Vitamin D-Dependent Rickets Type 3

Mendelian MONDO:0033640 Pathograph 30 Show in embeddings browser Metabolic Bone Disorders Inborn Error of Metabolism

Vitamin D-dependent rickets type 3 is an autosomal dominant vitamin D hypercatabolism disorder caused, in at least five molecularly described patients reported to date (four in peer-reviewed journal reports and one in a conference abstract), by the recurrent heterozygous CYP3A4 c.902T>C (p.Ile301Thr) gain-of-function variant. The altered enzyme accelerates conversion of calcifediol and calcitriol to metabolites with much lower vitamin D receptor affinity. Low circulating concentrations of both vitamin D metabolites lead to secondary hyperparathyroidism, hypocalcemia, hypophosphatemia, and childhood rickets. Unlike an activation defect or receptor resistance, the lesion is excessive degradation: conventional doses are inadequate, but pharmacologic-dose cholecalciferol or calcitriol can maintain mineral homeostasis; cholecalciferol regimens have also healed rickets. This disease entry is kept separate from acquired CYP3A4 induction by medications and from the other genetically distinct vitamin D-dependent rickets.

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1
Inheritance
6
Pathophys.
18
Phenotypes
2
Gaps
30
Pathograph
1
Genes
1
Variants
2
Medical Actions
8
Differentials
3
Models
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
A single heterozygous gain-of-function allele is sufficient. The two original patients, the Brazilian patient, and a Chinese patient described in a conference abstract had the variant absent from tested parents. The Saudi patient had an affected father, but the father was not genotyped, so inherited transmission in that family is plausible rather than proven.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:29461981 SUPPORT Human Clinical
"Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4)."
Establishes independent de novo occurrence of the same heterozygous variant in the two founding patients.
PMID:38179381 SUPPORT INDIRECT Human Clinical
"She has a strong family history of rickets. Her parents are first cousins; the father has a history of rickets, short stature, and genu varum, corrected surgically and followed with orthopedics, while the mother is healthy."
The affected father makes dominant transmission plausible, but parental molecular testing was not reported and therefore does not prove that the proband inherited the CYP3A4 allele.
url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422 SUPPORT Human Clinical
"p.Ile301Thr) which was further confirmed using Sanger sequencing. However, this variant was not found in his parents."
A conference abstract reports another molecularly confirmed de novo occurrence; its preliminary publication type is retained as a limitation.
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Discussions and Knowledge Gaps

2
What are the penetrance, phenotype range, long-term course, and true inherited transmission pattern of CYP3A4 p.Ile301Thr VDDR3?
KNOWLEDGE GAP OPEN gap_vddr3_natural_history_and_inheritance
Attached to
pathophysiology#CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
At least five molecularly described patients are published, all with the same allele; four are in peer-reviewed journal reports and one is in a conference abstract. The variant was absent from tested parents in four patients. The Saudi patient's father had rickets, short stature, and genu varum but was not genotyped, leaving vertical transmission unconfirmed. This evidence cannot establish penetrance, prevalence, sex effects, an allelic spectrum, or adult complications.
Show evidence (1 reference)
PMID:38179381 SUPPORT INDIRECT Human Clinical
"She has a strong family history of rickets. Her parents are first cousins; the father has a history of rickets, short stature, and genu varum, corrected surgically and followed with orthopedics, while the mother is healthy."
Establishes a potentially affected parent but not molecular cosegregation.
What age- and weight-adjusted vitamin D regimen provides durable skeletal healing without hypercalcemia, hypercalciuria, or other long-term toxicity?
KNOWLEDGE GAP OPEN gap_vddr3_optimal_replacement_regimen
Attached to
treatments#Pharmacologic-Dose Vitamin D Replacement
Effective regimens vary widely among five molecularly described cases and were not compared in a trial. Long-term target concentrations, dose adjustment, renal safety, and whether calcitriol, parent vitamin D, or their combination is preferable remain undefined.
Show evidence (1 reference)
PMID:38179381 SUPPORT Human Clinical
"The optimal dose of cholecalciferol for treatment remains to be determined."
The Saudi case report explicitly identifies dose optimization as unresolved.
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Pathophysiology

6
CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
Mechanism confidence: Established
The heterozygous p.Ile301Thr substitution remodels CYP3A4 substrate recognition site 4. It confers increased and altered hydroxylation of calcifediol and calcitriol rather than a nonspecific increase in all CYP3A4 activity.
CYP3A4 hgnc:2637 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYP3A4 (hgnc:2637). hgnc:2637 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context CYP3A4 hgnc:2637 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CYP3A4 (hgnc:2637). hgnc:2637 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: GERMLINE allelic_event: MISSENSE_VARIANT zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Recurrent germline c.902T>C (p.Ile301Thr); absent from tested parents in four molecularly described patients and of undetermined origin in the Saudi family.
Vitamin D metabolite steroid hydroxylase activity GO:0008395 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased Vitamin D metabolite steroid hydroxylase activity, annotated with steroid hydroxylase activity (GO:0008395). GO:0008395 is a molecular function from the Gene Ontology.
Experimental models
CYP3A4-I301T HEK293T Substrate-Selectivity Assays CELL LINE The paired reporters compare increased calcitriol-inactivating function with activity toward a non-vitamin D substrate.
Computational models
CYP3A4-I301T Vitamin D Molecular Docking Model MOLECULAR DOCKING Provides an in-silico substrate-pose explanation for variant-specific 11-alpha hydroxylation.
Downstream
Accelerated Formation of Low-Activity Vitamin D Metabolites The altered active site increases hydroxylation of both calcifediol and calcitriol and changes the product profile.
Show evidence (3 references)
PMID:29461981 SUPPORT In Vitro
"In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites."
Quantifies increased calcitriol oxidation by mutant CYP3A4 against both wild-type enzyme and the physiological vitamin D inactivator.
PMID:41046353 SUPPORT In Vitro
"These results indicate that the I301T mutation confers a gain-of-function phenotype on CYP3A4, enhancing its ability to metabolize 25(OH)D3 and 1α,25(OH)2D3 into low-activity derivatives."
The recombinant-enzyme study confirms gain of vitamin D metabolite hydroxylation and identifies low-activity products.
PMID:29461981 SUPPORT In Vitro
"The p.I301T mutant had significantly decreased activity for luciferin IPA relative to the WT enzyme (30.0 ± 1.6 vs. 50.1 ± 1.6, n = 4 for each, ***P < 0.001)."
The lack of a parallel gain for a non-vitamin D substrate supports a substrate-selective rather than global increase in CYP3A4 activity.
Accelerated Formation of Low-Activity Vitamin D Metabolites
Mechanism confidence: Established
CYP3A4-I301T rapidly converts calcifediol and calcitriol to hydroxylated derivatives. The 2026 enzyme study identified 11α,25-dihydroxyvitamin D3 and 1α,11α,25-trihydroxyvitamin D3 as additional products with much lower vitamin D receptor affinity than their parent metabolites.
Vitamin D metabolic process GO:0042359 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Vitamin D metabolic process (GO:0042359). GO:0042359 is a biological process from the Gene Ontology.
Experimental models
Recombinant E. coli CYP3A4-I301T Membrane-Fraction Assay OTHER Directly measures variant-specific vitamin D metabolite product formation.
Downstream
Vitamin D Metabolite Depletion Accelerated conversion shortens the persistence of circulating calcifediol and calcitriol after an absorbed vitamin D dose.
Show evidence (2 references)
PMID:29461981 SUPPORT In Vitro
"In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites."
Establishes accelerated calcitriol oxidation by the variant enzyme.
PMID:41046353 SUPPORT In Vitro
"Surprisingly, we found that CYP3A4-I301T efficiently produced additional metabolites compared to the wild-type CYP3A4, including 11α,25-dihydroxyvitamin D3 and 1α,11α,25-trihydroxyvitamin D3, which have much lower affinity for the vitamin D receptor than do 25(OH)D3 and 1α,25(OH)2D3, respectively."
Defines the additional products and their reduced receptor affinity.
Vitamin D Metabolite Depletion
Mechanism confidence: Established
Untreated or conventionally treated patients have low circulating calcifediol and calcitriol. A large oral dose produces an initial rise, demonstrating absorption and activation, followed by an abnormally rapid fall, distinguishing accelerated clearance from defective synthesis.
Downstream
Decreased circulating calcifediol concentration Depletion of the calcifediol pool is observed as low circulating 25-hydroxyvitamin D and also reduces substrate available for calcitriol synthesis.
Decreased circulating calcitriol concentration Depletion of active vitamin D is observed as low circulating 1,25-dihydroxyvitamin D and reduces vitamin D receptor ligand availability.
Calciopenic Mineral-Ion Disturbance Loss of calcitriol action reduces intestinal calcium transport; hypocalcemia stimulates parathyroid hormone, which promotes renal phosphate loss.
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Documents depletion of both major circulating vitamin D metabolites in the founding patients.
PMID:36656330 SUPPORT Human Clinical
"Serum levels of 25(OH)D and 1,25(OH)2D peaked on the 3rd day after the vitamin D challenge, reducing considerably by the 30th day, as shown in Fig. 2."
Serial sampling shows an initial response followed by rapid metabolite loss.
Calciopenic Mineral-Ion Disturbance
Mechanism confidence: Established
Reduced calcium delivery produces hypocalcemia and secondary hyperparathyroidism. Parathyroid hormone-driven renal phosphate loss adds hypophosphatemia; alkaline phosphatase rises with active rachitic bone turnover. This node represents the systemic calciopenic state rather than treating each laboratory measurement as a separate causal mechanism.
Enterocyte CL:0000584 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Enterocyte (CL:0000584). CL:0000584 is a cell type from the Cell Ontology.
Vitamin D receptor signaling pathway GO:0070561 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Vitamin D receptor signaling pathway (GO:0070561). GO:0070561 is a biological process from the Gene Ontology. Intestinal calcium absorption GO:0070509 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Intestinal calcium absorption, annotated with calcium ion import (GO:0070509). GO:0070509 is a biological process from the Gene Ontology.
Downstream
Hypocalcemia Reduced circulating calcium is a causally active component of the calciopenic state.
Hypophosphatemia Reduced circulating phosphate is a causally active component of the calciopenic state.
Elevated circulating parathyroid hormone level Secondary parathyroid hormone elevation is an active hormonal component of the calciopenic state.
Impaired Hydroxyapatite Deposition at the Mineralization Front Low calcium and phosphate reduce the substrate available for hydroxyapatite deposition at the mineralization front.
Growth-Plate Hypertrophic Zone Expansion The hypophosphatemic component directly impairs apoptosis of terminal hypertrophic chondrocytes in the growing skeleton.
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"bilateral genu varum, poor growth, and reduced serum calcium and phosphorus with elevated serum alkaline phosphatase and parathyroid hormone (Table 1)."
Records the complete calciopenic laboratory pattern in a founding patient.
PMID:36656330 SUPPORT Human Clinical
"His initial biochemical studies showed a low calcium of 1.3 mmol/L (NR 2.2–2.77), a low phosphorus of 1.07 mmol/L (NR 1.45–2.1), an elevated Alkaline Phosphatase at 18.45 μkat/L (NR < 8.3), a low 25(OH)D of 29.45 mmol/L (NR > 50), a high PTH of 371 ng/L (NR 12–88), and an elevated 1,25(OH)2D of..."
Confirms low calcium and phosphate with elevated alkaline phosphatase and parathyroid hormone in the Brazilian patient; calcitriol was elevated while he was taking calcitriol and is not used here as an untreated-state claim.
Impaired Hydroxyapatite Deposition at the Mineralization Front
Mechanism confidence: Established
Inadequate calcium-phosphate availability lowers hydroxyapatite deposition into bone matrix. This shared skeletal mineralization failure produces osteopenia and, in the growing skeleton, feeds a distinct growth-plate lesion.
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. Osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteocyte (CL:0000137). CL:0000137 is a cell type from the Cell Ontology.
Bone mineralization GO:0030282 ↓ DECREASED 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. Biomineral tissue development GO:0031214 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Biomineral tissue development (GO:0031214). GO:0031214 is a biological process from the Gene Ontology.
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
Osteopenia Reduced skeletal mineralization lowers radiographic bone density.
Frontal bossing Impaired cranial mineralization can produce frontal prominence.
Show evidence (3 references)
PMID:32596195 SUPPORT Other
"Hypocalcemia and hypophosphatemia collectively reduce the rate of mineralization of bone matrix. Reduced serum levels of calcium and/or phosphorus can produce osteomalacia, as the low concentrations of these minerals are insufficient to induce or propagate hydroxyapatite cystral deposition in..."
Directly supports impaired matrix mineralization and hydroxyapatite deposition downstream of the mineral deficits.
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Directly documents age-dependent rachitic and osteopenic radiographic abnormalities in the founding patients.
PMID:36656330 SUPPORT Human Clinical
"His radiographs were suggestive of active rickets—(Fig. 1A)."
Confirms active radiographic rickets in the Brazilian patient.
Growth-Plate Hypertrophic Zone Expansion
Mechanism confidence: Established
Extracellular phosphate deficiency impairs apoptosis of terminal hypertrophic chondrocytes. The hypertrophic zone expands and the growing metaphysis becomes widened, irregular, and cupped, producing the radiographic and load-bearing manifestations of childhood rickets.
Hypertrophic chondrocyte CL:0000743 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hypertrophic chondrocyte (CL:0000743). CL:0000743 is a cell type from the Cell Ontology.
Hypertrophic chondrocyte apoptosis GO:0006915 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Hypertrophic chondrocyte apoptosis, annotated with apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. Growth plate cartilage development GO:0003417 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Growth plate cartilage development (GO:0003417). GO:0003417 is a biological process from the Gene Ontology.
Growth plate UBERON:0002516 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Growth plate, annotated with epiphyseal plate (UBERON:0002516). UBERON:0002516 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Rickets Growth-plate expansion and disorganization are the defining rachitic lesion.
Genu varum Growth-plate weakness permits outward lower-limb bowing.
Genu valgum Growth-plate weakness can alternatively produce inward knee angulation.
Flared metaphysis Disorganized mineralization widens and splays the metaphysis.
Metaphyseal cupping Abnormal metaphyseal mineralization produces the cup-shaped contour.
Growth delay Persistent growth-plate disease slows linear growth.
Delayed ability to walk Severe rachitic lower-limb disease delays independent walking.
Unsteady gait Rachitic limb deformity impairs gait stability.
Bilateral knee pain Rachitic lower-limb disease can produce bilateral knee discomfort during mobility.
Show evidence (2 references)
PMID:32596195 SUPPORT Other
"rickets arises as a result of a growth plate defect that in which hypertrophic chondrocytes fail to undergo caspase 9-mediated apoptosis due to reduced concentrations of extracellular phosphate (20). This effect of hypophosphatemia provides a final common pathway that unifies the growth plate..."
Establishes phosphate-dependent hypertrophic-chondrocyte failure as the common growth-plate mechanism in calciopenic rickets.
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Documents the corresponding widened and cupped metaphyseal phenotype in VDDR3.
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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 3 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

18
Endocrine 1
Elevated circulating parathyroid hormone level HP:0003165 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating parathyroid hormone level (HP:0003165). HP:0003165 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"bilateral genu varum, poor growth, and reduced serum calcium and phosphorus with elevated serum alkaline phosphatase and parathyroid hormone (Table 1)."
Directly reports elevated parathyroid hormone.
Head and Neck 1
Frontal bossing HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38179381 SUPPORT Human Clinical
"Her physical examination revealed no dysmorphic features. She had mild frontal bossing and no widening in the wrists, and her gait was normal with mild genu valgum."
Directly reports frontal bossing during clinical evaluation.
Limbs 4
Genu varum HP:0002970 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu varum (HP:0002970). HP:0002970 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"bilateral genu varum, poor growth, and reduced serum calcium and phosphorus with elevated serum alkaline phosphatase and parathyroid hormone (Table 1)."
Directly reports bilateral genu varum in a founding patient.
PMID:36656330 SUPPORT Human Clinical
"His physical examination revealed a height of 83 cm in height (− 2.5 SDS) with a midparental target height of + 0.7 SDS. His weight was normal. He had thickened wrists and bowed legs (genu varum)."
Independently documents genu varum in the Brazilian patient.
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:38179381 SUPPORT Human Clinical
"We hereby report a case of a six-year-old girl with poor growth and bone deformities, such as genu valgum."
Directly reports genu valgum in the Saudi molecularly confirmed patient.
Flared metaphysis HP:0003015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flared metaphysis (HP:0003015). HP:0003015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
The HPO synonym metaphyseal splaying maps directly to flared metaphysis.
Metaphyseal cupping HP:0003021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal cupping (HP:0003021). HP:0003021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Directly reports metaphyseal cupping.
Metabolism 5
Decreased circulating calcifediol concentration HP:0012053 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating calcifediol concentration (HP:0012053). HP:0012053 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Reports low circulating 25-hydroxyvitamin D in both founding patients.
Decreased circulating calcitriol concentration HP:0012052 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating calcitriol concentration (HP:0012052). HP:0012052 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Reports low circulating calcitriol in both founding patients.
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 (1 reference)
PMID:29461981 SUPPORT Human Clinical
"bilateral genu varum, poor growth, and reduced serum calcium and phosphorus with elevated serum alkaline phosphatase and parathyroid hormone (Table 1)."
Directly reports reduced serum calcium.
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:29461981 SUPPORT Human Clinical
"bilateral genu varum, poor growth, and reduced serum calcium and phosphorus with elevated serum alkaline phosphatase and parathyroid hormone (Table 1)."
Directly reports reduced serum phosphorus.
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:29461981 SUPPORT Human Clinical
"bilateral genu varum, poor growth, and reduced serum calcium and phosphorus with elevated serum alkaline phosphatase and parathyroid hormone (Table 1)."
Directly reports elevated serum alkaline phosphatase.
Musculoskeletal 2
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:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Names rickets as the presenting skeletal disease.
Context-specific annotations (1)
Onset: CHILDHOOD
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Establishes early-onset rickets in both founding patients.
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Directly reports osteopenia in the older founding patient.
PMID:38179381 SUPPORT Human Clinical
"In addition, mild osteopenia was present (image B)."
Independently documents radiographic osteopenia in the Saudi patient.
Nervous System 3
Delayed ability to walk HP:0031936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed ability to walk (HP:0031936). HP:0031936 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"Proband 2.1 was of Middle Eastern descent and did not walk until 4.5 years of age."
Directly documents delayed independent walking in a founding patient.
PMID:38179381 SUPPORT Human Clinical
"Earlier at the age of two years, the family noted she had a delay in speech and walking. When she eventually started to walk at the age of three years, the family noticed that she had knock knees and an unsteady gait."
Independently documents delayed walking in the Saudi patient.
Unsteady gait HP:0002317 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Unsteady gait (HP:0002317). HP:0002317 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36656330 SUPPORT Human Clinical
"This 2 8/12-year-old Caucasian male presented with a history of bowed legs, gait instability, and growth arrest since 12 months of age."
Directly documents gait instability in the Brazilian patient.
PMID:38179381 SUPPORT Human Clinical
"Earlier at the age of two years, the family noted she had a delay in speech and walking. When she eventually started to walk at the age of three years, the family noticed that she had knock knees and an unsteady gait."
Independently documents an unsteady gait in the Saudi patient.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38179381 SUPPORT Human Clinical
"Earlier at the age of two years, the family noted she had a delay in speech and walking."
Directly reports delayed speech in one molecularly confirmed patient; it supports one observed phenotype but neither a causal neurodevelopmental mechanism nor a frequency estimate.
Constitutional 1
Bilateral knee pain HP:0030839 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral knee pain, annotated with Knee pain (HP:0030839), qualified as laterality bilateral. HP:0030839 is a phenotype from the Human Phenotype Ontology.
Laterality: BILATERAL
Show evidence (1 reference)
url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422 SUPPORT Human Clinical
"We report the case of a 32-month-old boy presented with discomfort of both knee-joints, poor mobility, and gait abnormality when running."
Directly reports bilateral knee-joint discomfort. Mapping the source term "discomfort" to knee pain is clinically close but calibrated, and the evidence is a conference abstract rather than a full peer-reviewed report. It establishes an observed case, not a frequency denominator.
Growth 1
Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36656330 SUPPORT Human Clinical
"Here, we describe the third case of VDDR3 due to the same CYP3A4 mutation in a 2-year-old boy with bone deformities associated with poor growth."
Directly reports poor growth in the Brazilian patient.
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Genetic Associations

1
Germline CYP3A4 gain-of-function disease association (Causative)
Gene: CYP3A4 hgnc:2637 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYP3A4 (hgnc:2637). hgnc:2637 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:29461981 SUPPORT Human Clinical
"Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4)."
Identifies the recurrent CYP3A4 variant in the two unrelated founding patients.
PMID:36656330 SUPPORT Human Clinical
"Here, we describe the third case of VDDR3 due to the same CYP3A4 mutation in a 2-year-old boy with bone deformities associated with poor growth."
Extends the genotype-disease association to the third patient reported in a peer-reviewed journal; a 2022 conference abstract described another molecularly confirmed patient before this article appeared.
PMID:38179381 SUPPORT Human Clinical
"the finding of a heterozygous missense variant in CYP3A4: c.902 T > C; p.Ile301Thr in the CYP3A4 gene confirms the diagnosis of VDDR3."
Identifies the recurrent allele in the fourth patient reported in a peer-reviewed journal; a 2022 conference abstract describes an additional molecularly confirmed Chinese patient.
+ 1 more reference
🔬

Variants

1
CYP3A4 c.902T>C (p.Ile301Thr) Pathogenic
Gene: CYP3A4 hgnc:2637 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CYP3A4 (hgnc:2637). hgnc:2637 is a gene from the HUGO Gene Nomenclature Committee. missense
A recurrent heterozygous germline missense variant affecting substrate recognition site 4. The threonine substitution changes CYP3A4 substrate positioning and selectively increases vitamin D metabolite hydroxylation; activity toward at least one non-vitamin D substrate was not increased.
Show evidence (1 reference)
PMID:29461981 SUPPORT In Vitro
"In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites."
Functional comparison demonstrates a strong, substrate-directed gain of vitamin D catabolic activity.
💊

Medical Actions

2
Pharmacologic-Dose Vitamin D 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: 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. 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. alfacalcidol CHEBI:31186 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses alfacalcidol (CHEBI:31186). CHEBI:31186 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The gain of catabolism makes conventional replacement inadequate, not futile. Pharmacologic-dose cholecalciferol or calcitriol can maintain vitamin D metabolites, calcium, phosphate, and parathyroid hormone; cholecalciferol regimens have also produced skeletal and functional improvement. Reported requirements vary substantially with age and body size: 50,000 IU cholecalciferol daily or high-dose calcitriol in the founding patients, 10,000 IU cholecalciferol daily plus calcium in a younger child, alfacalcidol 1.5–2 mcg with calcium 30 mg/kg daily followed by 50,000 IU cholecalciferol weekly in the Saudi case. The alfacalcidol-calcium regimen accompanied clinical improvement but residual generalized osteopenia, so it is not evidence of complete skeletal correction. These are case-derived observations, not a standardized regimen; dose selection and monitoring require specialist supervision.
Mechanism Target:
RESTORES Vitamin D Metabolite Depletion — Sustained pharmacologic input compensates for accelerated clearance and restores circulating metabolite and mineral-ion concentrations while treatment is maintained; it does not correct the CYP3A4 allele.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"Both patients required high doses of calcitriol or vitamin D3 (50,000 IU daily) to maintain normal serum concentrations of vitamin D metabolites as well as normal serum levels of PTH, calcium, and phosphorus."
Directly supports biochemical restoration of the depleted vitamin D and mineral-ion state while pharmacologic replacement is maintained.
RESTORES Impaired Hydroxyapatite Deposition at the Mineralization Front — Pharmacologic vitamin D treatment, often administered with calcium, produced radiographic improvement and healing of bone deformities. These clinical readouts support restoration of skeletal mineralization, although no biopsy or direct mineral-deposition assay was performed.
Show evidence (2 references)
PMID:36656330 SUPPORT Human Clinical
"Significant improvement in growth velocity and healing of bone deformities were achieved after a short period of treatment with 10.000 IU of cholecalciferol daily, showing the importance of early recognition and prompt precision therapy of this condition."
Directly reports skeletal healing after pharmacologic cholecalciferol; the patient also received calcium, so the vitamin D contribution is not experimentally isolated.
url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422 SUPPORT Human Clinical
"After several months of oral vitamin D treatment, the pathological changes improved in X-ray films."
Directly reports radiographic improvement, with the limitation that the source is a conference abstract and does not specify the regimen.
Target Phenotypes: Rickets HP:0002748 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology. Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (5 references)
PMID:32596195 SUPPORT Other
"Both patients required high doses of calcitriol or vitamin D3 (50,000 IU daily) to maintain normal serum concentrations of vitamin D metabolites as well as normal serum levels of PTH, calcium, and phosphorus."
The management review summarizes successful biochemical maintenance in the two founding patients.
PMID:36656330 SUPPORT Human Clinical
"At his most recent clinic visit, 3 months after the initiation of 10,000 IU of cholecalciferol daily, his height had increased to 91.4 cm (Z −1.3 SDS), with a greatly increased height velocity (5.9 cm in 3 months) and markedly improved gait."
Directly documents rapid growth and gait improvement in the Brazilian patient.
PMID:38179381 SUPPORT Human Clinical
"Approximately three months after beginning cholecalciferol 50,000 IU weekly, her lab results showed a significant improvement."
Documents biochemical improvement on a lower-frequency high-dose regimen in the Saudi patient.
+ 2 more references
Adjunctive 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: calcium ion CHEBI:29108 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcium ion, annotated with calcium(2+) (CHEBI:29108). CHEBI:29108 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral calcium was administered with pharmacologic vitamin D in the Brazilian and Saudi cases. The Brazilian combined regimen normalized serum calcium and produced marked radiographic improvement, while the Saudi alfacalcidol-calcium regimen accompanied clinical improvement but residual osteopenia. No calcium monotherapy result is available, so calcium is modeled as an adjunct and its independent efficacy cannot be inferred.
Mechanism Target:
RESTORES Calciopenic Mineral-Ion Disturbance — Supplemental calcium supplies one depleted mineral substrate while pharmacologic vitamin D compensates for accelerated vitamin D clearance. Normal serum calcium and skeletal improvement were observed only under combined therapy, not in a calcium-only comparison.
Show evidence (2 references)
PMID:36656330 SUPPORT INDIRECT Human Clinical
"Based on these results, we treated our patient with cholecalciferol 10,000 IU daily plus calcium supplements."
Directly documents calcium as part of the combined Brazilian regimen, but provides no calcium-only comparator.
PMID:36656330 SUPPORT INDIRECT Human Clinical
"His biochemical studies now showed a normal calcium (2.25 mmol/L), PTH (38 ng/L), and 25(OH)D (126.3 mmol/L) and radiographs of his bones showed marked improvements (Fig. 1B)."
Documents mineral-ion normalization and skeletal improvement under the combined regimen; it cannot isolate calcium's contribution.
Target Phenotypes: Rickets HP:0002748 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36656330 SUPPORT INDIRECT Human Clinical
"Based on these results, we treated our patient with cholecalciferol 10,000 IU daily plus calcium supplements."
Directly documents adjunctive calcium in the effective Brazilian combined regimen, without evidence for calcium monotherapy.
PMID:38179381 SUPPORT INDIRECT Human Clinical
"Upon follow-up at the age of eight years, the patient continued to receive alfacalcidol at a dosage of 1.5-2 mcg, along with a daily calcium supplement of 30 mg/kg. The patient clinically improved (mild genu valgum), and her height was -0.87 SD."
Directly documents the Saudi combined regimen and clinical improvement; attribution to calcium alone is impossible.
🔬

Diagnosis

3
Biochemical and Radiographic Assessment of Calciopenic Rickets
Initial evaluation establishes active calciopenic rickets and its severity with serum calcium, phosphate, alkaline phosphatase, parathyroid hormone, calcifediol, and calcitriol together with skeletal radiographs. The typical VDDR3 pattern combines low calcium, phosphate, calcifediol, and calcitriol with elevated parathyroid hormone and alkaline phosphatase; active treatment can alter individual measurements.
biochemical and radiographic assessment
Markers: Serum calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and metaphyseal radiographs.
Results: Calciopenic biochemical abnormalities with radiographic metaphyseal splaying, cupping, lucency, osteopenia, or other evidence of active rickets.
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"bilateral genu varum, poor growth, and reduced serum calcium and phosphorus with elevated serum alkaline phosphatase and parathyroid hormone (Table 1)."
Documents the characteristic mineral and regulatory-hormone pattern in a founding patient.
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Establishes the radiographic component and its age-dependent findings.
Serial Vitamin D Metabolite Clearance Challenge
In a child with calciopenic rickets and inadequate response to conventional vitamin D, serial calcifediol and calcitriol measurements after a supervised oral cholecalciferol dose can demonstrate adequate initial absorption and production followed by unusually rapid clearance. This is a mechanistic clue, not a substitute for molecular confirmation.
Vitamin D Measurement NCIT:C84818 NCI Thesaurus (NCIT)
Markers: Serial serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D.
Results: Initial rise after dosing followed by a substantially faster decline than expected in controls or nutritional rickets.
Show evidence (1 reference)
PMID:36656330 SUPPORT Human Clinical
"Serial measurements of vitamin D metabolites after a single 150,000 IU dose of cholecalciferol demonstrated an accelerated inactivation of 25(OH)D and 1,25(OH)2D."
Directly supports the dynamic clearance test in the Brazilian patient.
CYP3A4 Molecular Testing
Sequencing that includes CYP3A4 can confirm the diagnosis by identifying the recurrent heterozygous c.902T>C (p.Ile301Thr) variant. Because the published molecular spectrum currently consists of this single allele, another CYP3A4 variant requires independent pathogenicity assessment rather than automatic assignment to VDDR3.
Molecular Analysis NCIT:C19770 NCI Thesaurus (NCIT)
Markers: Heterozygous CYP3A4 c.902T>C (p.Ile301Thr).
Results: Molecular confirmation of CYP3A4-related VDDR3.
Show evidence (1 reference)
PMID:38179381 SUPPORT Human Clinical
"the finding of a heterozygous missense variant in CYP3A4: c.902 T > C; p.Ile301Thr in the CYP3A4 gene confirms the diagnosis of VDDR3."
Explicitly identifies the recurrent heterozygous allele as molecularly confirmatory in the Saudi patient.
🩻

Imaging Findings

6
Metaphyseal Splaying on Radiographs
Plain radiographs show metaphyseal splaying or flaring in younger patients with active rickets. This supports radiographic recognition of rickets but does not identify VDDR3 without biochemical and molecular evidence.
Xray Diagnostic
Metaphyseal splaying HP:0003015 Human Phenotype Ontology (HP) Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON) Flared metaphysis HP:0003015 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Directly identifies metaphyseal splaying on a founding patient's wrist radiograph as a typical feature of rickets.
Metaphyseal Cupping on Radiographs
Metaphyseal cupping is part of the active-rickets pattern on plain radiographs in younger patients. It supports radiographic recognition of rickets but is not specific to VDDR3.
Xray Diagnostic
Metaphyseal cupping HP:0003021 Human Phenotype Ontology (HP) Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON) Metaphyseal cupping HP:0003021 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Directly identifies metaphyseal cupping on a founding patient's wrist radiograph as a typical feature of rickets.
Metaphyseal Lucency on Radiographs
Older affected patients can show metaphyseal lucency on plain radiographs. The appearance supports the radiographic rickets pattern but is not specific to VDDR3.
Xray Diagnostic
Metaphyseal lucency Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON)
No sufficiently specific current HP or NCIT term was identified, so this imaging descriptor remains unbound rather than using an imprecise term.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Directly reports metaphyseal lucency on the older founding patient's wrist radiograph.
Osteopenia on Radiographs
Reduced radiographic bone density has been documented in a founding patient and in the Saudi patient. Osteopenia is supportive but nonspecific.
Xray
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON) Osteopenia HP:0000938 Human Phenotype Ontology (HP)
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"Wrist radiographs from these patients show the typical features of rickets: younger growing patients have bowing (green triangle), metaphyseal splaying (yellow triangle), and cupping (red triangle), as in proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue triangle) and osteopenia..."
Directly identifies osteopenia on the older founding patient's wrist radiograph.
PMID:38179381 SUPPORT Human Clinical
"In addition, mild osteopenia was present (image B)."
Independently reports osteopenia on the Saudi patient's radiographs.
Brush-Like Pelvic and Lower-Extremity Changes on Radiographs
The Chinese conference case described brush-like radiographic changes in the pelvis and lower extremities. This is preliminary case-level evidence for a rachitic appearance rather than a VDDR3-specific sign.
Xray Diagnostic
Brush-like skeletal changes Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON)
No sufficiently specific current HP or NCIT term was identified, so this imaging descriptor remains unbound; the source is a conference abstract.
Show evidence (1 reference)
url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422 SUPPORT Human Clinical
"X-ray films showed brush-like changes in the pelvis and lower extremities."
Directly reports the imaging appearance and its anatomic distribution in the molecularly confirmed Chinese conference case.
Treated-Rickets Metaphyseal Sclerosis on Radiographs
After alfacalcidol and calcium therapy, the Saudi patient's skeletal survey showed faint metaphyseal sclerosis of both distal femurs together with generalized osteopenia, interpreted by the authors as treated rickets. This is a treatment-context appearance, not a diagnostic sign of untreated VDDR3.
Xray Bilateral After alfacalcidol and calcium treatment
Metaphyseal sclerosis HP:0004979 Human Phenotype Ontology (HP) Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON)
Show evidence (1 reference)
PMID:38179381 SUPPORT Human Clinical
"However, the skeletal survey showed generalized osteopenia with a faint metaphyseal sclerosis involving bilateral distal femurs, suggestive of treated rickets (Figure 3)."
Directly reports the treated-rickets radiographic appearance, its bilaterality, and the involved distal femoral metaphyses.
🔀

Differential Diagnoses

8

Conditions with similar clinical presentations that must be differentiated from Vitamin D-Dependent Rickets Type 3:

Nutritional vitamin D deficiency rickets Not Yet Curated MONDO:0100471
Overlapping Features Nutritional deficiency can reproduce low calcifediol, low calcitriol, secondary hyperparathyroidism, and rickets. Adequate dosing ordinarily produces a sustained metabolite response, whereas VDDR3 shows rapid loss after an initial rise and carries the CYP3A4 p.Ile301Thr variant.
Distinguishing Features
  • Dietary or sunlight insufficiency rather than a pathogenic CYP3A4 allele.
  • Sustained response to conventional replacement rather than accelerated post-dose clearance.
Show evidence (1 reference)
PMID:36656330 SUPPORT Human Clinical
"Individuals who carry this heterozygous mutation have the same clinical and biochemical features as children with nutritional vitamin D deficiency, which makes it important to consider CYP3A4 mutations in patients with vitamin D deficiency who do not respond to conventional doses of vitamin D."
Establishes the close phenotypic overlap and deficient conventional-dose response that prompts evaluation for VDDR3.
Medication-induced CYP3A4 vitamin D hypercatabolism
Overlapping Features CYP3A4-inducing drugs can phenocopy selective vitamin D metabolite inactivation, but the process is exposure-related rather than the recurrent germline p.Ile301Thr disorder. Medication history and molecular testing separate this acquired mechanism from VDDR3.
Distinguishing Features
  • Exposure to a CYP3A4-inducing medication such as an anticonvulsant or rifampin.
  • Absence of the recurrent germline CYP3A4 p.Ile301Thr variant.
Show evidence (1 reference)
PMID:29461981 SUPPORT Other
"the genetic gain of function in CYP3A4 recapitulated the selective inactivation of vitamin D metabolites well described in patients taking drugs that induce CYP3A4 (21)."
Establishes the acquired medication-induced mechanistic phenocopy while distinguishing it from germline gain of function.
Vitamin D-dependent rickets type 1A MONDO:0020723
Overlapping Features CYP27B1 deficiency produces low calcitriol but normal or increased calcifediol because renal 1-alpha-hydroxylation is blocked. VDDR3 instead depletes both metabolites through accelerated catabolism and is associated with heterozygous CYP3A4 rather than biallelic CYP27B1 variation.
Distinguishing Features
  • Normal or increased calcifediol with low calcitriol.
  • Biallelic CYP27B1 loss of function.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"Plasma concentrations of 1,25(OH)2D are low or even undetectable. By contrast, plasma concentrations of 25 (OH)D are normal or increased, likely reflecting the effects of both vitamin D supplementation and decreased clearance of 25 (OH)D due to lack of induction of CYP24A1 by the absence of 1,25(OH)2D."
The review states the metabolite pattern that separates type 1A from VDDR3.
Vitamin D-dependent rickets type 1B MONDO:0010810
Overlapping Features CYP2R1 deficiency lowers calcifediol by impaired 25-hydroxylation and can therefore resemble VDDR3 biochemically. The distinction is the CYP2R1 genotype and failure to generate an adequate calcifediol increment, versus an initial increment followed by accelerated clearance in VDDR3.
Distinguishing Features
  • CYP2R1 loss-of-function genotype.
  • Negligible or blunted calcifediol generation rather than rapid post-peak clearance.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"VDDR1b (OMIM #600081) is due to mutations in CYP2R1 that decrease expression or function of the encoded CYP2R1 enzyme, the principal 25-hydroxylase. VDDR1b is associated with hypocalcemia, secondary hyperparathyroidism and low plasma concentrations of 25(OH)D, with reduced clinical and..."
Defines the CYP2R1 activation defect and its overlapping biochemical phenotype.
Vitamin D-dependent rickets type 2A MONDO:0010186
Overlapping Features Biallelic VDR loss causes target-tissue resistance with elevated rather than depleted calcitriol. Alopecia is a useful but incompletely sensitive clue.
Distinguishing Features
  • Elevated calcitriol despite hypocalcemic rickets.
  • Biallelic VDR loss of function; alopecia in about half of reported patients.
Show evidence (2 references)
PMID:32596195 SUPPORT Other
"Biochemical studies show low serum levels of calcium and phosphorus and elevated serum concentrations of 1,25(OH)2D, in the range of 50–1,000 pg/mL (normal in children is 30–100 pg/mL); serum concentrations of 25(OH)D may be normal or elevated due to lack of induction of CYP24A1, which requires..."
States the high-calcitriol pattern that distinguishes receptor resistance from VDDR3.
PMID:32596195 SUPPORT Other
"The clinical features of VDDR2a are very similar to those of patients with other forms of VDDR, but about fifty percent of patients with VDDR2a have alopecia."
Directly supports the approximate alopecia frequency used as a secondary distinguishing clue.
Vitamin D-dependent rickets type 2B MONDO:0010931
Overlapping Features VDDR2B has been proposed as a VDDR2A-like target-tissue resistance disorder without a VDR variant, potentially mediated by excess expression of a nuclear response-element-binding protein. No causative gene is established, and the review questions whether it is a distinct disorder. Its reported receptor-resistance pattern, rather than depleted vitamin D metabolites, separates the proposal from molecularly defined CYP3A4-related VDDR3.
Distinguishing Features
  • VDDR2A-like vitamin D target-tissue resistance without a VDR defect, rather than accelerated metabolite depletion.
  • No established causative gene and no CYP3A4 p.Ile301Thr variant; the status of VDDR2B as a distinct entity remains uncertain.
Show evidence (3 references)
PMID:32596195 SUPPORT Other
"VDDR2b (OMIM 600785) resembles VDDR2a but is not caused by a defect in the VDR gene. Rather, the molecular defect appears to be overexpression of a nuclear protein that specifically interacts with a DNA response element that binds retinoid X receptor-VDR heterodimers."
Defines the proposed receptor-response mechanism while appropriately using tentative language rather than assigning an established causative gene.
PMID:32596195 SUPPORT Other
"No gene has yet been identified as the cause of VDDR2b so it is impossible to state with precision the number of affected subjects."
Directly supports the lack of an established gene and the uncertainty of the published case denominator.
PMID:32596195 SUPPORT Other
"VDDR2b appears to be a very uncommon condition, if indeed it is a distinct disorder at all."
The review explicitly cautions that VDDR2B may not be a distinct disease, preventing overstatement of this differential.
Hypophosphatemic rickets Not Yet Curated MONDO:0024300
Overlapping Features Primary phosphopenic rickets shares hypophosphatemia, limb deformity, and growth-plate disease, but typically has normal calcium, parathyroid hormone, and vitamin D status with evidence of renal phosphate wasting; VDDR3 is a calciopenic disorder with elevated parathyroid hormone and depleted vitamin D metabolites.
Distinguishing Features
  • Normal calcium and parathyroid hormone in primary phosphopenic disease.
  • Reduced tubular phosphate reabsorption in genetic renal phosphate-wasting disorders such as XLH.
  • No CYP3A4 p.Ile301Thr variant or accelerated vitamin D metabolite clearance.
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..."
The diagnostic review gives the mineral pattern distinguishing primary phosphopenic rickets from calciopenic VDDR3.
Hypophosphatasia MONDO:0018570
Overlapping Features Hypophosphatasia can produce a rickets-like metaphyseal appearance, but tissue-nonspecific alkaline phosphatase activity is low rather than elevated. Persistently low age-adjusted alkaline phosphatase and pathogenic ALPL variation favor hypophosphatasia over VDDR3.
Distinguishing Features
  • Low rather than elevated age-adjusted serum alkaline phosphatase activity.
  • Pathogenic ALPL variation rather than CYP3A4 p.Ile301Thr.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"Because the appearance of the growth plate in children with rickets can resemble that of subjects with hypophosphatasia or metaphyseal dysplasias, a reasonable first step in diagnosis is to determine the serum level of alkaline phosphatase (Figure 2). Using age- and sex-related references..."
Directly establishes the radiographic mimic and the opposite alkaline phosphatase direction that separates it from VDDR3.
🧫

Experimental Models

2
CYP3A4-I301T HEK293T Substrate-Selectivity Assays CELL_LINE
HEK293T cells expressing wild-type CYP3A4, CYP3A4-I301T, or CYP24A1 were compared in a mammalian two-hybrid reporter system in which intracellular calcitriol drives luciferase; a parallel luciferin IPA assay compared activity toward a non-vitamin D CYP3A4 substrate. Increased calcitriol inactivation with decreased luciferin IPA turnover establishes substrate selectivity. The systems isolate the molecular enzymatic phenotype but do not reproduce patient mineral homeostasis or skeletal disease.
Recombinant CYP3A4-I301T Recombinant wild-type CYP3A4 Recombinant CYP24A1 comparator
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
HEK293T cells obtained from ATCC (CRL-3216)
Culture
Transfected mammalian two-hybrid calcitriol-responsive reporter and luciferin IPA CYP3A4 activity assays
Publication
PMID:29461981
Pathograph links
CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function measures fidelity: moderate The paired reporters compare increased calcitriol-inactivating function with activity toward a non-vitamin D substrate.
Limitations: Transient recombinant expression and an indirect reporter do not capture physiological hepatic abundance, whole-body pharmacokinetics, mineral feedback, or growth-plate disease.
Readouts
Calcitriol inactivation
Direction: INCREASED
Interpretation: CYP3A4-I301T inactivated calcitriol more strongly than wild-type CYP3A4 and CYP24A1 in the reporter comparison.
Show evidence (1 reference)
PMID:29461981 SUPPORT In Vitro
"CYP3A4 p.I301T had increased inactivation of calcitriol relative to WT (**P < 0.01 by 2-way ANOVA for curve)"
Directly reports the direction of the model readout.
Luciferin IPA turnover
Direction: DECREASED
Interpretation: CYP3A4-I301T showed lower activity than wild type toward this non-vitamin D substrate, demonstrating that the gain was not global.
Show evidence (1 reference)
PMID:29461981 SUPPORT In Vitro
"The p.I301T mutant had significantly decreased activity for luciferin IPA relative to the WT enzyme (30.0 ± 1.6 vs. 50.1 ± 1.6, n = 4 for each, ***P < 0.001)."
Directly reports the decreased non-vitamin D substrate readout.
Show evidence (1 reference)
PMID:29461981 SUPPORT In Vitro
"In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites."
Confirms that the recombinant variant system measures strongly increased calcitriol oxidation.
Show evidence (1 reference)
PMID:29461981 SUPPORT In Vitro
"Because the kidney cell line (HEK293T) does not express CYP3A4, we used it to create a cell-based assay."
Identifies the cell line and rationale for recombinant expression.
Recombinant E. coli CYP3A4-I301T Membrane-Fraction Assay OTHER
Membrane fractions from recombinant Escherichia coli expressing CYP3A4-I301T or wild-type CYP3A4 were used to characterize product formation from calcifediol and calcitriol. The system identified additional 11-alpha-hydroxylated, low-receptor-affinity products but cannot model human tissue expression or systemic clearance.
Recombinant human CYP3A4-I301T Recombinant human wild-type CYP3A4
Organism
Escherichia coli NCBITaxon:562 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Escherichia coli (NCBITaxon:562). NCBITaxon:562 is an organism from the NCBI Taxonomy.
Cell source
Membrane fractions from recombinant Escherichia coli
Culture
Cell-free recombinant CYP3A4 membrane-fraction enzymology
Publication
PMID:41046353
Pathograph links
Accelerated Formation of Low-Activity Vitamin D Metabolites measures fidelity: moderate Directly measures variant-specific vitamin D metabolite product formation.
Limitations: Bacterial membrane fractions isolate enzyme chemistry but omit mammalian cofactors, hepatic and intestinal regulation, circulating binding proteins, feedback, and whole-organism pharmacokinetics.
Readouts
Formation of additional low-affinity vitamin D metabolites
Direction: INCREASED
Interpretation: Relative to wild type, CYP3A4-I301T generated additional 11-alpha-hydroxylated products with lower vitamin D receptor affinity.
Show evidence (1 reference)
PMID:41046353 SUPPORT In Vitro
"Surprisingly, we found that CYP3A4-I301T efficiently produced additional metabolites compared to the wild-type CYP3A4, including 11α,25-dihydroxyvitamin D3 and 1α,11α,25-trihydroxyvitamin D3, which have much lower affinity for the vitamin D receptor than do 25(OH)D3 and 1α,25(OH)2D3, respectively."
Directly reports the product and affinity readout.
Show evidence (1 reference)
PMID:41046353 SUPPORT In Vitro
"In this study, we investigated the enzymatic properties of CYP3A4-I301T using membrane fractions from recombinant Escherichia coli expressing the variant."
Defines the recombinant membrane-fraction experimental system.
Show evidence (1 reference)
PMID:41046353 SUPPORT In Vitro
"In this study, we investigated the enzymatic properties of CYP3A4-I301T using membrane fractions from recombinant Escherichia coli expressing the variant."
Identifies the non-animal biochemical model.
🧮

Computational Models

1
CYP3A4-I301T Vitamin D Molecular Docking Model MOLECULAR_DOCKING
Molecular docking predicted a Thr301 hydrogen bond to the calcifediol 3-beta-hydroxyl group and interactions of the 25-hydroxyl group with Arg372 and Glu374, positioning substrate for 11-alpha hydroxylation. This is a structural explanation for product selectivity, not an experimentally determined CYP3A4-I301T structure.
PMID:41046353
Pathograph links
CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function partially recapitulates fidelity: low Provides an in-silico substrate-pose explanation for variant-specific 11-alpha hydroxylation.
Limitations: The predicted contacts have not been confirmed by an experimental CYP3A4-I301T-substrate structure and do not quantify in-vivo flux.
Show evidence (1 reference)
PMID:41046353 SUPPORT Computational
"Docking simulations suggested that the 3β-hydroxyl group of 25(OH)D3 forms a hydrogen bond with Thr301 of CYP3A4-I301T, while the 25-hydroxyl group interacts with Arg372 and Glu374, favoring hydroxylation at the 11α-position."
States the computationally predicted contacts and positional consequence without presenting them as experimental structure.
Show evidence (1 reference)
PMID:41046353 SUPPORT Computational
"Docking simulations suggested that the 3β-hydroxyl group of 25(OH)D3 forms a hydrogen bond with Thr301 of CYP3A4-I301T, while the 25-hydroxyl group interacts with Arg372 and Glu374, favoring hydroxylation at the 11α-position."
Defines the molecular-docking model and its predicted binding geometry.
{ }

Source YAML

click to show 
name: Vitamin D-Dependent Rickets Type 3
synonyms:
- VDDR3
- CYP3A4-related vitamin D-dependent rickets
- Vitamin D-dependent rickets, CYP3A4-related
- Vitamin D hypercatabolism rickets
creation_date: "2026-08-19T00:00:00Z"
updated_date: "2026-08-20T06:33:14Z"
category: Mendelian
description: >-
  Vitamin D-dependent rickets type 3 is an autosomal dominant vitamin D
  hypercatabolism disorder caused, in at least five molecularly described
  patients reported to date (four in peer-reviewed journal reports and one in a
  conference abstract), by the recurrent heterozygous CYP3A4 c.902T>C
  (p.Ile301Thr) gain-of-function variant. The altered enzyme accelerates
  conversion of calcifediol and calcitriol to metabolites with much lower
  vitamin D receptor affinity. Low circulating concentrations of both vitamin D
  metabolites lead to secondary hyperparathyroidism, hypocalcemia,
  hypophosphatemia, and childhood rickets. Unlike an activation defect or
  receptor resistance, the lesion is excessive degradation: conventional doses
  are inadequate, but pharmacologic-dose cholecalciferol or calcitriol can
  maintain mineral homeostasis; cholecalciferol regimens have also healed
  rickets. This disease entry is kept
  separate from acquired CYP3A4 induction by medications and from the other
  genetically distinct vitamin D-dependent rickets.
disease_term:
  preferred_term: vitamin D-dependent rickets, type 3
  term:
    id: MONDO:0033640
    label: vitamin D-dependent rickets, type 3
parents:
- Metabolic Bone Disorders
- Inborn Error of Metabolism
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous gain-of-function allele is sufficient. The two
    original patients, the Brazilian patient, and a Chinese patient described in
    a conference abstract had the variant absent from tested parents. The Saudi
    patient had an affected father, but the father was not genotyped, so
    inherited transmission in that family is plausible rather than proven.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neither patient had a mutation in any genes known to cause VDDR; however,
      using whole exome sequencing analysis, we identified a recurrent de novo
      missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that
      alters the conformation of substrate recognition site 4 (SRS-4).
    explanation: >-
      Establishes independent de novo occurrence of the same heterozygous
      variant in the two founding patients.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has a strong family history of rickets. Her parents are first cousins;
      the father has a history of rickets, short stature, and genu varum,
      corrected surgically and followed with orthopedics, while the mother is
      healthy.
    explanation: >-
      The affected father makes dominant transmission plausible, but parental
      molecular testing was not reported and therefore does not prove that the
      proband inherited the CYP3A4 allele.
  - reference: url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422
    reference_title: "A heterozygous variant of CYP3A4 in a Chinese boy with Vitamin D-dependent rickets type 3 | ESPE2022 | 60th Annual ESPE (ESPE 2022) | ESPE Abstracts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      p.Ile301Thr) which was further confirmed using Sanger sequencing. However,
      this variant was not found in his parents.
    explanation: >-
      A conference abstract reports another molecularly confirmed de novo
      occurrence; its preliminary publication type is retained as a limitation.
genetic:
- name: Germline CYP3A4 gain-of-function disease association
  gene_term:
    preferred_term: CYP3A4
    term:
      id: hgnc:2637
      label: CYP3A4
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Every molecularly described patient located through August 2026 carries
    c.902T>C (p.Ile301Thr). Four occurrences were absent from tested parents;
    the origin was not established in the Saudi family. No broader allelic
    series for VDDR3 has yet been demonstrated.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neither patient had a mutation in any genes known to cause VDDR; however,
      using whole exome sequencing analysis, we identified a recurrent de novo
      missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that
      alters the conformation of substrate recognition site 4 (SRS-4).
    explanation: >-
      Identifies the recurrent CYP3A4 variant in the two unrelated founding
      patients.
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe the third case of VDDR3 due to the same CYP3A4 mutation
      in a 2-year-old boy with bone deformities associated with poor growth.
    explanation: >-
      Extends the genotype-disease association to the third patient reported in
      a peer-reviewed journal; a 2022 conference abstract described another
      molecularly confirmed patient before this article appeared.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the finding of a heterozygous missense variant in CYP3A4: c.902 T > C;
      p.Ile301Thr in the CYP3A4 gene confirms the diagnosis of VDDR3.
    explanation: >-
      Identifies the recurrent allele in the fourth patient reported in a
      peer-reviewed journal; a 2022 conference abstract describes an additional
      molecularly confirmed Chinese patient.
  - reference: url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422
    reference_title: "A heterozygous variant of CYP3A4 in a Chinese boy with Vitamin D-dependent rickets type 3 | ESPE2022 | 60th Annual ESPE (ESPE 2022) | ESPE Abstracts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      p.Ile301Thr) which was further confirmed using Sanger sequencing. However,
      this variant was not found in his parents.
    explanation: >-
      Adds a fifth molecularly described patient while preserving that the
      source is a conference abstract rather than a full peer-reviewed report.
variants:
- name: CYP3A4 c.902T>C (p.Ile301Thr)
  gene:
    preferred_term: CYP3A4
    term:
      id: hgnc:2637
      label: CYP3A4
  type: missense
  clinical_significance: PATHOGENIC
  description: >-
    A recurrent heterozygous germline missense variant affecting substrate
    recognition site 4. The threonine substitution changes CYP3A4 substrate
    positioning and selectively increases vitamin D metabolite hydroxylation;
    activity toward at least one non-vitamin D substrate was not increased.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold
      greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1,
      the principal inactivator of vitamin D metabolites.
    explanation: >-
      Functional comparison demonstrates a strong, substrate-directed gain of
      vitamin D catabolic activity.
pathophysiology:
- name: CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
  description: >-
    The heterozygous p.Ile301Thr substitution remodels CYP3A4 substrate
    recognition site 4. It confers increased and altered hydroxylation of
    calcifediol and calcitriol rather than a nonspecific increase in all CYP3A4
    activity.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  gene:
    preferred_term: CYP3A4
    term:
      id: hgnc:2637
      label: CYP3A4
  genetic_context:
    gene:
      preferred_term: CYP3A4
      term:
        id: hgnc:2637
        label: CYP3A4
    allele_type: missense
    variant_origin: GERMLINE
    allelic_events:
    - MISSENSE_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Recurrent germline c.902T>C (p.Ile301Thr); absent from tested parents in
      four molecularly described patients and of undetermined origin in the
      Saudi family.
  molecular_functions:
  - preferred_term: Vitamin D metabolite steroid hydroxylase activity
    term:
      id: GO:0008395
      label: steroid hydroxylase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold
      greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1,
      the principal inactivator of vitamin D metabolites.
    explanation: >-
      Quantifies increased calcitriol oxidation by mutant CYP3A4 against both
      wild-type enzyme and the physiological vitamin D inactivator.
  - reference: PMID:41046353
    reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results indicate that the I301T mutation confers a gain-of-function
      phenotype on CYP3A4, enhancing its ability to metabolize 25(OH)D3 and
      1α,25(OH)2D3 into low-activity derivatives.
    explanation: >-
      The recombinant-enzyme study confirms gain of vitamin D metabolite
      hydroxylation and identifies low-activity products.
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The p.I301T mutant had significantly decreased activity for luciferin IPA
      relative to the WT enzyme (30.0 ± 1.6 vs. 50.1 ± 1.6, n = 4 for each, ***P
      < 0.001).
    explanation: >-
      The lack of a parallel gain for a non-vitamin D substrate supports a
      substrate-selective rather than global increase in CYP3A4 activity.
  downstream:
  - target: Accelerated Formation of Low-Activity Vitamin D Metabolites
    causal_link_type: DIRECT
    description: >-
      The altered active site increases hydroxylation of both calcifediol and
      calcitriol and changes the product profile.
    evidence:
    - reference: PMID:41046353
      reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Surprisingly, we found that CYP3A4-I301T efficiently produced additional
        metabolites compared to the wild-type CYP3A4, including
        11α,25-dihydroxyvitamin D3 and 1α,11α,25-trihydroxyvitamin D3, which have
        much lower affinity for the vitamin D receptor than do 25(OH)D3 and
        1α,25(OH)2D3, respectively.
      explanation: >-
        Direct recombinant-enzyme evidence establishes altered formation of
        additional low-affinity vitamin D products.
- name: Accelerated Formation of Low-Activity Vitamin D Metabolites
  description: >-
    CYP3A4-I301T rapidly converts calcifediol and calcitriol to hydroxylated
    derivatives. The 2026 enzyme study identified 11α,25-dihydroxyvitamin D3 and
    1α,11α,25-trihydroxyvitamin D3 as additional products with much lower
    vitamin D receptor affinity than their parent metabolites.
  role: central_effector
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  chemical_entities:
  - preferred_term: calcidiol
    term:
      id: CHEBI:17933
      label: calcidiol
  - preferred_term: calcitriol
    term:
      id: CHEBI:17823
      label: calcitriol
  biological_processes:
  - preferred_term: Vitamin D metabolic process
    term:
      id: GO:0042359
      label: vitamin D metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold
      greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1,
      the principal inactivator of vitamin D metabolites.
    explanation: >-
      Establishes accelerated calcitriol oxidation by the variant enzyme.
  - reference: PMID:41046353
    reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, we found that CYP3A4-I301T efficiently produced additional
      metabolites compared to the wild-type CYP3A4, including
      11α,25-dihydroxyvitamin D3 and 1α,11α,25-trihydroxyvitamin D3, which have
      much lower affinity for the vitamin D receptor than do 25(OH)D3 and
      1α,25(OH)2D3, respectively.
    explanation: >-
      Defines the additional products and their reduced receptor affinity.
  downstream:
  - target: Vitamin D Metabolite Depletion
    causal_link_type: DIRECT
    description: >-
      Accelerated conversion shortens the persistence of circulating
      calcifediol and calcitriol after an absorbed vitamin D dose.
    evidence:
    - reference: PMID:36656330
      reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Serial measurements of vitamin D metabolites after a single 150,000 IU
        dose of cholecalciferol demonstrated an accelerated inactivation of
        25(OH)D and 1,25(OH)2D.
      explanation: >-
        A serial human challenge directly demonstrates unusually rapid loss of
        both circulating metabolites after absorption.
- name: Vitamin D Metabolite Depletion
  description: >-
    Untreated or conventionally treated patients have low circulating
    calcifediol and calcitriol. A large oral dose produces an initial rise,
    demonstrating absorption and activation, followed by an abnormally rapid
    fall, distinguishing accelerated clearance from defective synthesis.
  role: central_effector
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  chemical_entities:
  - preferred_term: calcidiol
    term:
      id: CHEBI:17933
      label: calcidiol
  - preferred_term: calcitriol
    term:
      id: CHEBI:17823
      label: calcitriol
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Documents depletion of both major circulating vitamin D metabolites in
      the founding patients.
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum levels of 25(OH)D and 1,25(OH)2D peaked on the 3rd day after the
      vitamin D challenge, reducing considerably by the 30th day, as shown in
      Fig. 2.
    explanation: >-
      Serial sampling shows an initial response followed by rapid metabolite
      loss.
  downstream:
  - target: Decreased circulating calcifediol concentration
    causal_link_type: DIRECT
    description: >-
      Depletion of the calcifediol pool is observed as low circulating
      25-hydroxyvitamin D and also reduces substrate available for calcitriol
      synthesis.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe two unrelated patients with early-onset rickets,
        reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D
        and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
        activated forms of vitamin D.
      explanation: >-
        Directly supports low circulating calcifediol downstream of the
        depletion state.
  - target: Decreased circulating calcitriol concentration
    causal_link_type: DIRECT
    description: >-
      Depletion of active vitamin D is observed as low circulating
      1,25-dihydroxyvitamin D and reduces vitamin D receptor ligand availability.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe two unrelated patients with early-onset rickets,
        reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D
        and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
        activated forms of vitamin D.
      explanation: >-
        Directly supports low circulating calcitriol downstream of the
        depletion state.
  - target: Calciopenic Mineral-Ion Disturbance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced calcitriol-dependent duodenal calcium transport.
    - Secondary hyperparathyroidism with reduced renal phosphate reabsorption.
    description: >-
      Loss of calcitriol action reduces intestinal calcium transport;
      hypocalcemia stimulates parathyroid hormone, which promotes renal
      phosphate loss.
    evidence:
    - reference: PMID:32596195
      reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Nearly all features of vitamin D deficiency represent a direct or
        indirect consequence of the loss of vitamin D action on duodenal
        transport of calcium and to a lesser degree on impaired mobilization of
        calcium from skeletal stores. Hypocalcemia, and to some degree
        calciferol deficiency, results in increased section of PTH from the
        parathyroid glands (i.e., secondary hyperparathyroidism), which leads to
        decreased reabsorption of phosphate and bicarbonate in the proximal renal
        tubule, resulting in hypophosphatemia and hyperchloremic acidosis,
        respectively.
      explanation: >-
        The diagnostic-management review states the known intermediates between
        deficient vitamin D action and the mineral-ion pattern.
- name: Calciopenic Mineral-Ion Disturbance
  description: >-
    Reduced calcium delivery produces hypocalcemia and secondary
    hyperparathyroidism. Parathyroid hormone-driven renal phosphate loss adds
    hypophosphatemia; alkaline phosphatase rises with active rachitic bone
    turnover. This node represents the systemic calciopenic state rather than
    treating each laboratory measurement as a separate causal mechanism.
  role: central_effector
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  conforms_to: "defective_skeletal_mineralization#Calciopenic Substrate Deficiency"
  cell_types:
  - preferred_term: Enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: Vitamin D receptor signaling pathway
    term:
      id: GO:0070561
      label: vitamin D receptor signaling pathway
    modifier: DECREASED
  - preferred_term: Intestinal calcium absorption
    term:
      id: GO:0070509
      label: calcium ion import
    modifier: DECREASED
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral genu varum, poor growth, and reduced serum calcium and phosphorus
      with elevated serum alkaline phosphatase and parathyroid hormone (Table 1).
    explanation: >-
      Records the complete calciopenic laboratory pattern in a founding patient.
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His initial biochemical studies showed a low calcium of 1.3 mmol/L (NR
      2.2–2.77), a low phosphorus of 1.07 mmol/L (NR 1.45–2.1), an elevated
      Alkaline Phosphatase at 18.45 μkat/L (NR < 8.3), a low 25(OH)D of 29.45
      mmol/L (NR > 50), a high PTH of 371 ng/L (NR 12–88), and an elevated
      1,25(OH)2D of 252 pmol/mL (NR 49.7–198).
    explanation: >-
      Confirms low calcium and phosphate with elevated alkaline phosphatase and
      parathyroid hormone in the Brazilian patient; calcitriol was elevated while he
      was taking calcitriol and is not used here as an untreated-state claim.
  downstream:
  - target: Hypocalcemia
    causal_link_type: DIRECT
    description: Reduced circulating calcium is a causally active component of the calciopenic state.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral genu varum, poor growth, and reduced serum calcium and
        phosphorus with elevated serum alkaline phosphatase and parathyroid
        hormone (Table 1).
      explanation: Directly supports hypocalcemia as part of the systemic disturbance.
  - target: Hypophosphatemia
    causal_link_type: DIRECT
    description: Reduced circulating phosphate is a causally active component of the calciopenic state.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral genu varum, poor growth, and reduced serum calcium and
        phosphorus with elevated serum alkaline phosphatase and parathyroid
        hormone (Table 1).
      explanation: Directly supports hypophosphatemia as part of the systemic disturbance.
  - target: Elevated circulating parathyroid hormone level
    causal_link_type: DIRECT
    description: Secondary parathyroid hormone elevation is an active hormonal component of the calciopenic state.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral genu varum, poor growth, and reduced serum calcium and
        phosphorus with elevated serum alkaline phosphatase and parathyroid
        hormone (Table 1).
      explanation: Directly supports secondary parathyroid hormone elevation.
  - target: Impaired Hydroxyapatite Deposition at the Mineralization Front
    causal_link_type: DIRECT
    description: >-
      Low calcium and phosphate reduce the substrate available for
      hydroxyapatite deposition at the mineralization front.
    evidence:
    - reference: PMID:32596195
      reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Hypocalcemia and hypophosphatemia collectively reduce the rate of
        mineralization of bone matrix. Reduced serum levels of calcium and/or
        phosphorus can produce osteomalacia, as the low concentrations of these
        minerals are insufficient to induce or propagate hydroxyapatite cystral
        deposition in the skeleton. By contrast, rickets arises as a result of a
        growth plate defect that in which hypertrophic chondrocytes fail to
        undergo caspase 9-mediated apoptosis due to reduced concentrations of
        extracellular phosphate (20).
      explanation: >-
        The review directly links the mineral-ion deficits to reduced bone
        matrix mineralization.
  - target: Growth-Plate Hypertrophic Zone Expansion
    causal_link_type: DIRECT
    description: >-
      The hypophosphatemic component directly impairs apoptosis of terminal
      hypertrophic chondrocytes in the growing skeleton.
    evidence:
    - reference: PMID:32596195
      reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        rickets arises as a result of a growth plate defect that in which
        hypertrophic chondrocytes fail to undergo caspase 9-mediated apoptosis
        due to reduced concentrations of extracellular phosphate (20).
      explanation: >-
        Defines the direct phosphate-dependent route to the rachitic
        growth-plate lesion.
- name: Impaired Hydroxyapatite Deposition at the Mineralization Front
  description: >-
    Inadequate calcium-phosphate availability lowers hydroxyapatite deposition
    into bone matrix. This shared skeletal mineralization failure produces
    osteopenia and, in the growing skeleton, feeds a distinct growth-plate
    lesion.
  role: central_effector
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  conforms_to: "defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front"
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: Bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  - preferred_term: Biomineral tissue development
    term:
      id: GO:0031214
      label: biomineral tissue development
    modifier: DECREASED
  locations:
  - preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypocalcemia and hypophosphatemia collectively reduce the rate of
      mineralization of bone matrix. Reduced serum levels of calcium and/or
      phosphorus can produce osteomalacia, as the low concentrations of these
      minerals are insufficient to induce or propagate hydroxyapatite cystral
      deposition in the skeleton.
    explanation: >-
      Directly supports impaired matrix mineralization and hydroxyapatite
      deposition downstream of the mineral deficits.
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Directly documents age-dependent rachitic and osteopenic radiographic
      abnormalities in the founding patients.
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His radiographs were suggestive of active rickets—(Fig. 1A).
    explanation: >-
      Confirms active radiographic rickets in the Brazilian patient.
  downstream:
  - target: Osteopenia
    causal_link_type: DIRECT
    description: Reduced skeletal mineralization lowers radiographic bone density.
  - target: Frontal bossing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Rachitic remodeling of the growing skull.
    description: Impaired cranial mineralization can produce frontal prominence.
- name: Growth-Plate Hypertrophic Zone Expansion
  description: >-
    Extracellular phosphate deficiency impairs apoptosis of terminal
    hypertrophic chondrocytes. The hypertrophic zone expands and the growing
    metaphysis becomes widened, irregular, and cupped, producing the
    radiographic and load-bearing manifestations of childhood rickets.
  role: effector
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  conforms_to: "defective_skeletal_mineralization#Growth Plate Hypertrophic Zone Expansion"
  cell_types:
  - preferred_term: Hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: Hypertrophic chondrocyte apoptosis
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: DECREASED
  - preferred_term: Growth plate cartilage development
    term:
      id: GO:0003417
      label: growth plate cartilage development
    modifier: ABNORMAL
  locations:
  - preferred_term: Growth plate
    term:
      id: UBERON:0002516
      label: epiphyseal plate
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      rickets arises as a result of a growth plate defect that in which
      hypertrophic chondrocytes fail to undergo caspase 9-mediated apoptosis due
      to reduced concentrations of extracellular phosphate (20). This effect of
      hypophosphatemia provides a final common pathway that unifies the growth
      plate defect of calciopenic forms of rickets (i.e., rickets due to
      deficiency of vitamin D and/or calcium) with that of hypophosphatemic forms
      of rickets.
    explanation: >-
      Establishes phosphate-dependent hypertrophic-chondrocyte failure as the
      common growth-plate mechanism in calciopenic rickets.
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Documents the corresponding widened and cupped metaphyseal phenotype in
      VDDR3.
  downstream:
  - target: Rickets
    causal_link_type: DIRECT
    description: Growth-plate expansion and disorganization are the defining rachitic lesion.
  - target: Genu varum
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Load-dependent angulation across a weakened growing metaphysis.
    description: Growth-plate weakness permits outward lower-limb bowing.
  - target: Genu valgum
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Load-dependent angulation across a weakened growing metaphysis.
    description: Growth-plate weakness can alternatively produce inward knee angulation.
  - target: Flared metaphysis
    causal_link_type: DIRECT
    description: Disorganized mineralization widens and splays the metaphysis.
  - target: Metaphyseal cupping
    causal_link_type: DIRECT
    description: Abnormal metaphyseal mineralization produces the cup-shaped contour.
  - target: Growth delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic growth-plate dysfunction.
    description: Persistent growth-plate disease slows linear growth.
  - target: Delayed ability to walk
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Lower-limb deformity and impaired weight-bearing.
    description: Severe rachitic lower-limb disease delays independent walking.
  - target: Unsteady gait
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Lower-limb deformity and impaired weight-bearing.
    description: Rachitic limb deformity impairs gait stability.
  - target: Bilateral knee pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mechanical stress across undermineralized and deformed lower-limb bone.
    description: >-
      Rachitic lower-limb disease can produce bilateral knee discomfort during
      mobility.
phenotypes:
- category: Skeletal
  name: Rickets
  description: >-
    Childhood-onset active rickets is the defining skeletal presentation.
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  phenotype_contexts:
  - onset:
      onset_category: CHILDHOOD
      notes: >-
        The reported patients presented in early childhood, although one
        founding patient was evaluated as an adolescent after childhood disease.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe two unrelated patients with early-onset rickets,
        reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D
        and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
        activated forms of vitamin D.
      explanation: >-
        Establishes early-onset rickets in both founding patients.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Names rickets as the presenting skeletal disease.
- category: Skeletal
  name: Genu varum
  description: Outward bowing of the legs was present in the founding and Brazilian cases.
  phenotype_term:
    preferred_term: Genu varum
    term:
      id: HP:0002970
      label: Genu varum
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral genu varum, poor growth, and reduced serum calcium and phosphorus
      with elevated serum alkaline phosphatase and parathyroid hormone (Table 1).
    explanation: >-
      Directly reports bilateral genu varum in a founding patient.
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His physical examination revealed a height of 83 cm in height (− 2.5 SDS)
      with a midparental target height of + 0.7 SDS. His weight was normal. He
      had thickened wrists and bowed legs (genu varum).
    explanation: >-
      Independently documents genu varum in the Brazilian patient.
- category: Skeletal
  name: Genu valgum
  description: >-
    The Saudi patient broadened the limb-angulation spectrum to genu valgum.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hereby report a case of a six-year-old girl with poor growth and bone
      deformities, such as genu valgum.
    explanation: >-
      Directly reports genu valgum in the Saudi molecularly confirmed patient.
- category: Skeletal
  name: Bilateral knee pain
  description: >-
    Bilateral knee discomfort was the presenting symptom in the Chinese
    molecularly confirmed patient. The other case reports did not systematically
    assess its absence, so this positive observation does not support a disease
    frequency estimate.
  phenotype_term:
    preferred_term: Bilateral knee pain
    term:
      id: HP:0030839
      label: Knee pain
    laterality: BILATERAL
  evidence:
  - reference: url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422
    reference_title: "A heterozygous variant of CYP3A4 in a Chinese boy with Vitamin D-dependent rickets type 3 | ESPE2022 | 60th Annual ESPE (ESPE 2022) | ESPE Abstracts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the case of a 32-month-old boy presented with discomfort of
      both knee-joints, poor mobility, and gait abnormality when running.
    explanation: >-
      Directly reports bilateral knee-joint discomfort. Mapping the source term
      "discomfort" to knee pain is clinically close but calibrated, and the
      evidence is a conference abstract rather than a full peer-reviewed report.
      It establishes an observed case, not a frequency denominator.
- category: Skeletal
  name: Flared metaphysis
  description: Metaphyseal splaying was visible on wrist radiographs.
  phenotype_term:
    preferred_term: Flared metaphysis
    term:
      id: HP:0003015
      label: Flared metaphysis
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      The HPO synonym metaphyseal splaying maps directly to flared metaphysis.
- category: Skeletal
  name: Metaphyseal cupping
  description: Metaphyseal cupping was visible on wrist radiographs.
  phenotype_term:
    preferred_term: Metaphyseal cupping
    term:
      id: HP:0003021
      label: Metaphyseal cupping
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Directly reports metaphyseal cupping.
- category: Skeletal
  name: Osteopenia
  description: >-
    Osteopenia was reported radiographically in an older founding patient and
    in the Saudi patient.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Directly reports osteopenia in the older founding patient.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, mild osteopenia was present (image B).
    explanation: >-
      Independently documents radiographic osteopenia in the Saudi patient.
- category: Skeletal
  name: Frontal bossing
  description: Mild frontal bossing was observed in the Saudi patient.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her physical examination revealed no dysmorphic features. She had mild
      frontal bossing and no widening in the wrists, and her gait was normal with
      mild genu valgum.
    explanation: >-
      Directly reports frontal bossing during clinical evaluation.
- category: Growth
  name: Growth delay
  description: Poor linear growth or growth arrest accompanied active rickets.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe the third case of VDDR3 due to the same CYP3A4 mutation
      in a 2-year-old boy with bone deformities associated with poor growth.
    explanation: >-
      Directly reports poor growth in the Brazilian patient.
- category: Motor
  name: Delayed ability to walk
  description: Independent walking was markedly delayed in two reported patients.
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proband 2.1 was of Middle Eastern descent and did not walk until 4.5 years
      of age.
    explanation: >-
      Directly documents delayed independent walking in a founding patient.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Earlier at the age of two years, the family noted she had a delay in speech
      and walking. When she eventually started to walk at the age of three years,
      the family noticed that she had knock knees and an unsteady gait.
    explanation: >-
      Independently documents delayed walking in the Saudi patient.
- category: Motor
  name: Unsteady gait
  description: Gait instability accompanied lower-limb rickets and deformity.
  phenotype_term:
    preferred_term: Unsteady gait
    term:
      id: HP:0002317
      label: Unsteady gait
  evidence:
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This 2 8/12-year-old Caucasian male presented with a history of bowed legs,
      gait instability, and growth arrest since 12 months of age.
    explanation: >-
      Directly documents gait instability in the Brazilian patient.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Earlier at the age of two years, the family noted she had a delay in speech
      and walking. When she eventually started to walk at the age of three years,
      the family noticed that she had knock knees and an unsteady gait.
    explanation: >-
      Independently documents an unsteady gait in the Saudi patient.
- category: Nervous System
  name: Delayed speech and language development
  description: >-
    Speech delay was reported in the Saudi molecularly confirmed patient. The
    report does not establish that it was caused by VDDR3, and the other case
    reports did not systematically assess its absence, so no disease frequency
    is inferred.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Earlier at the age of two years, the family noted she had a delay in speech
      and walking.
    explanation: >-
      Directly reports delayed speech in one molecularly confirmed patient; it
      supports one observed phenotype but neither a causal neurodevelopmental
      mechanism nor a frequency estimate.
- category: Biochemical
  name: Decreased circulating calcifediol concentration
  description: Low 25-hydroxyvitamin D is a characteristic circulating readout.
  phenotype_term:
    preferred_term: Decreased circulating calcifediol concentration
    term:
      id: HP:0012053
      label: Decreased circulating calcifediol concentration
  reports_on:
  - target: Vitamin D Metabolite Depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reduced circulating calcifediol directly reports depletion of the
      CYP3A4-I301T substrate pool.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe two unrelated patients with early-onset rickets,
        reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D
        and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
        activated forms of vitamin D.
      explanation: >-
        Directly links low circulating 25-hydroxyvitamin D to the metabolite
        depletion state.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Reports low circulating 25-hydroxyvitamin D in both founding patients.
- category: Biochemical
  name: Decreased circulating calcitriol concentration
  description: Low 1,25-dihydroxyvitamin D is a characteristic circulating readout.
  phenotype_term:
    preferred_term: Decreased circulating calcitriol concentration
    term:
      id: HP:0012052
      label: Decreased circulating calcitriol concentration
  reports_on:
  - target: Vitamin D Metabolite Depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reduced circulating calcitriol directly reports depletion of the active
      vitamin D substrate pool.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe two unrelated patients with early-onset rickets,
        reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D
        and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
        activated forms of vitamin D.
      explanation: >-
        Directly links low circulating 1,25-dihydroxyvitamin D to metabolite
        depletion.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Reports low circulating calcitriol in both founding patients.
- category: Biochemical
  name: Hypocalcemia
  description: Serum calcium may be markedly reduced during active disease.
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  reports_on:
  - target: Calciopenic Mineral-Ion Disturbance
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low serum calcium reports the calciopenic systemic state.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral genu varum, poor growth, and reduced serum calcium and
        phosphorus with elevated serum alkaline phosphatase and parathyroid
        hormone (Table 1).
      explanation: >-
        Directly reports low serum calcium in active VDDR3.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral genu varum, poor growth, and reduced serum calcium and phosphorus
      with elevated serum alkaline phosphatase and parathyroid hormone (Table 1).
    explanation: >-
      Directly reports reduced serum calcium.
- category: Biochemical
  name: Hypophosphatemia
  description: Serum phosphate is reduced during active calciopenic rickets.
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  reports_on:
  - target: Calciopenic Mineral-Ion Disturbance
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low serum phosphate reports the secondary phosphaturic state.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral genu varum, poor growth, and reduced serum calcium and
        phosphorus with elevated serum alkaline phosphatase and parathyroid
        hormone (Table 1).
      explanation: >-
        Directly reports low serum phosphorus in active VDDR3.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral genu varum, poor growth, and reduced serum calcium and phosphorus
      with elevated serum alkaline phosphatase and parathyroid hormone (Table 1).
    explanation: >-
      Directly reports reduced serum phosphorus.
- category: Biochemical
  name: Elevated circulating parathyroid hormone level
  description: Secondary hyperparathyroidism accompanies active disease.
  phenotype_term:
    preferred_term: Elevated circulating parathyroid hormone level
    term:
      id: HP:0003165
      label: Elevated circulating parathyroid hormone level
  reports_on:
  - target: Calciopenic Mineral-Ion Disturbance
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated PTH reports the secondary hyperparathyroid response.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral genu varum, poor growth, and reduced serum calcium and
        phosphorus with elevated serum alkaline phosphatase and parathyroid
        hormone (Table 1).
      explanation: >-
        Directly reports elevated parathyroid hormone in active VDDR3.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral genu varum, poor growth, and reduced serum calcium and phosphorus
      with elevated serum alkaline phosphatase and parathyroid hormone (Table 1).
    explanation: >-
      Directly reports elevated parathyroid hormone.
- category: Biochemical
  name: Elevated circulating alkaline phosphatase concentration
  description: Alkaline phosphatase rises with active rachitic bone turnover.
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  reports_on:
  - target: Impaired Hydroxyapatite Deposition at the Mineralization Front
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated alkaline phosphatase reports active rachitic bone turnover.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        bilateral genu varum, poor growth, and reduced serum calcium and
        phosphorus with elevated serum alkaline phosphatase and parathyroid
        hormone (Table 1).
      explanation: >-
        Reports alkaline phosphatase elevation together with active clinical
        rickets.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral genu varum, poor growth, and reduced serum calcium and phosphorus
      with elevated serum alkaline phosphatase and parathyroid hormone (Table 1).
    explanation: >-
      Directly reports elevated serum alkaline phosphatase.
imaging_findings:
- name: Metaphyseal Splaying on Radiographs
  modality: XRAY
  imaging_finding_term:
    preferred_term: Metaphyseal splaying
    term:
      id: HP:0003015
      label: Flared metaphysis
  description: >-
    Plain radiographs show metaphyseal splaying or flaring in younger patients
    with active rickets. This supports radiographic recognition of rickets but
    does not identify VDDR3 without biochemical and molecular evidence.
  located_in:
    preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  phenotype_term:
    preferred_term: Flared metaphysis
    term:
      id: HP:0003015
      label: Flared metaphysis
  diagnostic: true
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Directly identifies metaphyseal splaying on a founding patient's wrist
      radiograph as a typical feature of rickets.
- name: Metaphyseal Cupping on Radiographs
  modality: XRAY
  imaging_finding_term:
    preferred_term: Metaphyseal cupping
    term:
      id: HP:0003021
      label: Metaphyseal cupping
  description: >-
    Metaphyseal cupping is part of the active-rickets pattern on plain
    radiographs in younger patients. It supports radiographic recognition of
    rickets but is not specific to VDDR3.
  located_in:
    preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  phenotype_term:
    preferred_term: Metaphyseal cupping
    term:
      id: HP:0003021
      label: Metaphyseal cupping
  diagnostic: true
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Directly identifies metaphyseal cupping on a founding patient's wrist
      radiograph as a typical feature of rickets.
- name: Metaphyseal Lucency on Radiographs
  modality: XRAY
  imaging_finding_term:
    preferred_term: Metaphyseal lucency
  description: >-
    Older affected patients can show metaphyseal lucency on plain radiographs.
    The appearance supports the radiographic rickets pattern but is not specific
    to VDDR3.
  located_in:
    preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  diagnostic: true
  notes: >-
    No sufficiently specific current HP or NCIT term was identified, so this
    imaging descriptor remains unbound rather than using an imprecise term.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Directly reports metaphyseal lucency on the older founding patient's
      wrist radiograph.
- name: Osteopenia on Radiographs
  modality: XRAY
  imaging_finding_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  description: >-
    Reduced radiographic bone density has been documented in a founding patient
    and in the Saudi patient. Osteopenia is supportive but nonspecific.
  located_in:
    preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  diagnostic: false
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Directly identifies osteopenia on the older founding patient's wrist
      radiograph.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, mild osteopenia was present (image B).
    explanation: >-
      Independently reports osteopenia on the Saudi patient's radiographs.
- name: Brush-Like Pelvic and Lower-Extremity Changes on Radiographs
  modality: XRAY
  imaging_finding_term:
    preferred_term: Brush-like skeletal changes
  description: >-
    The Chinese conference case described brush-like radiographic changes in
    the pelvis and lower extremities. This is preliminary case-level evidence
    for a rachitic appearance rather than a VDDR3-specific sign.
  located_in:
    preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  diagnostic: true
  notes: >-
    No sufficiently specific current HP or NCIT term was identified, so this
    imaging descriptor remains unbound; the source is a conference abstract.
  evidence:
  - reference: url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422
    reference_title: "A heterozygous variant of CYP3A4 in a Chinese boy with Vitamin D-dependent rickets type 3 | ESPE2022 | 60th Annual ESPE (ESPE 2022) | ESPE Abstracts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-ray films showed brush-like changes in the pelvis and lower extremities.
    explanation: >-
      Directly reports the imaging appearance and its anatomic distribution in
      the molecularly confirmed Chinese conference case.
- name: Treated-Rickets Metaphyseal Sclerosis on Radiographs
  modality: XRAY
  imaging_finding_term:
    preferred_term: Metaphyseal sclerosis
    term:
      id: HP:0004979
      label: Metaphyseal sclerosis
  description: >-
    After alfacalcidol and calcium therapy, the Saudi patient's skeletal survey
    showed faint metaphyseal sclerosis of both distal femurs together with
    generalized osteopenia, interpreted by the authors as treated rickets. This
    is a treatment-context appearance, not a diagnostic sign of untreated VDDR3.
  located_in:
    preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  laterality: BILATERAL
  diagnostic: false
  context: After alfacalcidol and calcium treatment
  evidence:
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the skeletal survey showed generalized osteopenia with a faint
      metaphyseal sclerosis involving bilateral distal femurs, suggestive of
      treated rickets (Figure 3).
    explanation: >-
      Directly reports the treated-rickets radiographic appearance, its
      bilaterality, and the involved distal femoral metaphyses.
treatments:
- name: Pharmacologic-Dose Vitamin D Replacement
  description: >-
    The gain of catabolism makes conventional replacement inadequate, not
    futile. Pharmacologic-dose cholecalciferol or calcitriol can maintain
    vitamin D metabolites, calcium, phosphate, and parathyroid hormone;
    cholecalciferol regimens have also produced skeletal and functional
    improvement. Reported requirements vary substantially with age and body
    size: 50,000 IU cholecalciferol daily or high-dose calcitriol in the
    founding patients, 10,000 IU cholecalciferol daily plus calcium in a younger
    child, alfacalcidol 1.5–2 mcg with calcium 30 mg/kg daily followed by 50,000
    IU cholecalciferol weekly in the Saudi case. The alfacalcidol-calcium regimen
    accompanied clinical improvement but residual generalized osteopenia, so it
    is not evidence of complete skeletal correction. These are case-derived
    observations, not a standardized regimen; dose selection and monitoring
    require specialist supervision.
  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: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
    - preferred_term: alfacalcidol
      term:
        id: CHEBI:31186
        label: alfacalcidol
  target_phenotypes:
  - preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  - preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  target_mechanisms:
  - target: Vitamin D Metabolite Depletion
    treatment_effect: RESTORES
    description: >-
      Sustained pharmacologic input compensates for accelerated clearance and
      restores circulating metabolite and mineral-ion concentrations while
      treatment is maintained; it does not correct the CYP3A4 allele.
    evidence:
    - reference: PMID:32596195
      reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Both patients required high doses of calcitriol or vitamin D3 (50,000 IU
        daily) to maintain normal serum concentrations of vitamin D metabolites as
        well as normal serum levels of PTH, calcium, and phosphorus.
      explanation: >-
        Directly supports biochemical restoration of the depleted vitamin D and
        mineral-ion state while pharmacologic replacement is maintained.
  - target: Impaired Hydroxyapatite Deposition at the Mineralization Front
    treatment_effect: RESTORES
    description: >-
      Pharmacologic vitamin D treatment, often administered with calcium,
      produced radiographic improvement and healing of bone deformities. These
      clinical readouts support restoration of skeletal mineralization, although
      no biopsy or direct mineral-deposition assay was performed.
    evidence:
    - reference: PMID:36656330
      reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Significant improvement in growth velocity and healing of bone
        deformities were achieved after a short period of treatment with 10.000
        IU of cholecalciferol daily, showing the importance of early recognition
        and prompt precision therapy of this condition.
      explanation: >-
        Directly reports skeletal healing after pharmacologic cholecalciferol;
        the patient also received calcium, so the vitamin D contribution is not
        experimentally isolated.
    - reference: url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422
      reference_title: "A heterozygous variant of CYP3A4 in a Chinese boy with Vitamin D-dependent rickets type 3 | ESPE2022 | 60th Annual ESPE (ESPE 2022) | ESPE Abstracts"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After several months of oral vitamin D treatment, the pathological
        changes improved in X-ray films.
      explanation: >-
        Directly reports radiographic improvement, with the limitation that the
        source is a conference abstract and does not specify the regimen.
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Both patients required high doses of calcitriol or vitamin D3 (50,000 IU
      daily) to maintain normal serum concentrations of vitamin D metabolites as
      well as normal serum levels of PTH, calcium, and phosphorus.
    explanation: >-
      The management review summarizes successful biochemical maintenance in
      the two founding patients.
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At his most recent clinic visit, 3 months after the initiation of 10,000 IU
      of cholecalciferol daily, his height had increased to 91.4 cm (Z −1.3
      SDS), with a greatly increased height velocity (5.9 cm in 3 months) and
      markedly improved gait.
    explanation: >-
      Directly documents rapid growth and gait improvement in the Brazilian patient.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately three months after beginning cholecalciferol 50,000 IU
      weekly, her lab results showed a significant improvement.
    explanation: >-
      Documents biochemical improvement on a lower-frequency high-dose regimen
      in the Saudi patient.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon follow-up at the age of eight years, the patient continued to receive
      alfacalcidol at a dosage of 1.5-2 mcg, along with a daily calcium supplement
      of 30 mg/kg. The patient clinically improved (mild genu valgum), and her
      height was -0.87 SD.
    explanation: >-
      Documents the alfacalcidol-calcium regimen and clinical improvement, but
      the combined treatment prevents attribution to alfacalcidol alone and the
      same visit retained generalized osteopenia.
  - reference: url:https://abstracts.eurospe.org/hrp/0095/hrp0095p1-422
    reference_title: "A heterozygous variant of CYP3A4 in a Chinese boy with Vitamin D-dependent rickets type 3 | ESPE2022 | 60th Annual ESPE (ESPE 2022) | ESPE Abstracts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After several months of oral vitamin D treatment, the pathological changes
      improved in X-ray films.
    explanation: >-
      Directly reports radiographic improvement in the conference case, while
      leaving the vitamin D formulation and dose unspecified.
  notes: >-
    Calcium supplements accompanied treatment in the two recent case reports,
    so their independent contribution cannot be separated. Published experience
    is too small to define an age- or weight-standardized optimal dose.
- name: Adjunctive Calcium Supplementation
  description: >-
    Oral calcium was administered with pharmacologic vitamin D in the Brazilian
    and Saudi cases. The Brazilian combined regimen normalized serum calcium and
    produced marked radiographic improvement, while the Saudi alfacalcidol-calcium
    regimen accompanied clinical improvement but residual osteopenia. No calcium
    monotherapy result is available, so calcium is modeled as an adjunct and its
    independent efficacy cannot be inferred.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcium ion
      term:
        id: CHEBI:29108
        label: calcium(2+)
  target_phenotypes:
  - preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  target_mechanisms:
  - target: Calciopenic Mineral-Ion Disturbance
    treatment_effect: RESTORES
    description: >-
      Supplemental calcium supplies one depleted mineral substrate while
      pharmacologic vitamin D compensates for accelerated vitamin D clearance.
      Normal serum calcium and skeletal improvement were observed only under
      combined therapy, not in a calcium-only comparison.
    evidence:
    - reference: PMID:36656330
      reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Based on these results, we treated our patient with cholecalciferol
        10,000 IU daily plus calcium supplements.
      explanation: >-
        Directly documents calcium as part of the combined Brazilian regimen,
        but provides no calcium-only comparator.
    - reference: PMID:36656330
      reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        His biochemical studies now showed a normal calcium (2.25 mmol/L), PTH
        (38 ng/L), and 25(OH)D (126.3 mmol/L) and radiographs of his bones showed
        marked improvements (Fig. 1B).
      explanation: >-
        Documents mineral-ion normalization and skeletal improvement under the
        combined regimen; it cannot isolate calcium's contribution.
  evidence:
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on these results, we treated our patient with cholecalciferol 10,000
      IU daily plus calcium supplements.
    explanation: >-
      Directly documents adjunctive calcium in the effective Brazilian combined
      regimen, without evidence for calcium monotherapy.
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon follow-up at the age of eight years, the patient continued to receive
      alfacalcidol at a dosage of 1.5-2 mcg, along with a daily calcium supplement
      of 30 mg/kg. The patient clinically improved (mild genu valgum), and her
      height was -0.87 SD.
    explanation: >-
      Directly documents the Saudi combined regimen and clinical improvement;
      attribution to calcium alone is impossible.
  notes: >-
    Calcium is supported only as a component of combined case regimens. Neither
    independent calcium efficacy nor an optimal calcium dose has been established.
diagnosis:
- name: Biochemical and Radiographic Assessment of Calciopenic Rickets
  description: >-
    Initial evaluation establishes active calciopenic rickets and its severity
    with serum calcium, phosphate, alkaline phosphatase, parathyroid hormone,
    calcifediol, and calcitriol together with skeletal radiographs. The typical
    VDDR3 pattern combines low calcium, phosphate, calcifediol, and calcitriol
    with elevated parathyroid hormone and alkaline phosphatase; active treatment
    can alter individual measurements.
  diagnosis_term:
    preferred_term: biochemical and radiographic assessment
  markers: >-
    Serum calcium, phosphate, alkaline phosphatase, parathyroid hormone,
    25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and metaphyseal radiographs.
  results: >-
    Calciopenic biochemical abnormalities with radiographic metaphyseal
    splaying, cupping, lucency, osteopenia, or other evidence of active rickets.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral genu varum, poor growth, and reduced serum calcium and phosphorus
      with elevated serum alkaline phosphatase and parathyroid hormone (Table 1).
    explanation: >-
      Documents the characteristic mineral and regulatory-hormone pattern in a
      founding patient.
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist radiographs from these patients show the typical features of
      rickets: younger growing patients have bowing (green triangle),
      metaphyseal splaying (yellow triangle), and cupping (red triangle), as in
      proband 1.1 (P 1.1); older patients have metaphyseal lucency (blue
      triangle) and osteopenia (purple triangle), as in proband 2.1
    explanation: >-
      Establishes the radiographic component and its age-dependent findings.
- name: Serial Vitamin D Metabolite Clearance Challenge
  description: >-
    In a child with calciopenic rickets and inadequate response to conventional
    vitamin D, serial calcifediol and calcitriol measurements after a supervised
    oral cholecalciferol dose can demonstrate adequate initial absorption and
    production followed by unusually rapid clearance. This is a mechanistic
    clue, not a substitute for molecular confirmation.
  diagnosis_term:
    preferred_term: Vitamin D Measurement
    term:
      id: NCIT:C84818
      label: Vitamin D Measurement
  markers: Serial serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D.
  results: >-
    Initial rise after dosing followed by a substantially faster decline than
    expected in controls or nutritional rickets.
  evidence:
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serial measurements of vitamin D metabolites after a single 150,000 IU
      dose of cholecalciferol demonstrated an accelerated inactivation of
      25(OH)D and 1,25(OH)2D.
    explanation: >-
      Directly supports the dynamic clearance test in the Brazilian patient.
- name: CYP3A4 Molecular Testing
  description: >-
    Sequencing that includes CYP3A4 can confirm the diagnosis by identifying the
    recurrent heterozygous c.902T>C (p.Ile301Thr) variant. Because the published
    molecular spectrum currently consists of this single allele, another CYP3A4
    variant requires independent pathogenicity assessment rather than automatic
    assignment to VDDR3.
  diagnosis_term:
    preferred_term: Molecular Analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  markers: Heterozygous CYP3A4 c.902T>C (p.Ile301Thr).
  results: Molecular confirmation of CYP3A4-related VDDR3.
  evidence:
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the finding of a heterozygous missense variant in CYP3A4: c.902 T > C;
      p.Ile301Thr in the CYP3A4 gene confirms the diagnosis of VDDR3.
    explanation: >-
      Explicitly identifies the recurrent heterozygous allele as molecularly
      confirmatory in the Saudi patient.
differential_diagnoses:
- name: Nutritional vitamin D deficiency rickets
  description: >-
    Nutritional deficiency can reproduce low calcifediol, low calcitriol,
    secondary hyperparathyroidism, and rickets. Adequate dosing ordinarily
    produces a sustained metabolite response, whereas VDDR3 shows rapid loss
    after an initial rise and carries the CYP3A4 p.Ile301Thr variant.
  disease_term:
    preferred_term: vitamin D deficiency
    term:
      id: MONDO:0100471
      label: vitamin D deficiency
  distinguishing_features:
  - Dietary or sunlight insufficiency rather than a pathogenic CYP3A4 allele.
  - Sustained response to conventional replacement rather than accelerated post-dose clearance.
  evidence:
  - reference: PMID:36656330
    reference_title: "Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals who carry this heterozygous mutation have the same clinical
      and biochemical features as children with nutritional vitamin D
      deficiency, which makes it important to consider CYP3A4 mutations in
      patients with vitamin D deficiency who do not respond to conventional
      doses of vitamin D.
    explanation: >-
      Establishes the close phenotypic overlap and deficient conventional-dose
      response that prompts evaluation for VDDR3.
- name: Medication-induced CYP3A4 vitamin D hypercatabolism
  description: >-
    CYP3A4-inducing drugs can phenocopy selective vitamin D metabolite
    inactivation, but the process is exposure-related rather than the recurrent
    germline p.Ile301Thr disorder. Medication history and molecular testing
    separate this acquired mechanism from VDDR3.
  disease_term:
    preferred_term: medication-induced vitamin D hypercatabolism
  distinguishing_features:
  - Exposure to a CYP3A4-inducing medication such as an anticonvulsant or rifampin.
  - Absence of the recurrent germline CYP3A4 p.Ile301Thr variant.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the genetic gain of function in CYP3A4 recapitulated the selective
      inactivation of vitamin D metabolites well described in patients taking
      drugs that induce CYP3A4 (21).
    explanation: >-
      Establishes the acquired medication-induced mechanistic phenocopy while
      distinguishing it from germline gain of function.
- name: Vitamin D-dependent rickets type 1A
  description: >-
    CYP27B1 deficiency produces low calcitriol but normal or increased
    calcifediol because renal 1-alpha-hydroxylation is blocked. VDDR3 instead
    depletes both metabolites through accelerated catabolism and is associated
    with heterozygous CYP3A4 rather than biallelic CYP27B1 variation.
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 1A
    term:
      id: MONDO:0020723
      label: vitamin D-dependent rickets, type 1A
  distinguishing_features:
  - Normal or increased calcifediol with low calcitriol.
  - Biallelic CYP27B1 loss of function.
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Plasma concentrations of 1,25(OH)2D are low or even undetectable. By
      contrast, plasma concentrations of 25 (OH)D are normal or increased,
      likely reflecting the effects of both vitamin D supplementation and
      decreased clearance of 25 (OH)D due to lack of induction of CYP24A1 by the
      absence of 1,25(OH)2D.
    explanation: >-
      The review states the metabolite pattern that separates type 1A from
      VDDR3.
- name: Vitamin D-dependent rickets type 1B
  description: >-
    CYP2R1 deficiency lowers calcifediol by impaired 25-hydroxylation and can
    therefore resemble VDDR3 biochemically. The distinction is the CYP2R1
    genotype and failure to generate an adequate calcifediol increment, versus
    an initial increment followed by accelerated clearance in VDDR3.
  disease_term:
    preferred_term: vitamin D hydroxylation-deficient rickets, type 1B
    term:
      id: MONDO:0010810
      label: vitamin D hydroxylation-deficient rickets, type 1B
  distinguishing_features:
  - CYP2R1 loss-of-function genotype.
  - Negligible or blunted calcifediol generation rather than rapid post-peak clearance.
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR1b (OMIM #600081) is due to mutations in CYP2R1 that decrease
      expression or function of the encoded CYP2R1 enzyme, the principal
      25-hydroxylase. 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 (28–33).
    explanation: >-
      Defines the CYP2R1 activation defect and its overlapping biochemical
      phenotype.
- name: Vitamin D-dependent rickets type 2A
  description: >-
    Biallelic VDR loss causes target-tissue resistance with elevated rather than
    depleted calcitriol. Alopecia is a useful but incompletely sensitive clue.
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 2A
    term:
      id: MONDO:0010186
      label: vitamin D-dependent rickets, type 2A
  distinguishing_features:
  - Elevated calcitriol despite hypocalcemic rickets.
  - Biallelic VDR loss of function; alopecia in about half of reported patients.
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Biochemical studies show low serum levels of calcium and phosphorus and
      elevated serum concentrations of 1,25(OH)2D, in the range of 50–1,000
      pg/mL (normal in children is 30–100 pg/mL); serum concentrations of
      25(OH)D may be normal or elevated due to lack of induction of CYP24A1,
      which requires VDR action.
    explanation: >-
      States the high-calcitriol pattern that distinguishes receptor resistance
      from VDDR3.
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical features of VDDR2a are very similar to those of patients with
      other forms of VDDR, but about fifty percent of patients with VDDR2a have
      alopecia.
    explanation: >-
      Directly supports the approximate alopecia frequency used as a secondary
      distinguishing clue.
- name: Vitamin D-dependent rickets type 2B
  description: >-
    VDDR2B has been proposed as a VDDR2A-like target-tissue resistance disorder
    without a VDR variant, potentially mediated by excess expression of a
    nuclear response-element-binding protein. No causative gene is established,
    and the review questions whether it is a distinct disorder. Its reported
    receptor-resistance pattern, rather than depleted vitamin D metabolites,
    separates the proposal from molecularly defined CYP3A4-related VDDR3.
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 2B
    term:
      id: MONDO:0010931
      label: vitamin D-dependent rickets, type 2B
  distinguishing_features:
  - VDDR2A-like vitamin D target-tissue resistance without a VDR defect, rather than accelerated metabolite depletion.
  - No established causative gene and no CYP3A4 p.Ile301Thr variant; the status of VDDR2B as a distinct entity remains uncertain.
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR2b (OMIM 600785) resembles VDDR2a but is not caused by a defect in the
      VDR gene. Rather, the molecular defect appears to be overexpression of a
      nuclear protein that specifically interacts with a DNA response element
      that binds retinoid X receptor-VDR heterodimers.
    explanation: >-
      Defines the proposed receptor-response mechanism while appropriately using
      tentative language rather than assigning an established causative gene.
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      No gene has yet been identified as the cause of VDDR2b so it is impossible
      to state with precision the number of affected subjects.
    explanation: >-
      Directly supports the lack of an established gene and the uncertainty of
      the published case denominator.
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR2b appears to be a very uncommon condition, if indeed it is a distinct
      disorder at all.
    explanation: >-
      The review explicitly cautions that VDDR2B may not be a distinct disease,
      preventing overstatement of this differential.
- name: Hypophosphatemic rickets
  description: >-
    Primary phosphopenic rickets shares hypophosphatemia, limb deformity, and
    growth-plate disease, but typically has normal calcium, parathyroid hormone,
    and vitamin D status with evidence of renal phosphate wasting; VDDR3 is a
    calciopenic disorder with elevated parathyroid hormone and depleted vitamin
    D metabolites.
  disease_term:
    preferred_term: hypophosphatemic rickets
    term:
      id: MONDO:0024300
      label: hypophosphatemic rickets
  distinguishing_features:
  - Normal calcium and parathyroid hormone in primary phosphopenic disease.
  - Reduced tubular phosphate reabsorption in genetic renal phosphate-wasting disorders such as XLH.
  - No CYP3A4 p.Ile301Thr variant or accelerated vitamin D metabolite clearance.
  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: >-
      The diagnostic review gives the mineral pattern distinguishing primary
      phosphopenic rickets from calciopenic VDDR3.
- name: Hypophosphatasia
  description: >-
    Hypophosphatasia can produce a rickets-like metaphyseal appearance, but
    tissue-nonspecific alkaline phosphatase activity is low rather than elevated.
    Persistently low age-adjusted alkaline phosphatase and pathogenic ALPL
    variation favor hypophosphatasia over VDDR3.
  disease_term:
    preferred_term: hypophosphatasia
    term:
      id: MONDO:0018570
      label: hypophosphatasia
  distinguishing_features:
  - Low rather than elevated age-adjusted serum alkaline phosphatase activity.
  - Pathogenic ALPL variation rather than CYP3A4 p.Ile301Thr.
  evidence:
  - reference: PMID:32596195
    reference_title: "Diagnosis and Management of Vitamin D Dependent Rickets."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Because the appearance of the growth plate in children with rickets can
      resemble that of subjects with hypophosphatasia or metaphyseal dysplasias,
      a reasonable first step in diagnosis is to determine the serum level of
      alkaline phosphatase (Figure 2). Using age- and sex-related references
      ranges, alkaline phosphatase activity will usually be elevated in rickets,
      normal in metaphyseal dysplasia, and low in hypophosphatasia.
    explanation: >-
      Directly establishes the radiographic mimic and the opposite alkaline
      phosphatase direction that separates it from VDDR3.
animal_models: []
experimental_models:
- name: CYP3A4-I301T HEK293T Substrate-Selectivity Assays
  description: >-
    HEK293T cells expressing wild-type CYP3A4, CYP3A4-I301T, or CYP24A1 were
    compared in a mammalian two-hybrid reporter system in which intracellular
    calcitriol drives luciferase; a parallel luciferin IPA assay compared activity
    toward a non-vitamin D CYP3A4 substrate. Increased calcitriol inactivation
    with decreased luciferin IPA turnover establishes substrate selectivity. The
    systems isolate the molecular enzymatic phenotype but do not reproduce
    patient mineral homeostasis or skeletal disease.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: HEK293T cells obtained from ATCC (CRL-3216)
  culture_system: >-
    Transfected mammalian two-hybrid calcitriol-responsive reporter and luciferin
    IPA CYP3A4 activity assays
  conditions:
  - Recombinant CYP3A4-I301T
  - Recombinant wild-type CYP3A4
  - Recombinant CYP24A1 comparator
  publication: PMID:29461981
  modeled_mechanisms:
  - target: CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
    relationship: MEASURES
    description: >-
      The paired reporters compare increased calcitriol-inactivating function
      with activity toward a non-vitamin D substrate.
    fidelity: MODERATE
    limitations: >-
      Transient recombinant expression and an indirect reporter do not capture
      physiological hepatic abundance, whole-body pharmacokinetics, mineral
      feedback, or growth-plate disease.
    readouts:
    - name: Calcitriol inactivation
      target: CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
      direction: INCREASED
      interpretation: >-
        CYP3A4-I301T inactivated calcitriol more strongly than wild-type CYP3A4
        and CYP24A1 in the reporter comparison.
      evidence:
      - reference: PMID:29461981
        reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          CYP3A4 p.I301T had increased inactivation of calcitriol relative to WT
          (**P < 0.01 by 2-way ANOVA for curve)
        explanation: >-
          Directly reports the direction of the model readout.
    - name: Luciferin IPA turnover
      target: CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
      direction: DECREASED
      interpretation: >-
        CYP3A4-I301T showed lower activity than wild type toward this
        non-vitamin D substrate, demonstrating that the gain was not global.
      evidence:
      - reference: PMID:29461981
        reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The p.I301T mutant had significantly decreased activity for luciferin
          IPA relative to the WT enzyme (30.0 ± 1.6 vs. 50.1 ± 1.6, n = 4 for
          each, ***P < 0.001).
        explanation: >-
          Directly reports the decreased non-vitamin D substrate readout.
    evidence:
    - reference: PMID:29461981
      reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with
        10-fold greater activity than WT CYP3A4 and 2-fold greater activity than
        CYP24A1, the principal inactivator of vitamin D metabolites.
      explanation: >-
        Confirms that the recombinant variant system measures strongly increased
        calcitriol oxidation.
  evidence:
  - reference: PMID:29461981
    reference_title: "CYP3A4 mutation causes vitamin D-dependent rickets type 3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Because the kidney cell line (HEK293T) does not express CYP3A4, we used it
      to create a cell-based assay.
    explanation: >-
      Identifies the cell line and rationale for recombinant expression.
- name: Recombinant E. coli CYP3A4-I301T Membrane-Fraction Assay
  description: >-
    Membrane fractions from recombinant Escherichia coli expressing
    CYP3A4-I301T or wild-type CYP3A4 were used to characterize product formation
    from calcifediol and calcitriol. The system identified additional
    11-alpha-hydroxylated, low-receptor-affinity products but cannot model human
    tissue expression or systemic clearance.
  experimental_model_type: OTHER
  organism:
    preferred_term: Escherichia coli
    term:
      id: NCBITaxon:562
      label: Escherichia coli
  cell_source: Membrane fractions from recombinant Escherichia coli
  culture_system: Cell-free recombinant CYP3A4 membrane-fraction enzymology
  conditions:
  - Recombinant human CYP3A4-I301T
  - Recombinant human wild-type CYP3A4
  publication: PMID:41046353
  modeled_mechanisms:
  - target: Accelerated Formation of Low-Activity Vitamin D Metabolites
    relationship: MEASURES
    description: >-
      Directly measures variant-specific vitamin D metabolite product formation.
    fidelity: MODERATE
    limitations: >-
      Bacterial membrane fractions isolate enzyme chemistry but omit mammalian
      cofactors, hepatic and intestinal regulation, circulating binding
      proteins, feedback, and whole-organism pharmacokinetics.
    readouts:
    - name: Formation of additional low-affinity vitamin D metabolites
      target: Accelerated Formation of Low-Activity Vitamin D Metabolites
      direction: INCREASED
      interpretation: >-
        Relative to wild type, CYP3A4-I301T generated additional
        11-alpha-hydroxylated products with lower vitamin D receptor affinity.
      evidence:
      - reference: PMID:41046353
        reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Surprisingly, we found that CYP3A4-I301T efficiently produced
          additional metabolites compared to the wild-type CYP3A4, including
          11α,25-dihydroxyvitamin D3 and 1α,11α,25-trihydroxyvitamin D3, which
          have much lower affinity for the vitamin D receptor than do 25(OH)D3
          and 1α,25(OH)2D3, respectively.
        explanation: >-
          Directly reports the product and affinity readout.
    evidence:
    - reference: PMID:41046353
      reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this study, we investigated the enzymatic properties of CYP3A4-I301T
        using membrane fractions from recombinant Escherichia coli expressing
        the variant.
      explanation: >-
        Defines the recombinant membrane-fraction experimental system.
  evidence:
  - reference: PMID:41046353
    reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we investigated the enzymatic properties of CYP3A4-I301T
      using membrane fractions from recombinant Escherichia coli expressing the
      variant.
    explanation: >-
      Identifies the non-animal biochemical model.
computational_models:
- name: CYP3A4-I301T Vitamin D Molecular Docking Model
  description: >-
    Molecular docking predicted a Thr301 hydrogen bond to the calcifediol
    3-beta-hydroxyl group and interactions of the 25-hydroxyl group with Arg372
    and Glu374, positioning substrate for 11-alpha hydroxylation. This is a
    structural explanation for product selectivity, not an experimentally
    determined CYP3A4-I301T structure.
  model_type: MOLECULAR_DOCKING
  perturbations:
  - preferred_term: CYP3A4
    term:
      id: hgnc:2637
      label: CYP3A4
  publication: PMID:41046353
  modeled_mechanisms:
  - target: CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      Provides an in-silico substrate-pose explanation for variant-specific
      11-alpha hydroxylation.
    fidelity: LOW
    limitations: >-
      The predicted contacts have not been confirmed by an experimental
      CYP3A4-I301T-substrate structure and do not quantify in-vivo flux.
    evidence:
    - reference: PMID:41046353
      reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Docking simulations suggested that the 3β-hydroxyl group of 25(OH)D3
        forms a hydrogen bond with Thr301 of CYP3A4-I301T, while the
        25-hydroxyl group interacts with Arg372 and Glu374, favoring
        hydroxylation at the 11α-position.
      explanation: >-
        States the computationally predicted contacts and positional
        consequence without presenting them as experimental structure.
  evidence:
  - reference: PMID:41046353
    reference_title: "Distinct and potent vitamin D hydroxylation activity acquired by the CYP3A4 I301T single amino acid substitution causes type 3 rickets."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Docking simulations suggested that the 3β-hydroxyl group of 25(OH)D3
      forms a hydrogen bond with Thr301 of CYP3A4-I301T, while the 25-hydroxyl
      group interacts with Arg372 and Glu374, favoring hydroxylation at the
      11α-position.
    explanation: >-
      Defines the molecular-docking model and its predicted binding geometry.
clinical_trials: []
datasets: []
discussions:
- discussion_id: gap_vddr3_natural_history_and_inheritance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are the penetrance, phenotype range, long-term course, and true
    inherited transmission pattern of CYP3A4 p.Ile301Thr VDDR3?
  attaches_to:
  - pathophysiology#CYP3A4 p.Ile301Thr Substrate-Selective Gain of Function
  rationale: >-
    At least five molecularly described patients are published, all with the
    same allele; four are in peer-reviewed journal reports and one is in a
    conference abstract. The variant was absent from tested parents in four
    patients. The Saudi patient's father had rickets, short stature, and genu
    varum but was not genotyped, leaving vertical transmission unconfirmed.
    This evidence cannot establish
    penetrance, prevalence, sex effects, an allelic spectrum, or adult
    complications.
  evidence:
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has a strong family history of rickets. Her parents are first cousins;
      the father has a history of rickets, short stature, and genu varum,
      corrected surgically and followed with orthopedics, while the mother is
      healthy.
    explanation: >-
      Establishes a potentially affected parent but not molecular
      cosegregation.
- discussion_id: gap_vddr3_optimal_replacement_regimen
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What age- and weight-adjusted vitamin D regimen provides durable skeletal
    healing without hypercalcemia, hypercalciuria, or other long-term toxicity?
  attaches_to:
  - treatments#Pharmacologic-Dose Vitamin D Replacement
  rationale: >-
    Effective regimens vary widely among five molecularly described cases and
    were not compared in a trial. Long-term target concentrations, dose
    adjustment, renal safety, and
    whether calcitriol, parent vitamin D, or their combination is preferable
    remain undefined.
  evidence:
  - reference: PMID:38179381
    reference_title: "CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The optimal dose of cholecalciferol for treatment remains to be
      determined.
    explanation: >-
      The Saudi case report explicitly identifies dose optimization as
      unresolved.
notes: >-
  The phenotype spectrum is based on four patients in peer-reviewed journal
  reports plus one patient in a conference abstract. These reports provide
  positive case observations but did not systematically ascertain the absence
  of each feature across a shared denominator, so no disease frequency bands
  are assigned. The entry includes the recurrent
  germline p.Ile301Thr disorder only; acquired vitamin D hypercatabolism from
  CYP3A4-inducing drugs is mechanistically analogous but is not lumped into this
  Mendelian disease.
review_notes: >-
  Literature was re-searched through 2026-08-19. PubMed identified the 2018
  founding study, two 2023 case reports (four patients in peer-reviewed journal
  reports), and the 2026 recombinant-enzyme/docking study; later
  disease-focused PubMed hits were reviews. A broader allele-level web search
  identified a 2022 ESPE conference abstract describing a fifth molecularly
  confirmed patient. A 2025 genetic-rickets cohort was checked and contained
  VDDR1, VDDR2, and hypophosphatemic cases only; its VDDR3 mention was
  background rather than a new patient. An exact NCBI GEO search returned no
  disease-specific dataset. An exact ClinicalTrials.gov condition search
  returned only broad genomic newborn-screening protocols, not a
  VDDR3-directed interventional trial. No whole-organism animal model was
  located, so animal_models, clinical_trials, and datasets are deliberately
  empty. Phenotype frequencies are likewise left unassigned because the small
  case literature does not provide systematic feature ascertainment.