGANISM
CYP2R1-vitamin D3 crystal structure 18511070 (Strushkevich et al. 2008) COMPUTATIONAL/structural (IN_VITRO)

Sources: - Novel Mutation in CYP2R1 Causing Vitamin D-Dependent Rickets Type 1b (JCEM Case Reports 2024) - OMIM #600081 – VITAMIN D HYDROXYLATION-DEFICIENT RICKETS, TYPE 1B - OMIM *608713 – CYP2R1 - Vitamin D–Dependent Rickets Type 1B: A Rare Condition or a Misdiagnosed Condition? (JBMR 2017) - 25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects (Endocrine Connections 2021) - Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase (PNAS 2004) - CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo (PNAS 2013) - Mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family (2012) - CYP2R1 mutations causing vitamin D-deficiency rickets (review, 2017) - vitamin D hydroxylation-deficient rickets, type 1B – MONDO/NORD - Vitamin D Hydroxylation-Deficient Rickets, Type 1b – MalaCards - Structural Analysis of CYP2R1 in Complex with Vitamin D3 (J Mol Biol 2008) - New Variants of the CYP2R1 Gene in Individuals with Severe 25(OH)D Deficiency - Two novel CYP2R1 mutations in a family with vitamin D-dependent rickets type 1b (2021) - Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With CYP2R1 Deficiency (Calcif Tissue Int 2020) - ClinVar VCV000002216 – CYP2R1 c.296T>C (p.Leu99Pro) - ClinVar VCV000977185 – CYP2R1 c.768dupT

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