Vitamin D-Dependent Rickets Type 1A

Mendelian MONDO:0020723 Pathograph 23 Show in embeddings browser Metabolic Bone Disorders Inborn Error of Metabolism

Vitamin D-dependent rickets type 1A is an autosomal recessive disorder of vitamin D activation caused by biallelic loss-of-function variants in CYP27B1, which encodes 25-hydroxyvitamin D 1-alpha-hydroxylase. Reduced or absent 1-alpha-hydroxylation limits conversion of 25-hydroxyvitamin D to calcitriol, reducing intestinal calcium absorption and causing a calciopenic cascade of hypocalcemia, secondary hyperparathyroidism, renal phosphate wasting, and defective skeletal mineralization. Presentation is usually in infancy or early childhood, but residual enzyme activity and clinical context modify severity and age at diagnosis. Normal or high 25-hydroxyvitamin D with low or inappropriately normal calcitriol is a useful pattern, not an invariant rule: contemporary genetically confirmed cohorts also include low 25-hydroxyvitamin D. Activated hormone or analogue replacement with calcitriol or alfacalcidol bypasses the synthesis defect; response supports management but is not by itself diagnostic.

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1
Inheritance
8
Pathophys.
9
Phenotypes
23
Pathograph
1
Genes
3
Medical Actions
6
Differentials
1
Datasets
2
Models
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry pathogenic variants on both CYP27B1 alleles.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in the 1α-hydroxylase gene (CYB27B1)."
The patient-cohort report explicitly identifies the disorder as autosomal recessive. The source spells the gene CYB27B1 in this sentence; the established symbol used in the entry is CYP27B1.
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Pathophysiology

8
Renal 1-Alpha-Hydroxylase Deficiency
CYP27B1 encodes the mitochondrial enzyme that performs renal 1-alpha-hydroxylation of 25-hydroxyvitamin D. Biallelic pathogenic variants reduce or abolish this catalytic activity. The directly assayed founding patient had two null alleles and no detectable activity in primary keratinocytes; that nonrenal culture is functional evidence for the enzyme defect, not a measurement of kidney expression or population-wide residual activity.
Kidney Proximal Tubule Epithelial Cell CL:1000838 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Kidney Proximal Tubule Epithelial Cell, annotated with kidney proximal convoluted tubule epithelial cell (CL:1000838). CL:1000838 is a cell type from the Cell Ontology.
CYP27B1 hgnc:2606 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CYP27B1 (hgnc:2606). hgnc:2606 is a gene from the HUGO Gene Nomenclature Committee.
25-Hydroxyvitamin D 1-Alpha-Hydroxylase Activity GO:0004498 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves 25-Hydroxyvitamin D 1-Alpha-Hydroxylase Activity, annotated with calcidiol 1-monooxygenase activity (GO:0004498), qualified as loss of function. GO:0004498 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Experimental models
Patient-derived VDDR-1 keratinocyte cultures PRIMARY CELL CULTURE The patient-derived culture recapitulates loss of CYP27B1 catalytic activity, while its nonrenal lineage limits tissue-level fidelity.
Animal models
Cyp27b1-deficient mouse Mouse (Mus musculus) recapitulates Targeted loss of the ortholog reproduces the initiating enzyme-deficiency mechanism.
Downstream
Calcitriol Deficiency Loss of the enzyme that converts 25-hydroxyvitamin D reduces production of its active product, calcitriol.
Show evidence (2 references)
PMID:9415400 SUPPORT In Vitro
"Primary cultures of human adult and neonatal keratinocytes exhibit abundant 1 alpha-hydroxylase activity, whereas those from a patient with VDDR-1 lacked detectable activity."
Demonstrates absent 1-alpha-hydroxylase activity in patient-derived cells; the assay is in vitro and the sampled cell type is not the renal proximal tubule.
PMID:32596195 SUPPORT Other
"To gain full potency, 25 (OH)D undergoes 1α-hydroxylation to 1,25 (OH)2D by the mitochondrial cytochrome P450 by CYP27B1 in kidney proximal tubule cells."
The clinical review directly locates the CYP27B1 reaction in renal proximal-tubule cells and identifies its substrate and product.
Calcitriol Deficiency
Impaired 1-alpha-hydroxylation produces calcitriol concentrations that are low or inappropriately normal for the accompanying hypocalcemia and secondary hyperparathyroidism. Serum 25-hydroxyvitamin D is often normal or high when substrate supply is adequate, but it can be low in genetically confirmed patients and must not be encoded as necessarily preserved.
Downstream
Reduced Intestinal Calcium Absorption Loss of active vitamin D signaling reduces the intestinal transport of calcium.
Show evidence (2 references)
PMID:30282619 SUPPORT Human Clinical
"The patients also had biochemical features suggestive of rickets such as hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or high 25-OHD levels and low or normal 1,25-OH2D levels."
Defines the Turkish cohort's low-or-normal calcitriol pattern without treating a normal-range value as physiologically appropriate.
PMID:36321535 SUPPORT Human Clinical
"low 25OHD and low 1,25(OH)2D3"
A separate 24-case French cohort directly documents that low 25OHD can coexist with genetically confirmed VDDR1A, while calcitriol is also low.
Reduced Intestinal Calcium Absorption
Reduced calcitriol-dependent VDR signaling in enterocytes decreases active intestinal calcium transport. This node isolates the intestinal transport step from its systemic calcium consequence.
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 GO:0070561 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Vitamin D Receptor Signaling, annotated with vitamin D receptor signaling pathway (GO:0070561). GO:0070561 is a biological process from the Gene Ontology. ↓ DECREASED Intestinal Calcium Absorption GO:0070509 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. ↓ DECREASED
Downstream
Systemic Calcium Deficit Reduced gastrointestinal calcium entry lowers the calcium available to the extracellular compartment.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"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."
Identifies duodenal calcium transport as a principal target of vitamin D action.
Systemic Calcium Deficit
Calcium supply becomes inadequate relative to physiologic demand. Serum calcium may be low or maintained within the reference interval by compensatory PTH, so normocalcemia at one measurement does not sever the causal chain.
Downstream
Hypocalcemia When compensation is insufficient, the systemic calcium deficit is measurable as hypocalcemia.
Compensatory PTH Elevation Falling calcium stimulates compensatory PTH secretion.
Calcium-Phosphate Mineral Substrate Deficit Inadequate systemic calcium supply is one arm of the combined mineral substrate deficit; PTH-mediated phosphate loss supplies the other arm.
Muscle weakness Disturbed mineral and vitamin D physiology contributes to hypotonia and weakness, but the cited cohort does not isolate a single direct mediator.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"Seven patients had mild hypocalcemia at presentation while four patients had normal calcium concentrations."
Demonstrates the variable measured calcium state in an 11-patient cohort.
Compensatory PTH Elevation
Compensatory PTH elevation maintains serum calcium in some patients but decreases renal tubular phosphate reabsorption, transferring the deficit to phosphate homeostasis.
Downstream
Secondary hyperparathyroidism The compensatory endocrine mechanism is observed clinically as elevated PTH and encoded by the corresponding HPO phenotype.
PTH-Driven Renal Phosphate Wasting Elevated PTH decreases proximal-tubular phosphate reabsorption.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"All patients had low levels of phosphorus with quite high levels of PTH and ALP levels"
Reports the coupled high-PTH and low-phosphorus state in the 11-patient Turkish cohort.
PTH-Driven Renal Phosphate Wasting
Secondary hyperparathyroidism reduces renal phosphate reabsorption and increases urinary phosphate loss, producing a secondary rather than primary phosphopenic state.
Kidney Proximal Tubule Epithelial Cell CL:1000838 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Kidney Proximal Tubule Epithelial Cell, annotated with kidney proximal convoluted tubule epithelial cell (CL:1000838). CL:1000838 is a cell type from the Cell Ontology.
Downstream
Hypophosphatemia Renal phosphate loss lowers circulating phosphate.
Calcium-Phosphate Mineral Substrate Deficit Phosphate wasting adds a phosphate deficit to the calcium deficit at the mineralization front.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"The hypophosphatemia in VDDR1A is a result of elevated PTH and renal excretion of phosphate."
Directly supports the renal phosphate-wasting mechanism.
Calcium-Phosphate Mineral Substrate Deficit
Reduced calcium availability and PTH-mediated phosphate loss lower the mineral ion supply needed for hydroxyapatite deposition. This is the VDDR1A instance of the calciopenic substrate-deficiency arm in the shared skeletal module.
Downstream
Defective Skeletal Mineralization Inadequate calcium and phosphate prevent normal mineral deposition into osteoid and growth-plate matrix.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"Hypocalcemia and hypophosphatemia collectively reduce the rate of mineralization of bone matrix."
Supports convergence of both mineral deficits on impaired matrix mineralization.
Defective Skeletal Mineralization
Hydroxyapatite is not deposited into newly formed osteoid, and in the open growth plates of infancy the hypertrophic chondrocyte layer expands, producing the widened, cupped and frayed metaphyses of rickets together with bone pain, deformity of the weight-bearing long bones, and growth failure.
Osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
Bone Mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Bone Mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↓ DECREASED
Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bone, annotated with bone element (UBERON:0001474). UBERON:0001474 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Cyp27b1-deficient mouse Mouse (Mus musculus) recapitulates The untreated knockout carries the rachitic/osteomalacic skeletal endpoint, and calcitriol rescue normalizes histology and mechanics.
Downstream
Rickets Failed mineralization at open growth plates produces the widened, cupped, and frayed metaphyses of rickets.
Genu varum Weight bearing deforms undermineralized long bones, producing bowed legs; the cohort sentence lists deformities without a per-feature denominator.
Growth failure Growth-plate disease and chronic mineral deficiency impair linear growth.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"Wrist and knee radiographs of all patients demonstrated widened epiphyses and metaphyseal cupping and fraying."
Directly documents defective growth-plate mineralization and classic rachitic metaphyseal architecture in every member of this cohort.
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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 1A 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

9
Endocrine 1
Secondary hyperparathyroidism HP:0000867 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary hyperparathyroidism (HP:0000867). HP:0000867 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"The patients also had biochemical features suggestive of rickets such as hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or high 25-OHD levels and low or normal 1,25-OH2D levels."
Reports elevated parathyroid hormone, the compensatory response to calcitriol-dependent calcium malabsorption.
Limbs 1
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.
Bowing of the weight-bearing long bones is the usual deformity once walking begins. No frequency is asserted: the cited sentence reports bowing within a list of findings across eleven patients without separating how many had this one.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"Eleven patients had the clinical findings of rickets including X-bain deformity or bowed leg, chest rosary"
Documents bowing of the legs among the rachitic deformities in the cohort.
Metabolism 2
Hypocalcemia HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"Seven patients had mild hypocalcemia at presentation while four patients had normal calcium concentrations."
Reports hypocalcemia in the majority but not all patients at presentation.
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:30282619 SUPPORT Human Clinical
"The patients also had biochemical features suggestive of rickets such as hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or high 25-OHD levels and low or normal 1,25-OH2D levels."
Reports hypophosphatemia in the cohort, produced by the parathyroid-hormone-driven phosphaturia of the calciopenic arm.
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 (4 references)
PMID:30282619 SUPPORT Human Clinical
"Clinically, VDDR1A is characterized by hypotonia, muscle weakness, inability to walk, growth failure and radiographic findings of rickets."
States rickets as a defining clinical feature of the disorder.
PMID:30282619 SUPPORT Human Clinical
"Wrist and knee radiographs of all patients demonstrated widened epiphyses and metaphyseal cupping and fraying."
Documents the radiographic rachitic changes in every patient of the genotyped cohort.
PMID:30282619 SUPPORT Human Clinical
"The mean ± standard deviation age at diagnosis was 13.1±7.4 months."
Supports the early-infantile onset asserted in this phenotype's description, not the presence of rickets itself.
+ 1 more reference
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"Clinically, VDDR1A is characterized by hypotonia, muscle weakness, inability to walk, growth failure and radiographic findings of rickets."
Names muscle weakness and hypotonia among the defining clinical features.
Growth 1
Growth failure 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:30282619 SUPPORT Human Clinical
"Clinically, VDDR1A is characterized by hypotonia, muscle weakness, inability to walk, growth failure and radiographic findings of rickets."
Names growth failure among the defining clinical features.
Other 2
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.
This phenotype is intentionally not linked to a single pathophysiology node. The cited cohort establishes frequency but does not separate the effects of rachitic pain or deformity, muscle weakness, and developmental context, so it does not entail a causal ordering among those mechanisms and delayed walking.
Show evidence (1 reference)
PMID:36405822 SUPPORT Human Clinical
"The most common clinical symptoms at diagnosis were delayed walking (10/12) and severe growth retardation (9/12)."
Directly documents delayed walking in 10 of 12 children in the southern Chinese VDDR1A cohort.
Context-specific annotations (1)
Southern Chinese pediatric VDDR1A cohort (n=12) VERY_FREQUENT
The observed 10/12 (83.3%) cohort frequency maps to the HPO-aligned VERY_FREQUENT band of 80-99%. This small referral-cohort estimate is not a population-wide penetrance claim.
Show evidence (1 reference)
PMID:36405822 SUPPORT Human Clinical
"The most common clinical symptoms at diagnosis were delayed walking (10/12) and severe growth retardation (9/12)."
The direct 10/12 estimate is 83.3%, which falls within the VERY_FREQUENT band for this explicitly scoped pediatric cohort.
Elevated circulating alkaline phosphatase Elevated circulating alkaline phosphatase concentration HP:0003155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating alkaline phosphatase concentration (HP:0003155). HP:0003155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"The patients also had biochemical features suggestive of rickets such as hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or high 25-OHD levels and low or normal 1,25-OH2D levels."
Reports elevated alkaline phosphatase, the marker of increased but ineffective bone turnover in rickets.
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Genetic Associations

1
Biallelic CYP27B1 loss-of-function variants (Causative)
Gene: CYP27B1 hgnc:2606 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYP27B1 (hgnc:2606). hgnc:2606 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:9415400 SUPPORT Human Clinical
"The gene encoding P450c1 alpha was localized to chromosome 12, where the 1 alpha-hydroxylase deficiency syndrome, vitamin D-dependent rickets type 1 (VDDR-1), has been localized."
Maps the 1-alpha-hydroxylase gene to the VDDR-1 locus, establishing it as the candidate disease gene.
PMID:30282619 SUPPORT Human Clinical
"The most prevalent mutation was the c.195 + 2T>G splice donor site mutation, affecting five out of 11 patients with VDDR1A."
Documents the recurrent splice variant in this 11-patient Turkish cohort; geographic founder inference is scoped in the notes rather than generalized.
PMID:36321535 SUPPORT Human Clinical
"The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase (759 vs 2082 IU/L)."
A 24-case multicenter cohort identifies a partial-loss allele and its milder group-level biochemical and age-at-diagnosis profile, showing that CYP27B1 activity is not invariably abolished.
💊

Medical Actions

3
Calcitriol Replacement
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcitriol CHEBI:17823 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcitriol (CHEBI:17823). CHEBI:17823 is a therapeutic agent from Chemical Entities of Biological Interest.
Calcitriol supplies the active hormone downstream of CYP27B1. Dose is individualized against calcium, phosphate, PTH, alkaline phosphatase, urinary calcium, skeletal healing, and growth; response depends on adherence and age at diagnosis and is not a stand-alone diagnostic test.
Mechanism Target:
BYPASSES Renal 1-Alpha-Hydroxylase Deficiency — Supplying calcitriol bypasses the missing renal 1-alpha-hydroxylation step and restores hormone availability downstream of the enzyme defect.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"Differentiation of nutritional rickets and VDDR1A was made by normal/high 25-OHD levels, low/inappropriately normal 1,25-OH2D levels and improvement in the clinical, biochemical and radiological findings of rickets after replacement with calcitriol."
Records multi-domain improvement after replacement with the product of the blocked reaction.
Show evidence (2 references)
PMID:30282619 SUPPORT Human Clinical
"After the definitive diagnosis of VDDR1A all patients received calcitriol treatment. The duration of treatment with calcitriol ranged between six months and seven years. Biochemical improvement with treatment occurred within a period ranging between four and 12 months."
Reports calcitriol exposure and the observed time to biochemical improvement in this cohort, without converting it into a universal dosing or response estimate.
PMID:32596195 SUPPORT Other
"Serum (calcium, phosphorus, PTH, alkaline phosphatase, creatinine, and appropriate vitamin D metabolites) and urinary (24-h urine calcium or random urine calcium/creatinine ratio) biochemistries should be measured every 3–6 months."
Supports biochemical and urinary-calcium monitoring during ongoing replacement; exact intervals remain clinical guidance, not a target value.
Alfacalcidol Replacement
Category: Therapeutic 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: 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.
Alfacalcidol is already 1-alpha-hydroxylated and requires hepatic 25-hydroxylation to become active, so it also bypasses CYP27B1. It is curated separately from calcitriol because activation, half-life, and dosing are not interchangeable.
Mechanism Target:
BYPASSES Renal 1-Alpha-Hydroxylase Deficiency — The analogue overcomes the renal enzymatic block because its remaining activation step is 25-hydroxylation.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"Treatment with 1α-cholecalciferol is similarly effective as this metabolite also overcomes the enzymatic block, and due to its longer half-life than calcitriol, it can be administered once daily."
Directly supports alfacalcidol as a distinct analogue that overcomes the block; the entry does not turn the cited general schedule into an individualized prescription.
Show evidence (1 reference)
PMID:36321535 SUPPORT Human Clinical
"Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical, and radiological outcomes were satisfactory, and complications occurred if there was bad adherence."
Reports satisfactory multidomain outcomes in a 24-case cohort while preserving the source's adherence caveat.
Calcium Supplementation for Hypocalcemia and Remineralization
Category: Therapeutic 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 CHEBI:29108 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcium, annotated with calcium(2+) (CHEBI:29108). CHEBI:29108 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral calcium is added when hypocalcemia or the calcium demand of skeletal remineralization warrants it. It is adjunctive to activated vitamin D, not a correction of the CYP27B1 defect, and should not be inferred as necessary for every patient at every phase.
Mechanism Target:
RESTORES Systemic Calcium Deficit — Supplemental calcium directly increases substrate available to correct hypocalcemia and support remineralization while active vitamin D restores absorption.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"All patients received calcitriol and patients with hypocalcaemia received calcium replacement."
Supports selective calcium replacement in hypocalcemic patients rather than universal supplementation.
Target Phenotypes: Hypocalcemia HP:0002901 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30282619 SUPPORT Human Clinical
"All patients received calcitriol and patients with hypocalcaemia received calcium replacement."
Directly documents the cohort's calcium-replacement indication.
PMID:32596195 SUPPORT Other
"Calcium supplements (50 mg/kg of elemental calcium per day for children) should also be given during initial treatment to prevent worsening of hypocalcemia due to the “hungry bones” phenomenon that occurs with remineralization of the skeleton."
Supports the distinct early-remodeling indication for adjunctive calcium; the quoted review dose is not promoted as a universal prescription here.
🔬

Biochemical Markers

2
1,25-dihydroxyvitamin D (calcitriol) (Decreased or inappropriately normal)
Context: Low or inappropriately normal calcitriol is the proximal biochemical readout of impaired CYP27B1-dependent activation. Interpretation must be relative to calcium, phosphate, PTH, treatment, and assay context: a value inside the laboratory interval may still be inadequate during hypocalcemia and marked PTH elevation. The value is not interpreted through a rigid two-analyte table.
Pathograph Readouts
Readout Of Calcitriol Deficiency Negative Diagnostic
A low or physiologically inappropriate calcitriol concentration reports the failed activation step, but a normal-range value does not exclude VDDR1A.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"We also found that the concentrations of 1,25-dihydroxyvitamin D levels may be within inappropriately normal ranges in genetically proven vitamin D dependent rickets type 1A and lead to diagnostic confusion."
Directly supports physiologic interpretation of a normal-range result and the risk of false exclusion.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"The patients also had biochemical features suggestive of rickets such as hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or high 25-OHD levels and low or normal 1,25-OH2D levels."
Reports the pattern of normal-to-high 25-hydroxyvitamin D with low or inappropriately normal calcitriol that defines the type 1A biochemistry.
25-hydroxyvitamin D (calcifediol) (Variable; often normal or elevated)
Context: Hepatic 25-hydroxylation is intact, so normal or high 25-hydroxyvitamin D can distinguish VDDR1A from nutritional deficiency and CYP2R1-related VDDR1B. It is not required to be normal: nutritional status, prior supplementation, and other clinical factors can move the measured concentration, and a 24-case genetically confirmed cohort reported low 25OHD.
Show evidence (2 references)
PMID:30282619 SUPPORT Human Clinical
"VDDR1A should definitely be considered when a patient with signs of rickets has a normal 25-OHD level or when there is unresponsiveness to vitamin D treatment."
States the diagnostic value of a normal 25-hydroxyvitamin D result in a child with rickets, without making normality necessary.
PMID:36321535 SUPPORT Human Clinical
"low 25OHD and low 1,25(OH)2D3"
Demonstrates low 25OHD in a genetically confirmed cohort and prevents a required-normal biochemical rule.
🔬

Diagnosis

2
Clinical, radiographic, and biochemical evaluation
Evaluate rachitic signs and growth, wrist or knee radiographs, serum calcium, phosphate, alkaline phosphatase, PTH, 25-hydroxyvitamin D, and calcitriol. Low or inappropriately normal calcitriol in a calciopenic-rickets context is particularly informative, but calcium and both vitamin D metabolites can fall inside or outside their usual pattern; biochemical response to treatment is supportive rather than confirmatory.
Clinical Evaluation NCIT:C124351 NCI Thesaurus (NCIT)
Results: A calciopenic-rickets phenotype with secondary hyperparathyroidism and inadequate calcitriol should prompt molecular testing for VDDR1A while competing nutritional, phosphopenic, activation, and receptor disorders are assessed.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"The patients also had biochemical features suggestive of rickets such as hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or high 25-OHD levels and low or normal 1,25-OH2D levels. Wrist and knee radiographs of all patients demonstrated widened epiphyses and metaphyseal..."
Provides the measured laboratory and radiographic pattern in the 11-patient Turkish cohort; the entry does not generalize every component as obligatory.
Biallelic CYP27B1 molecular confirmation
Demonstration of pathogenic variants on both CYP27B1 alleles confirms the molecular diagnosis. Variant interpretation should allow partial-loss alleles and should not rely on a normal/high 25-hydroxyvitamin D prerequisite.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A pathogenic biallelic CYP27B1 genotype establishes VDDR1A in the appropriate phenotype and distinguishes it from genetically different rickets disorders.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"As it may be confused with nutritional rickets and hypophosphatemic rickets, genetic analysis is important for making a correct diagnosis."
Directly supports molecular analysis as the resolving test when clinical and biochemical presentations overlap.
🔀

Differential Diagnoses

6

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

Nutritional rickets
Overlapping Features Nutritional vitamin D or calcium deficiency shares calciopenia, secondary hyperparathyroidism, hypophosphatemia, high alkaline phosphatase, and rachitic radiographs. Low 25-hydroxyvitamin D and response to ordinary nutritional replacement favor deficiency, but low 25-hydroxyvitamin D can coexist with VDDR1A and cannot exclude a biallelic CYP27B1 diagnosis.
Distinguishing Features
  • Normal or high 25-hydroxyvitamin D supports VDDR1A over vitamin D deficiency but is not required for VDDR1A.
  • Low or inappropriately normal calcitriol despite strong PTH drive supports impaired 1-alpha-hydroxylation.
  • Biallelic pathogenic CYP27B1 variants confirm VDDR1A.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"The clinical and laboratory features of VDDR1A are very similar to nutritional rickets although the differential diagnosis can be made by a low or inappropriately normal 1, 25-OH2D level and unresponsiveness to vitamin D treatment."
Directly identifies the clinical overlap and the value of physiologically inadequate calcitriol and poor response to usual vitamin D therapy.
X-linked hypophosphatemic rickets MONDO:0010619
Overlapping Features Both disorders can present with hypophosphatemia, growth failure, bowed legs, and rachitic radiographs. In VDDR1A, phosphate wasting is secondary to high PTH from the calcium/calcitriol defect; in X-linked hypophosphatemia it is a primary FGF23-mediated renal phosphate-wasting disorder and calcium and PTH are usually not calciopenic-pattern abnormalities.
Distinguishing Features
  • Markedly elevated PTH with low or inappropriately normal calcitriol favors VDDR1A.
  • Primary renal phosphate wasting with a pathogenic PHEX variant favors X-linked hypophosphatemia.
Show evidence (1 reference)
PMID:30282619 SUPPORT Human Clinical
"The clinical presentations of patients with VDDR1A could lead to a misdiagnosis of nutritional rickets or hypophosphatemic rickets, which can be differentiated from hypophosphatemic rickets by a high PTH level and from nutritional rickets by a normal 25-OHD level."
Identifies high PTH as a useful discriminator from hypophosphatemic rickets; it is interpreted as a pattern rather than an absolute threshold.
Vitamin D-Dependent Rickets Type 1B MONDO:0010810
Overlapping Features CYP2R1-related VDDR1B also impairs vitamin D activation but blocks hepatic 25-hydroxylation rather than renal 1-alpha-hydroxylation. Very low 25-hydroxyvitamin D with normal or high calcitriol and response to calcifediol favor VDDR1B.
Distinguishing Features
  • Biallelic CYP2R1 rather than CYP27B1 variants establish VDDR1B.
  • Very low 25-hydroxyvitamin D with normal or high calcitriol supports VDDR1B.
Show evidence (2 references)
PMID:28548312 SUPPORT Human Clinical
"We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)2 D."
Defines the CYP2R1-deficiency metabolite pattern that contrasts with the CYP27B1 activation block.
PMID:28548312 SUPPORT Human Clinical
"we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry)."
Directly supports response to calcifediol as a treatment clue in the reported CYP2R1-deficient families, not as a stand-alone diagnostic test.
Vitamin D-Dependent Rickets Type 2A MONDO:0010186
Overlapping Features VDR-related VDDR2A produces target-organ resistance rather than deficient calcitriol synthesis. Elevated calcitriol and alopecia in about half of reported patients favor VDDR2A; absence of alopecia does not exclude it.
Distinguishing Features
  • Elevated rather than inadequate calcitriol supports receptor resistance.
  • Biallelic pathogenic VDR variants establish VDDR2A.
  • Alopecia is supportive when present but is not obligatory.
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..."
Supports the high-calcitriol receptor-resistance pattern that separates VDDR2A from deficient CYP27B1-mediated synthesis.
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."
Supports alopecia as a common but non-obligate discriminator.
Vitamin D-Dependent Rickets Type 2B MONDO:0010931
Overlapping Features Historical VDDR2B reports describe receptor-positive/postreceptor vitamin D resistance with high calcitriol despite a normal VDR coding sequence. The entity boundary remains unresolved, and HNRNPC overexpression in one index lineage must not be converted into an established germline HNRNPC cause.
Distinguishing Features
  • Elevated calcitriol with target-organ resistance contrasts with the deficient or inappropriately normal calcitriol of VDDR1A.
  • A normal VDR coding sequence was reported, but there is no validated positive molecular test for VDDR2B.
  • Biallelic pathogenic CYP27B1 variants establish VDDR1A rather than VDDR2B.
Show evidence (2 references)
PMID:7586652 SUPPORT Human Clinical
"Serum analysis showed significantly lower serum calcium as compared to normal relatives, though in the normal low range, normal phosphorus, high alkaline phosphatase, normal 25-hydroxyvitamin D3 and high 1,25-dihydroxyvitamin D3, indicating target organ resistance. The cDNA analysis showed..."
Defines the reported receptor-positive cluster pattern and normal VDR cDNA without assigning it the separate index-case HNRNPC mechanism.
PMID:32596195 SUPPORT Other
"VDDR2b appears to be a very uncommon condition, if indeed it is a distinct disorder at all."
Preserves the current review's explicit uncertainty about the entity.
Vitamin D-Dependent Rickets Type 3 MONDO:0033640
Overlapping Features VDDR3 is accelerated vitamin D-metabolite inactivation caused by the recurrent de novo CYP3A4 p.Ile301Thr gain-of-function variant in the two originally reported unrelated patients. Both major metabolites were low and responsiveness to parent and activated vitamin D was deficient; CYP3A4 rather than CYP27B1 establishes this reported mechanism.
Distinguishing Features
  • A heterozygous CYP3A4 p.Ile301Thr gain-of-function variant establishes the reported VDDR3 mechanism.
  • Low concentrations of both 25-hydroxyvitamin D and calcitriol with deficient replacement responsiveness support accelerated catabolism.
Show evidence (3 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."
Defines the original two-patient VDDR3 metabolite and response pattern; the entry does not generalize beyond that evidence.
PMID:29461981 SUPPORT Human Clinical
"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)."
Directly establishes the recurrent de novo variant in the two reported patients.
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."
Functionally establishes gain of calcitriol-inactivation activity in the mutant enzyme rather than relying on sequence inference alone.
📊

Related Datasets

1
1,25-Dihydroxyvitamin D3 Controls a Cohort of Vitamin D Receptor Target Genes in the Proximal Intestine That Is Enriched for Calcium Regulating Components (RNA-seq) geo:GSE69170
Bulk RNA-seq of duodenum from Cyp27b1-null male mice on a vitamin-D-deficient normal-mineral diet or a high-calcium/high-phosphate rescue diet, sampled six hours after vehicle or calcitriol treatment. The four-condition design directly interrogates the intestinal calcitriol-response program downstream of the modeled synthesis defect; it is not a human VDDR1A cohort.
mouse BULK RNA SEQ n=24 GPL13112
Conditions: Vitamin-D-deficient normal-mineral diet plus vehicle Vitamin-D-deficient normal-mineral diet plus calcitriol Vitamin-D-deficient high-calcium/high-phosphate rescue diet plus vehicle Vitamin-D-deficient high-calcium/high-phosphate rescue diet plus calcitriol
PMID:26041780
Accession, organism, 24-sample four-group design, platform, and linked publication were verified against the full NCBI GEO record on 2026-08-24. GEO lists this series within SuperSeries GSE69180. Relevance is confined to the Cyp27b1-null mouse and downstream intestinal vitamin-D response.
Show evidence (1 reference)
GEO:GSE69170 SUPPORT Model Organism
"To examine this issue, Cyp27b1 null mice on either a normal or a high calcium/phosphate-containing rescue diet were treated with either vehicle or 1,25(OH)2D3 and evaluated 6h later. RNA samples from duodena were then subjected to RNA-seq analysis and the data analyzed bioinformatically."
The accession record directly establishes the genotype, dietary and calcitriol perturbations, intestinal tissue, timing, and RNA-seq assay.
🧫

Experimental Models

1
Patient-derived VDDR-1 keratinocyte cultures PRIMARY_CELL_CULTURE
Primary keratinocytes from the founding patient and adult or neonatal human comparison cultures were used to assay 1-alpha-hydroxylase activity. The patient cells lacked detectable activity and carried compound-heterozygous deletion/frameshift null variants. This directly tests the catalytic lesion in patient-derived cells but is not a renal proximal-tubule model.
VDDR-1 patient primary keratinocytes Adult and neonatal comparison keratinocytes
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
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
Primary human keratinocytes from one VDDR-1 patient and comparison donors
Culture
Primary keratinocyte culture
Publication
PMID:9415400
Pathograph links
Renal 1-Alpha-Hydroxylase Deficiency recapitulates fidelity: moderate The patient-derived culture recapitulates loss of CYP27B1 catalytic activity, while its nonrenal lineage limits tissue-level fidelity.
Limitations: One founding patient was studied; keratinocytes can assay the enzyme but do not reproduce proximal-tubule regulation or whole-body mineral homeostasis.
Show evidence (1 reference)
PMID:9415400 SUPPORT In Vitro
"Primary cultures of human adult and neonatal keratinocytes exhibit abundant 1 alpha-hydroxylase activity, whereas those from a patient with VDDR-1 lacked detectable activity."
Directly compares patient and human comparison cultures for the modeled enzyme activity.
Show evidence (1 reference)
PMID:9415400 SUPPORT In Vitro
"Keratinocyte P450c1 alpha cDNA from the patient with VDDR-1 contained deletion/frameshift mutations either at codon 211 or at codon 231, indicating that the patient was a compound heterozygote for two null mutations."
Grounds the model in the patient's two null alleles rather than an ungenotyped culture phenotype.
🐁

Animal Models

1
Cyp27b1-deficient mouse Targeted loss-of-function model
Targeted Cyp27b1 inactivation produces a pseudo-vitamin-D-deficiency-rickets model. Chronic calcitriol treatment corrected hypocalcemia and secondary hyperparathyroidism, cured rickets and osteomalacia histologically, and restored bone biomechanical properties. This is causal model-organism evidence, not a human treatment-effect estimate.
Hypocalcemia Secondary hyperparathyroidism Rickets
Species
Mouse (Mus musculus)
Genotype
Cyp27b1-/- targeted loss of function
Publication
PMID:12674324
Pathograph links
Renal 1-Alpha-Hydroxylase Deficiency recapitulates fidelity: moderate Targeted loss of the ortholog reproduces the initiating enzyme-deficiency mechanism.
Limitations: A constitutive engineered mouse does not capture the full allelic and treatment-history heterogeneity of human VDDR1A.
Show evidence (1 reference)
PMID:12674324 SUPPORT Model Organism
"We have previously engineered an animal model of PDDR by targeted inactivation of the 1alpha-OHase gene in mice."
Directly establishes the targeted enzyme-loss model.
Defective Skeletal Mineralization recapitulates fidelity: moderate The untreated knockout carries the rachitic/osteomalacic skeletal endpoint, and calcitriol rescue normalizes histology and mechanics.
Limitations: Rescue under an experimental injection regimen cannot set a human dose or guarantee human growth recovery.
Show evidence (1 reference)
PMID:12674324 SUPPORT Model Organism
"Bone histology and histomorphometry confirmed that the rickets and osteomalacia were cured. The rescue regimen also restored the biomechanical properties of the bone tissue within normal parameters."
Directly supports the skeletal phenotype and its calcitriol-responsive rescue in the mouse.
Show evidence (1 reference)
PMID:12674324 SUPPORT Model Organism
"Blood biochemistry analysis revealed that the rescue treatment corrected the hypocalcemia and secondary hyperparathyroidism."
Supports biochemical rescue of two modeled downstream consequences.
{ }

Source YAML

click to show 
name: Vitamin D-Dependent Rickets Type 1A
synonyms:
- VDDR1A
- VDDR-I
- Pseudovitamin D-deficiency rickets
- 1-alpha-hydroxylase deficiency
creation_date: "2026-08-19T00:00:00Z"
category: Mendelian
description: >-
  Vitamin D-dependent rickets type 1A is an autosomal recessive disorder of
  vitamin D activation caused by biallelic loss-of-function variants in CYP27B1,
  which encodes 25-hydroxyvitamin D 1-alpha-hydroxylase. Reduced or absent
  1-alpha-hydroxylation limits conversion of 25-hydroxyvitamin D to calcitriol,
  reducing intestinal calcium absorption and causing a calciopenic cascade of
  hypocalcemia, secondary hyperparathyroidism, renal phosphate wasting, and
  defective skeletal mineralization. Presentation is usually in infancy or early
  childhood, but residual enzyme activity and clinical context modify severity
  and age at diagnosis. Normal or high 25-hydroxyvitamin D with low or
  inappropriately normal calcitriol is a useful pattern, not an invariant rule:
  contemporary genetically confirmed cohorts also include low 25-hydroxyvitamin
  D. Activated hormone or analogue replacement with calcitriol or alfacalcidol
  bypasses the synthesis defect; response supports management but is not by
  itself diagnostic.
disease_term:
  preferred_term: vitamin D-dependent rickets, type 1A
  term:
    id: MONDO:0020723
    label: vitamin D-dependent rickets, type 1A
parents:
- Metabolic Bone Disorders
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry pathogenic variants on both CYP27B1 alleles.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive
      disorder caused by mutations in the 1α-hydroxylase gene (CYB27B1).
    explanation: >-
      The patient-cohort report explicitly identifies the disorder as autosomal
      recessive. The source spells the gene CYB27B1 in this sentence; the
      established symbol used in the entry is CYP27B1.
genetic:
- name: Biallelic CYP27B1 loss-of-function variants
  gene_term:
    preferred_term: CYP27B1
    term:
      id: hgnc:2606
      label: CYP27B1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Splice-site, frameshift, nonsense and missense alleles are reported. The
    c.195+2T>G splice-donor variant was recurrent among the Turkish families in
    PMID:30282619 and clustered by city of origin, supporting a local founder or
    common-ancestor interpretation; it is not asserted as a universal founder
    allele. Loss of function can be partial rather than complete, as shown for
    p.(Ala129Thr).
  evidence:
  - reference: PMID:9415400
    reference_title: Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gene encoding P450c1 alpha was localized to chromosome 12, where the 1
      alpha-hydroxylase deficiency syndrome, vitamin D-dependent rickets type 1
      (VDDR-1), has been localized.
    explanation: >-
      Maps the 1-alpha-hydroxylase gene to the VDDR-1 locus, establishing it as
      the candidate disease gene.
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prevalent mutation was the c.195 + 2T>G splice donor site
      mutation, affecting five out of 11 patients with VDDR1A.
    explanation: >-
      Documents the recurrent splice variant in this 11-patient Turkish cohort;
      geographic founder inference is scoped in the notes rather than generalized.
  - reference: PMID:36321535
    reference_title: "Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The partial loss-of-function variation p.(Ala129Thr) was associated with a
      milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs
      1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase
      (759 vs 2082 IU/L).
    explanation: >-
      A 24-case multicenter cohort identifies a partial-loss allele and its
      milder group-level biochemical and age-at-diagnosis profile, showing that
      CYP27B1 activity is not invariably abolished.
pathophysiology:
- name: Renal 1-Alpha-Hydroxylase Deficiency
  description: >-
    CYP27B1 encodes the mitochondrial enzyme that performs renal
    1-alpha-hydroxylation of 25-hydroxyvitamin D. Biallelic pathogenic variants
    reduce or abolish this catalytic activity. The directly assayed founding
    patient had two null alleles and no detectable activity in primary
    keratinocytes; that nonrenal culture is functional evidence for the enzyme
    defect, not a measurement of kidney expression or population-wide residual
    activity.
  role: trigger
  biological_scale: MOLECULAR
  gene:
    preferred_term: CYP27B1
    term:
      id: hgnc:2606
      label: CYP27B1
  cell_types:
  - preferred_term: Kidney Proximal Tubule Epithelial Cell
    term:
      id: CL:1000838
      label: kidney proximal convoluted tubule epithelial cell
  molecular_functions:
  - preferred_term: 25-Hydroxyvitamin D 1-Alpha-Hydroxylase Activity
    term:
      id: GO:0004498
      label: calcidiol 1-monooxygenase activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:9415400
    reference_title: Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Primary cultures of human adult and neonatal keratinocytes exhibit abundant
      1 alpha-hydroxylase activity, whereas those from a patient with VDDR-1
      lacked detectable activity.
    explanation: >-
      Demonstrates absent 1-alpha-hydroxylase activity in patient-derived cells;
      the assay is in vitro and the sampled cell type is not the renal proximal
      tubule.
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To gain full potency, 25 (OH)D undergoes 1α-hydroxylation to 1,25 (OH)2D
      by the mitochondrial cytochrome P450 by CYP27B1 in kidney proximal tubule
      cells.
    explanation: >-
      The clinical review directly locates the CYP27B1 reaction in renal
      proximal-tubule cells and identifies its substrate and product.
  downstream:
  - target: Calcitriol Deficiency
    causal_link_type: DIRECT
    description: >-
      Loss of the enzyme that converts 25-hydroxyvitamin D reduces production of
      its active product, calcitriol.
    evidence:
    - reference: PMID:32596195
      reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Patients with VDDR1a (OMIM 264700) are unable to convert 25(OH)D to
        1,25(OH)2D owing to biallelic mutations in the CYP27B1 gene on chromosome
        12q13.3 that encodes 25-hydroxyvitamin D3-1α-hydroxylase.
      explanation: >-
        The review directly links biallelic CYP27B1 defects to failure of the
        substrate-to-product conversion.
- name: Calcitriol Deficiency
  description: >-
    Impaired 1-alpha-hydroxylation produces calcitriol concentrations that are
    low or inappropriately normal for the accompanying hypocalcemia and secondary
    hyperparathyroidism. Serum 25-hydroxyvitamin D is often normal or high when
    substrate supply is adequate, but it can be low in genetically confirmed
    patients and must not be encoded as necessarily preserved.
  role: trigger
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients also had biochemical features suggestive of rickets such as
      hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or
      high 25-OHD levels and low or normal 1,25-OH2D levels.
    explanation: >-
      Defines the Turkish cohort's low-or-normal calcitriol pattern without
      treating a normal-range value as physiologically appropriate.
  - reference: PMID:36321535
    reference_title: "Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      low 25OHD and low 1,25(OH)2D3
    explanation: >-
      A separate 24-case French cohort directly documents that low 25OHD can
      coexist with genetically confirmed VDDR1A, while calcitriol is also low.
  downstream:
  - target: Reduced Intestinal Calcium Absorption
    causal_link_type: DIRECT
    description: >-
      Loss of active vitamin D signaling reduces the intestinal transport of
      calcium.
    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.
      explanation: >-
        Supports reduced duodenal calcium transport as the proximal physiologic
        consequence of lost calcitriol action.
- name: Reduced Intestinal Calcium Absorption
  description: >-
    Reduced calcitriol-dependent VDR signaling in enterocytes decreases active
    intestinal calcium transport. This node isolates the intestinal transport
    step from its systemic calcium consequence.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: Vitamin D Receptor Signaling
    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: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.
    explanation: >-
      Identifies duodenal calcium transport as a principal target of vitamin D
      action.
  downstream:
  - target: Systemic Calcium Deficit
    causal_link_type: DIRECT
    description: >-
      Reduced gastrointestinal calcium entry lowers the calcium available to the
      extracellular compartment.
    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.
      explanation: >-
        Supports the physiologic bridge from reduced intestinal transport to
        systemic calcium deficiency.
- name: Systemic Calcium Deficit
  description: >-
    Calcium supply becomes inadequate relative to physiologic demand. Serum
    calcium may be low or maintained within the reference interval by
    compensatory PTH, so normocalcemia at one measurement does not sever the
    causal chain.
  role: central_effector
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients had mild hypocalcemia at presentation while four patients
      had normal calcium concentrations.
    explanation: >-
      Demonstrates the variable measured calcium state in an 11-patient cohort.
  downstream:
  - target: Hypocalcemia
    causal_link_type: DIRECT
    description: >-
      When compensation is insufficient, the systemic calcium deficit is
      measurable as hypocalcemia.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seven patients had mild hypocalcemia at presentation while four patients
        had normal calcium concentrations.
      explanation: >-
        Supports hypocalcemia as a variably expressed biochemical consequence.
  - target: Compensatory PTH Elevation
    causal_link_type: DIRECT
    description: >-
      Falling calcium stimulates compensatory PTH secretion.
    evidence:
    - reference: PMID:32596195
      reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Hypocalcemia, and to some degree calciferol deficiency, results in
        increased section of PTH from the parathyroid glands (i.e., secondary
        hyperparathyroidism)
      explanation: >-
        The exact cached text (including its apparent "section" typographical
        error) directly links hypocalcemia to secondary hyperparathyroidism.
  - target: Calcium-Phosphate Mineral Substrate Deficit
    causal_link_type: DIRECT
    description: >-
      Inadequate systemic calcium supply is one arm of the combined mineral
      substrate deficit; PTH-mediated phosphate loss supplies the other arm.
    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.
      explanation: >-
        Explicitly supports convergence of the calcium deficit with the
        phosphate deficit at the mineralization step.
  - target: Muscle weakness
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neuromuscular dysfunction in disturbed calcium and vitamin D homeostasis
    description: >-
      Disturbed mineral and vitamin D physiology contributes to hypotonia and
      weakness, but the cited cohort does not isolate a single direct mediator.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinically, VDDR1A is characterized by hypotonia, muscle weakness,
        inability to walk, growth failure and radiographic findings of rickets.
      explanation: >-
        Supports co-occurrence of weakness with VDDR1A; the causal ordering is
        deliberately indirect because this sentence does not identify a mediator.
- name: Compensatory PTH Elevation
  description: >-
    Compensatory PTH elevation maintains serum calcium in some patients but
    decreases renal tubular phosphate reabsorption, transferring the deficit to
    phosphate homeostasis.
  role: amplifier
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had low levels of phosphorus with quite high levels of PTH
      and ALP levels
    explanation: >-
      Reports the coupled high-PTH and low-phosphorus state in the 11-patient
      Turkish cohort.
  downstream:
  - target: Secondary hyperparathyroidism
    causal_link_type: DIRECT
    description: >-
      The compensatory endocrine mechanism is observed clinically as elevated
      PTH and encoded by the corresponding HPO phenotype.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had low levels of phosphorus with quite high levels of PTH
        and ALP levels
      explanation: >-
        Directly supports elevated PTH in this cohort.
  - target: PTH-Driven Renal Phosphate Wasting
    causal_link_type: DIRECT
    description: >-
      Elevated PTH decreases proximal-tubular phosphate reabsorption.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The hypophosphatemia in VDDR1A is a result of elevated PTH and renal
        excretion of phosphate.
      explanation: >-
        Directly identifies PTH-driven renal phosphate excretion in VDDR1A.
- name: PTH-Driven Renal Phosphate Wasting
  description: >-
    Secondary hyperparathyroidism reduces renal phosphate reabsorption and
    increases urinary phosphate loss, producing a secondary rather than primary
    phosphopenic state.
  role: amplifier
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Kidney Proximal Tubule Epithelial Cell
    term:
      id: CL:1000838
      label: kidney proximal convoluted tubule epithelial cell
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hypophosphatemia in VDDR1A is a result of elevated PTH and renal
      excretion of phosphate.
    explanation: >-
      Directly supports the renal phosphate-wasting mechanism.
  downstream:
  - target: Hypophosphatemia
    causal_link_type: DIRECT
    description: >-
      Renal phosphate loss lowers circulating phosphate.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The hypophosphatemia in VDDR1A is a result of elevated PTH and renal
        excretion of phosphate.
      explanation: >-
        Directly links the renal loss to hypophosphatemia.
  - target: Calcium-Phosphate Mineral Substrate Deficit
    causal_link_type: DIRECT
    description: >-
      Phosphate wasting adds a phosphate deficit to the calcium deficit 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.
      explanation: >-
        Identifies the joint calcium-phosphate deficit as limiting bone-matrix
        mineralization.
- name: Calcium-Phosphate Mineral Substrate Deficit
  description: >-
    Reduced calcium availability and PTH-mediated phosphate loss lower the mineral
    ion supply needed for hydroxyapatite deposition. This is the VDDR1A instance
    of the calciopenic substrate-deficiency arm in the shared skeletal module.
  role: central_effector
  biological_scale: ORGANISM
  conforms_to: "defective_skeletal_mineralization#Calciopenic Substrate Deficiency"
  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.
    explanation: >-
      Supports convergence of both mineral deficits on impaired matrix
      mineralization.
  downstream:
  - target: Defective Skeletal Mineralization
    causal_link_type: DIRECT
    description: >-
      Inadequate calcium and phosphate prevent normal mineral deposition into
      osteoid and growth-plate matrix.
    evidence:
    - reference: PMID:32596195
      reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        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: >-
        The exact cached text directly links low mineral concentrations to failed
        hydroxyapatite deposition.
- name: Defective Skeletal Mineralization
  description: >-
    Hydroxyapatite is not deposited into newly formed osteoid, and in the open
    growth plates of infancy the hypertrophic chondrocyte layer expands, producing
    the widened, cupped and frayed metaphyses of rickets together with bone pain,
    deformity of the weight-bearing long bones, and growth failure.
  role: effector
  biological_scale: TISSUE
  conforms_to: "defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front"
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Bone Mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  locations:
  - preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist and knee radiographs of all patients demonstrated widened epiphyses
      and metaphyseal cupping and fraying.
    explanation: >-
      Directly documents defective growth-plate mineralization and classic
      rachitic metaphyseal architecture in every member of this cohort.
  downstream:
  - target: Rickets
    causal_link_type: DIRECT
    description: >-
      Failed mineralization at open growth plates produces the widened, cupped,
      and frayed metaphyses of rickets.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Wrist and knee radiographs of all patients demonstrated widened
        epiphyses and metaphyseal cupping and fraying.
      explanation: >-
        Directly supports the radiographic rickets consequence.
  - target: Genu varum
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mechanical deformation of undermineralized weight-bearing long bones
    description: >-
      Weight bearing deforms undermineralized long bones, producing bowed legs;
      the cohort sentence lists deformities without a per-feature denominator.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Eleven patients had the clinical findings of rickets including X-bain
        deformity or bowed leg, chest rosary
      explanation: >-
        Documents bowed legs among the cohort's rachitic deformities without
        implying that all 11 had this specific finding.
  - target: Growth failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Growth-plate dysfunction and chronic rachitic skeletal disease
    description: >-
      Growth-plate disease and chronic mineral deficiency impair linear growth.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinically, VDDR1A is characterized by hypotonia, muscle weakness,
        inability to walk, growth failure and radiographic findings of rickets.
      explanation: >-
        Supports co-occurring growth failure and rickets; the edge records the
        known growth-plate intermediary rather than asserting a one-step effect.
phenotypes:
- category: Skeletal
  name: Rickets
  description: >-
    Metaphyseal rickets usually becomes evident in infancy or early childhood;
    later diagnosis can occur, particularly with partial residual enzyme
    activity or delayed recognition.
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, VDDR1A is characterized by hypotonia, muscle weakness,
      inability to walk, growth failure and radiographic findings of rickets.
    explanation: >-
      States rickets as a defining clinical feature of the disorder.
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrist and knee radiographs of all patients demonstrated widened epiphyses
      and metaphyseal cupping and fraying.
    explanation: >-
      Documents the radiographic rachitic changes in every patient of the
      genotyped cohort.
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean ± standard deviation age at diagnosis was 13.1±7.4 months.
    explanation: >-
      Supports the early-infantile onset asserted in this phenotype's
      description, not the presence of rickets itself.
  - reference: PMID:36321535
    reference_title: "Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone radiographs were abnormal in 83% of patients.
    explanation: >-
      Provides a separate multicenter-cohort radiographic frequency. The abstract
      reports the percentage but not the feature-specific numerator, so none is
      inferred here.
- category: Biochemical
  name: Hypocalcemia
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven patients had mild hypocalcemia at presentation while four patients
      had normal calcium concentrations.
    explanation: >-
      Reports hypocalcemia in the majority but not all patients at presentation.
- category: Skeletal
  name: Genu varum
  phenotype_term:
    preferred_term: Genu varum
    term:
      id: HP:0002970
      label: Genu varum
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eleven patients had the clinical findings of rickets including X-bain
      deformity or bowed leg, chest rosary
    explanation: >-
      Documents bowing of the legs among the rachitic deformities in the
      cohort.
  notes: >-
    Bowing of the weight-bearing long bones is the usual deformity once walking
    begins. No frequency is asserted: the cited sentence reports bowing within a
    list of findings across eleven patients without separating how many had
    this one.
- category: Musculoskeletal
  name: Muscle weakness
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, VDDR1A is characterized by hypotonia, muscle weakness,
      inability to walk, growth failure and radiographic findings of rickets.
    explanation: >-
      Names muscle weakness and hypotonia among the defining clinical
      features.
- category: Developmental
  name: Delayed ability to walk
  description: >-
    Delayed walking was the most common presenting symptom in a retrospective
    cohort of 12 children with VDDR1A from southern China. This motor milestone
    finding is not evidence of a primary neurodevelopmental disorder.
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  phenotype_contexts:
  - population: Southern Chinese pediatric VDDR1A cohort (n=12)
    frequency: VERY_FREQUENT
    notes: >-
      The observed 10/12 (83.3%) cohort frequency maps to the HPO-aligned
      VERY_FREQUENT band of 80-99%. This small referral-cohort estimate is not a
      population-wide penetrance claim.
    evidence:
    - reference: PMID:36405822
      reference_title: "Clinical characteristics and long-term outcomes of 12 children with vitamin D-dependent rickets type 1A: A retrospective study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common clinical symptoms at diagnosis were delayed walking
        (10/12) and severe growth retardation (9/12).
      explanation: >-
        The direct 10/12 estimate is 83.3%, which falls within the
        VERY_FREQUENT band for this explicitly scoped pediatric cohort.
  evidence:
  - reference: PMID:36405822
    reference_title: "Clinical characteristics and long-term outcomes of 12 children with vitamin D-dependent rickets type 1A: A retrospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical symptoms at diagnosis were delayed walking
      (10/12) and severe growth retardation (9/12).
    explanation: >-
      Directly documents delayed walking in 10 of 12 children in the southern
      Chinese VDDR1A cohort.
  notes: >-
    This phenotype is intentionally not linked to a single pathophysiology node.
    The cited cohort establishes frequency but does not separate the effects of
    rachitic pain or deformity, muscle weakness, and developmental context, so it
    does not entail a causal ordering among those mechanisms and delayed walking.
- category: Growth
  name: Growth failure
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, VDDR1A is characterized by hypotonia, muscle weakness,
      inability to walk, growth failure and radiographic findings of rickets.
    explanation: >-
      Names growth failure among the defining clinical features.
- category: Biochemical
  name: Hypophosphatemia
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients also had biochemical features suggestive of rickets such as
      hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or
      high 25-OHD levels and low or normal 1,25-OH2D levels.
    explanation: >-
      Reports hypophosphatemia in the cohort, produced by the
      parathyroid-hormone-driven phosphaturia of the calciopenic arm.
- category: Biochemical
  name: Secondary hyperparathyroidism
  phenotype_term:
    preferred_term: Secondary hyperparathyroidism
    term:
      id: HP:0000867
      label: Secondary hyperparathyroidism
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients also had biochemical features suggestive of rickets such as
      hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or
      high 25-OHD levels and low or normal 1,25-OH2D levels.
    explanation: >-
      Reports elevated parathyroid hormone, the compensatory response to
      calcitriol-dependent calcium malabsorption.
- category: Biochemical
  name: Elevated circulating alkaline phosphatase
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  reports_on:
  - target: Defective Skeletal Mineralization
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated total serum alkaline phosphatase is a laboratory correlate of
      active rickets, but without isoenzyme fractionation it is not bone-specific
      and does not itself measure mineral deposition.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had clinical and laboratory features of rickets at the time
        of diagnosis. All patients had low levels of phosphorus with quite high
        levels of PTH and ALP levels
      explanation: >-
        Supports positive association of high ALP with the cohort's active
        rachitic state, without assigning bone specificity.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients also had biochemical features suggestive of rickets such as
      hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or
      high 25-OHD levels and low or normal 1,25-OH2D levels.
    explanation: >-
      Reports elevated alkaline phosphatase, the marker of increased but
      ineffective bone turnover in rickets.
treatments:
- name: Calcitriol Replacement
  action_category: THERAPEUTIC
  description: >-
    Calcitriol supplies the active hormone downstream of CYP27B1. Dose is
    individualized against calcium, phosphate, PTH, alkaline phosphatase, urinary
    calcium, skeletal healing, and growth; response depends on adherence and age
    at diagnosis and is not a stand-alone diagnostic test.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
  target_mechanisms:
  - target: Renal 1-Alpha-Hydroxylase Deficiency
    treatment_effect: BYPASSES
    description: >-
      Supplying calcitriol bypasses the missing renal 1-alpha-hydroxylation step
      and restores hormone availability downstream of the enzyme defect.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Differentiation of nutritional rickets and VDDR1A was made by
        normal/high 25-OHD levels, low/inappropriately normal 1,25-OH2D levels
        and improvement in the clinical, biochemical and radiological findings
        of rickets after replacement with calcitriol.
      explanation: >-
        Records multi-domain improvement after replacement with the product of
        the blocked reaction.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After the definitive diagnosis of VDDR1A all patients received calcitriol
      treatment. The duration of treatment with calcitriol ranged between six
      months and seven years. Biochemical improvement with treatment occurred
      within a period ranging between four and 12 months.
    explanation: >-
      Reports calcitriol exposure and the observed time to biochemical
      improvement in this cohort, without converting it into a universal dosing
      or response estimate.
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Serum (calcium, phosphorus, PTH, alkaline phosphatase, creatinine, and
      appropriate vitamin D metabolites) and urinary (24-h urine calcium or
      random urine calcium/creatinine ratio) biochemistries should be measured
      every 3–6 months.
    explanation: >-
      Supports biochemical and urinary-calcium monitoring during ongoing
      replacement; exact intervals remain clinical guidance, not a target value.
- name: Alfacalcidol Replacement
  action_category: THERAPEUTIC
  description: >-
    Alfacalcidol is already 1-alpha-hydroxylated and requires hepatic
    25-hydroxylation to become active, so it also bypasses CYP27B1. It is curated
    separately from calcitriol because activation, half-life, and dosing are not
    interchangeable.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alfacalcidol
      term:
        id: CHEBI:31186
        label: alfacalcidol
  target_mechanisms:
  - target: Renal 1-Alpha-Hydroxylase Deficiency
    treatment_effect: BYPASSES
    description: >-
      The analogue overcomes the renal enzymatic block because its remaining
      activation step is 25-hydroxylation.
    evidence:
    - reference: PMID:32596195
      reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Treatment with 1α-cholecalciferol is similarly effective as this
        metabolite also overcomes the enzymatic block, and due to its longer
        half-life than calcitriol, it can be administered once daily.
      explanation: >-
        Directly supports alfacalcidol as a distinct analogue that overcomes the
        block; the entry does not turn the cited general schedule into an
        individualized prescription.
  evidence:
  - reference: PMID:36321535
    reference_title: "Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients were treated with alfacalcidol. Clinical (skeletal, neurological),
      biochemical, and radiological outcomes were satisfactory, and complications
      occurred if there was bad adherence.
    explanation: >-
      Reports satisfactory multidomain outcomes in a 24-case cohort while
      preserving the source's adherence caveat.
- name: Calcium Supplementation for Hypocalcemia and Remineralization
  action_category: THERAPEUTIC
  description: >-
    Oral calcium is added when hypocalcemia or the calcium demand of skeletal
    remineralization warrants it. It is adjunctive to activated vitamin D, not a
    correction of the CYP27B1 defect, and should not be inferred as necessary for
    every patient at every phase.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcium
      term:
        id: CHEBI:29108
        label: calcium(2+)
  target_mechanisms:
  - target: Systemic Calcium Deficit
    treatment_effect: RESTORES
    description: >-
      Supplemental calcium directly increases substrate available to correct
      hypocalcemia and support remineralization while active vitamin D restores
      absorption.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients received calcitriol and patients with hypocalcaemia received
        calcium replacement.
      explanation: >-
        Supports selective calcium replacement in hypocalcemic patients rather
        than universal supplementation.
  target_phenotypes:
  - preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients received calcitriol and patients with hypocalcaemia received
      calcium replacement.
    explanation: >-
      Directly documents the cohort's calcium-replacement indication.
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Calcium supplements (50 mg/kg of elemental calcium per day for children)
      should also be given during initial treatment to prevent worsening of
      hypocalcemia due to the “hungry bones” phenomenon that occurs with
      remineralization of the skeleton.
    explanation: >-
      Supports the distinct early-remodeling indication for adjunctive calcium;
      the quoted review dose is not promoted as a universal prescription here.
biochemical:
- name: 1,25-dihydroxyvitamin D (calcitriol)
  presence: Decreased or inappropriately normal
  biomarker_term:
    preferred_term: 1,25-Dihydroxyvitamin D3 Measurement
    term:
      id: NCIT:C179754
      label: 1,25-Dihydroxyvitamin D3 Measurement
  context: >-
    Low or inappropriately normal calcitriol is the proximal biochemical readout
    of impaired CYP27B1-dependent activation. Interpretation must be relative to
    calcium, phosphate, PTH, treatment, and assay context: a value inside the
    laboratory interval may still be inadequate during hypocalcemia and marked
    PTH elevation. The value is not interpreted through a rigid two-analyte table.
  readouts:
  - target: Calcitriol Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A low or physiologically inappropriate calcitriol concentration reports the
      failed activation step, but a normal-range value does not exclude VDDR1A.
    evidence:
    - reference: PMID:30282619
      reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We also found that the concentrations of 1,25-dihydroxyvitamin D levels
        may be within inappropriately normal ranges in genetically proven vitamin
        D dependent rickets type 1A and lead to diagnostic confusion.
      explanation: >-
        Directly supports physiologic interpretation of a normal-range result and
        the risk of false exclusion.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients also had biochemical features suggestive of rickets such as
      hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or
      high 25-OHD levels and low or normal 1,25-OH2D levels.
    explanation: >-
      Reports the pattern of normal-to-high 25-hydroxyvitamin D with low or
      inappropriately normal calcitriol that defines the type 1A biochemistry.
- name: 25-hydroxyvitamin D (calcifediol)
  presence: Variable; often normal or elevated
  biomarker_term:
    preferred_term: 25-Hydroxyvitamin D Measurement
    term:
      id: NCIT:C92268
      label: 25-Hydroxyvitamin D Measurement
  context: >-
    Hepatic 25-hydroxylation is intact, so normal or high 25-hydroxyvitamin D can
    distinguish VDDR1A from nutritional deficiency and CYP2R1-related VDDR1B.
    It is not required to be normal: nutritional status, prior supplementation,
    and other clinical factors can move the measured concentration, and a
    24-case genetically confirmed cohort reported low 25OHD.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VDDR1A should definitely be considered when a patient with signs of
      rickets has a normal 25-OHD level or when there is unresponsiveness to
      vitamin D treatment.
    explanation: >-
      States the diagnostic value of a normal 25-hydroxyvitamin D result in a
      child with rickets, without making normality necessary.
  - reference: PMID:36321535
    reference_title: "Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      low 25OHD and low 1,25(OH)2D3
    explanation: >-
      Demonstrates low 25OHD in a genetically confirmed cohort and prevents a
      required-normal biochemical rule.
diagnosis:
- name: Clinical, radiographic, and biochemical evaluation
  diagnosis_term:
    preferred_term: Clinical Evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >-
    Evaluate rachitic signs and growth, wrist or knee radiographs, serum calcium,
    phosphate, alkaline phosphatase, PTH, 25-hydroxyvitamin D, and calcitriol.
    Low or inappropriately normal calcitriol in a calciopenic-rickets context is
    particularly informative, but calcium and both vitamin D metabolites can
    fall inside or outside their usual pattern; biochemical response to treatment
    is supportive rather than confirmatory.
  results: >-
    A calciopenic-rickets phenotype with secondary hyperparathyroidism and
    inadequate calcitriol should prompt molecular testing for VDDR1A while
    competing nutritional, phosphopenic, activation, and receptor disorders are
    assessed.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients also had biochemical features suggestive of rickets such as
      hypophosphatemia, hypo- or normocalcemia, elevated PTH and ALP, normal or
      high 25-OHD levels and low or normal 1,25-OH2D levels. Wrist and knee
      radiographs of all patients demonstrated widened epiphyses and metaphyseal
      cupping and fraying.
    explanation: >-
      Provides the measured laboratory and radiographic pattern in the
      11-patient Turkish cohort; the entry does not generalize every component as
      obligatory.
- name: Biallelic CYP27B1 molecular confirmation
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Demonstration of pathogenic variants on both CYP27B1 alleles confirms the
    molecular diagnosis. Variant interpretation should allow partial-loss alleles
    and should not rely on a normal/high 25-hydroxyvitamin D prerequisite.
  results: >-
    A pathogenic biallelic CYP27B1 genotype establishes VDDR1A in the appropriate
    phenotype and distinguishes it from genetically different rickets disorders.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As it may be confused with nutritional rickets and hypophosphatemic
      rickets, genetic analysis is important for making a correct diagnosis.
    explanation: >-
      Directly supports molecular analysis as the resolving test when clinical
      and biochemical presentations overlap.
differential_diagnoses:
- name: Nutritional rickets
  description: >-
    Nutritional vitamin D or calcium deficiency shares calciopenia, secondary
    hyperparathyroidism, hypophosphatemia, high alkaline phosphatase, and rachitic
    radiographs. Low 25-hydroxyvitamin D and response to ordinary nutritional
    replacement favor deficiency, but low 25-hydroxyvitamin D can coexist with
    VDDR1A and cannot exclude a biallelic CYP27B1 diagnosis.
  distinguishing_features:
  - Normal or high 25-hydroxyvitamin D supports VDDR1A over vitamin D deficiency but is not required for VDDR1A.
  - Low or inappropriately normal calcitriol despite strong PTH drive supports impaired 1-alpha-hydroxylation.
  - Biallelic pathogenic CYP27B1 variants confirm VDDR1A.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical and laboratory features of VDDR1A are very similar to
      nutritional rickets although the differential diagnosis can be made by a
      low or inappropriately normal 1, 25-OH2D level and unresponsiveness to
      vitamin D treatment.
    explanation: >-
      Directly identifies the clinical overlap and the value of physiologically
      inadequate calcitriol and poor response to usual vitamin D therapy.
- name: X-linked hypophosphatemic rickets
  disease_term:
    preferred_term: X-linked dominant hypophosphatemic rickets
    term:
      id: MONDO:0010619
      label: X-linked dominant hypophosphatemic rickets
  description: >-
    Both disorders can present with hypophosphatemia, growth failure, bowed legs,
    and rachitic radiographs. In VDDR1A, phosphate wasting is secondary to high
    PTH from the calcium/calcitriol defect; in X-linked hypophosphatemia it is a
    primary FGF23-mediated renal phosphate-wasting disorder and calcium and PTH
    are usually not calciopenic-pattern abnormalities.
  distinguishing_features:
  - Markedly elevated PTH with low or inappropriately normal calcitriol favors VDDR1A.
  - Primary renal phosphate wasting with a pathogenic PHEX variant favors X-linked hypophosphatemia.
  evidence:
  - reference: PMID:30282619
    reference_title: Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentations of patients with VDDR1A could lead to a
      misdiagnosis of nutritional rickets or hypophosphatemic rickets, which can
      be differentiated from hypophosphatemic rickets by a high PTH level and
      from nutritional rickets by a normal 25-OHD level.
    explanation: >-
      Identifies high PTH as a useful discriminator from hypophosphatemic rickets;
      it is interpreted as a pattern rather than an absolute threshold.
- name: Vitamin D-Dependent Rickets Type 1B
  disease_term:
    preferred_term: vitamin D hydroxylation-deficient rickets, type 1B
    term:
      id: MONDO:0010810
      label: vitamin D hydroxylation-deficient rickets, type 1B
  description: >-
    CYP2R1-related VDDR1B also impairs vitamin D activation but blocks hepatic
    25-hydroxylation rather than renal 1-alpha-hydroxylation. Very low
    25-hydroxyvitamin D with normal or high calcitriol and response to
    calcifediol favor VDDR1B.
  distinguishing_features:
  - Biallelic CYP2R1 rather than CYP27B1 variants establish VDDR1B.
  - Very low 25-hydroxyvitamin D with normal or high calcitriol supports VDDR1B.
  evidence:
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discuss the difficulties in establishing the correct diagnosis and the
      specific biochemical pattern, namely, very low 25-OH-D suggestive of
      classical vitamin D deficiency, in the face of normal/high concentrations
      of 1,25-(OH)2 D.
    explanation: >-
      Defines the CYP2R1-deficiency metabolite pattern that contrasts with the
      CYP27B1 activation block.
  - reference: PMID:28548312
    reference_title: "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we demonstrate dramatic improvements in patients who were given 25-OH-D
      therapy (clinical symptoms, biochemical data, and bone densitometry).
    explanation: >-
      Directly supports response to calcifediol as a treatment clue in the
      reported CYP2R1-deficient families, not as a stand-alone diagnostic test.
- name: Vitamin D-Dependent Rickets Type 2A
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 2A
    term:
      id: MONDO:0010186
      label: vitamin D-dependent rickets, type 2A
  description: >-
    VDR-related VDDR2A produces target-organ resistance rather than deficient
    calcitriol synthesis. Elevated calcitriol and alopecia in about half of
    reported patients favor VDDR2A; absence of alopecia does not exclude it.
  distinguishing_features:
  - Elevated rather than inadequate calcitriol supports receptor resistance.
  - Biallelic pathogenic VDR variants establish VDDR2A.
  - Alopecia is supportive when present but is not obligatory.
  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: >-
      Supports the high-calcitriol receptor-resistance pattern that separates
      VDDR2A from deficient CYP27B1-mediated synthesis.
  - 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: >-
      Supports alopecia as a common but non-obligate discriminator.
- name: Vitamin D-Dependent Rickets Type 2B
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 2B
    term:
      id: MONDO:0010931
      label: vitamin D-dependent rickets, type 2B
  description: >-
    Historical VDDR2B reports describe receptor-positive/postreceptor vitamin D
    resistance with high calcitriol despite a normal VDR coding sequence. The
    entity boundary remains unresolved, and HNRNPC overexpression in one index
    lineage must not be converted into an established germline HNRNPC cause.
  distinguishing_features:
  - Elevated calcitriol with target-organ resistance contrasts with the deficient or inappropriately normal calcitriol of VDDR1A.
  - A normal VDR coding sequence was reported, but there is no validated positive molecular test for VDDR2B.
  - Biallelic pathogenic CYP27B1 variants establish VDDR1A rather than VDDR2B.
  evidence:
  - reference: PMID:7586652
    reference_title: Vitamin D dependent rickets type II and normal vitamin D receptor cDNA sequence. A cluster in a rural area of Cauca, Colombia, with more than 200 affected children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum analysis showed significantly lower serum calcium as compared to
      normal relatives, though in the normal low range, normal phosphorus, high
      alkaline phosphatase, normal 25-hydroxyvitamin D3 and high
      1,25-dihydroxyvitamin D3, indicating target organ resistance. The cDNA
      analysis showed normal nucleotide sequence.
    explanation: >-
      Defines the reported receptor-positive cluster pattern and normal VDR cDNA
      without assigning it the separate index-case HNRNPC mechanism.
  - 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: >-
      Preserves the current review's explicit uncertainty about the entity.
- name: Vitamin D-Dependent Rickets Type 3
  disease_term:
    preferred_term: vitamin D-dependent rickets, type 3
    term:
      id: MONDO:0033640
      label: vitamin D-dependent rickets, type 3
  description: >-
    VDDR3 is accelerated vitamin D-metabolite inactivation caused by the
    recurrent de novo CYP3A4 p.Ile301Thr gain-of-function variant in the two
    originally reported unrelated patients. Both major metabolites were low and
    responsiveness to parent and activated vitamin D was deficient; CYP3A4
    rather than CYP27B1 establishes this reported mechanism.
  distinguishing_features:
  - A heterozygous CYP3A4 p.Ile301Thr gain-of-function variant establishes the reported VDDR3 mechanism.
  - Low concentrations of both 25-hydroxyvitamin D and calcitriol with deficient replacement responsiveness support accelerated catabolism.
  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: >-
      Defines the original two-patient VDDR3 metabolite and response pattern;
      the entry does not generalize beyond that evidence.
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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: >-
      Directly establishes the recurrent de novo variant in the two reported
      patients.
  - 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: >-
      Functionally establishes gain of calcitriol-inactivation activity in the
      mutant enzyme rather than relying on sequence inference alone.
experimental_models:
- name: Patient-derived VDDR-1 keratinocyte cultures
  description: >-
    Primary keratinocytes from the founding patient and adult or neonatal human
    comparison cultures were used to assay 1-alpha-hydroxylase activity. The
    patient cells lacked detectable activity and carried compound-heterozygous
    deletion/frameshift null variants. This directly tests the catalytic lesion
    in patient-derived cells but is not a renal proximal-tubule model.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  conditions:
  - VDDR-1 patient primary keratinocytes
  - Adult and neonatal comparison keratinocytes
  cell_source: Primary human keratinocytes from one VDDR-1 patient and comparison donors
  culture_system: Primary keratinocyte culture
  publication: PMID:9415400
  modeled_mechanisms:
  - target: Renal 1-Alpha-Hydroxylase Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The patient-derived culture recapitulates loss of CYP27B1 catalytic
      activity, while its nonrenal lineage limits tissue-level fidelity.
    limitations: >-
      One founding patient was studied; keratinocytes can assay the enzyme but do
      not reproduce proximal-tubule regulation or whole-body mineral homeostasis.
    evidence:
    - reference: PMID:9415400
      reference_title: Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Primary cultures of human adult and neonatal keratinocytes exhibit
        abundant 1 alpha-hydroxylase activity, whereas those from a patient with
        VDDR-1 lacked detectable activity.
      explanation: >-
        Directly compares patient and human comparison cultures for the modeled
        enzyme activity.
  evidence:
  - reference: PMID:9415400
    reference_title: Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Keratinocyte P450c1 alpha cDNA from the patient with VDDR-1 contained
      deletion/frameshift mutations either at codon 211 or at codon 231,
      indicating that the patient was a compound heterozygote for two null
      mutations.
    explanation: >-
      Grounds the model in the patient's two null alleles rather than an
      ungenotyped culture phenotype.
animal_models:
- name: Cyp27b1-deficient mouse
  species: Mouse (Mus musculus)
  genotype: Cyp27b1-/- targeted loss of function
  category: Targeted loss-of-function model
  description: >-
    Targeted Cyp27b1 inactivation produces a pseudo-vitamin-D-deficiency-rickets
    model. Chronic calcitriol treatment corrected hypocalcemia and secondary
    hyperparathyroidism, cured rickets and osteomalacia histologically, and
    restored bone biomechanical properties. This is causal model-organism
    evidence, not a human treatment-effect estimate.
  publication: PMID:12674324
  associated_phenotypes:
  - Hypocalcemia
  - Secondary hyperparathyroidism
  - Rickets
  modeled_mechanisms:
  - target: Renal 1-Alpha-Hydroxylase Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Targeted loss of the ortholog reproduces the initiating enzyme-deficiency
      mechanism.
    limitations: >-
      A constitutive engineered mouse does not capture the full allelic and
      treatment-history heterogeneity of human VDDR1A.
    evidence:
    - reference: PMID:12674324
      reference_title: "Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3: biochemical, histomorphometric, and biomechanical analyses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We have previously engineered an animal model of PDDR by targeted
        inactivation of the 1alpha-OHase gene in mice.
      explanation: >-
        Directly establishes the targeted enzyme-loss model.
  - target: Defective Skeletal Mineralization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The untreated knockout carries the rachitic/osteomalacic skeletal endpoint,
      and calcitriol rescue normalizes histology and mechanics.
    limitations: >-
      Rescue under an experimental injection regimen cannot set a human dose or
      guarantee human growth recovery.
    evidence:
    - reference: PMID:12674324
      reference_title: "Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3: biochemical, histomorphometric, and biomechanical analyses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Bone histology and histomorphometry confirmed that the rickets and
        osteomalacia were cured. The rescue regimen also restored the
        biomechanical properties of the bone tissue within normal parameters.
      explanation: >-
        Directly supports the skeletal phenotype and its calcitriol-responsive
        rescue in the mouse.
  evidence:
  - reference: PMID:12674324
    reference_title: "Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3: biochemical, histomorphometric, and biomechanical analyses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Blood biochemistry analysis revealed that the rescue treatment corrected
      the hypocalcemia and secondary hyperparathyroidism.
    explanation: >-
      Supports biochemical rescue of two modeled downstream consequences.
datasets:
- accession: geo:GSE69170
  title: >-
    1,25-Dihydroxyvitamin D3 Controls a Cohort of Vitamin D Receptor Target
    Genes in the Proximal Intestine That Is Enriched for Calcium Regulating
    Components (RNA-seq)
  description: >-
    Bulk RNA-seq of duodenum from Cyp27b1-null male mice on a vitamin-D-deficient
    normal-mineral diet or a high-calcium/high-phosphate rescue diet, sampled six
    hours after vehicle or calcitriol treatment. The four-condition design
    directly interrogates the intestinal calcitriol-response program downstream
    of the modeled synthesis defect; it is not a human VDDR1A cohort.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 24
  conditions:
  - Vitamin-D-deficient normal-mineral diet plus vehicle
  - Vitamin-D-deficient normal-mineral diet plus calcitriol
  - Vitamin-D-deficient high-calcium/high-phosphate rescue diet plus vehicle
  - Vitamin-D-deficient high-calcium/high-phosphate rescue diet plus calcitriol
  platform: GPL13112
  publication: PMID:26041780
  evidence:
  - reference: GEO:GSE69170
    reference_title: >-
      1,25-Dihydroxyvitamin D3 Controls a Cohort of Vitamin D Receptor Target
      Genes in the Proximal Intestine That Is Enriched for Calcium Regulating
      Components (RNA-seq)
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To examine this issue, Cyp27b1 null mice on either a normal or a high
      calcium/phosphate-containing rescue diet were treated with either vehicle
      or 1,25(OH)2D3 and evaluated 6h later. RNA samples from duodena were then
      subjected to RNA-seq analysis and the data analyzed bioinformatically.
    explanation: >-
      The accession record directly establishes the genotype, dietary and
      calcitriol perturbations, intestinal tissue, timing, and RNA-seq assay.
  notes: >-
    Accession, organism, 24-sample four-group design, platform, and linked
    publication were verified against the full NCBI GEO record on 2026-08-24.
    GEO lists this series within SuperSeries GSE69180. Relevance is confined to
    the Cyp27b1-null mouse and downstream intestinal vitamin-D response.
notes: >-
  Naming caution: "vitamin D-dependent" describes dependence on the active
  hormone, not on dietary vitamin D. Historical labels such as VDDR-I and
  pseudovitamin-D-deficiency rickets predate or blur the modern type 1A/type 1B
  split and should not be mapped to this entry without CYP27B1 or compatible
  mechanistic evidence. VDDR types 2A and 2B instead concern target-organ
  resistance with high calcitriol; type 2B remains an unresolved entity and is
  not an established germline HNRNPC disorder. The 11-patient Turkish and
  24-case French referral cohorts used here are complementary but small, so
  their frequencies and treatment observations remain cohort-scoped. See the
  `Vitamin_D-Dependent_Rickets` grouping for member boundaries.
📚

References & Deep Research

Deep Research

1
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Vitamin D-Dependent Rickets Type 1A (VDDR1A) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 32 citations 2026-08-19T18:08:36.074004

Vitamin D-Dependent Rickets Type 1A (VDDR1A) — Comprehensive Research Report

1. Disease Information

Overview. Vitamin D-dependent rickets type 1A (VDDR1A), also called pseudovitamin D deficiency rickets (PDDR) or vitamin D hydroxylation-deficient rickets type 1A, is a rare autosomal recessive inborn error of vitamin D metabolism caused by biallelic loss-of-function variants in CYP27B1, the gene encoding renal 25-hydroxyvitamin D-1α-hydroxylase. The enzyme defect abolishes or severely impairs the final activating hydroxylation step that converts 25-hydroxyvitamin D (25(OH)D, calcidiol) to 1,25-dihydroxyvitamin D (1,25(OH)₂D, calcitriol), the biologically active vitamin D hormone. The resulting selective calcitriol deficiency causes intestinal calcium malabsorption, hypocalcemia, secondary hyperparathyroidism, and impaired bone mineralization (rickets in children; osteomalacia if it persisted to adulthood), despite normal-to-elevated levels of the inactive precursor 25(OH)D (OMIM #264700; PMC4489500).

Key identifiers: - OMIM: #264700 (VDDR1A phenotype); CYP27B1 gene OMIM 609506 - Orphanet: ORPHA289157 (Hypocalcemic vitamin D-dependent rickets) - ICD-10-CM: E83.32 (Hereditary vitamin D-dependent rickets, type 1 and type 2); Orphanet also cross-maps to E55.0 (Rickets, active) - GARD (NIH Genetic and Rare Diseases Information Center): "Vitamin D-dependent rickets, type 1" - Gene: CYP27B1, chromosome 12q14.1 (some sources cite 12q13.3/12q14) - MeSH/synonym set: Pseudo-vitamin D deficiency rickets; PDDR; Type I vitamin D-dependent rickets; 1α-hydroxylase deficiency; hereditary pseudo-vitamin D deficiency rickets

Synonyms/alternative names: Pseudovitamin D-deficiency rickets (PDDR), vitamin D-dependent rickets type I, 25-hydroxyvitamin D-1α-hydroxylase deficiency, hereditary vitamin D dependency, hypocalcemic vitamin D-dependent rickets.

Data source character: Understanding of VDDR1A derives almost entirely from aggregated case reports and small case series/cohorts (individual-patient literature), plus a founder-population registry (Saguenay–Lac-Saint-Jean, Quebec) and structured aggregations such as OMIM, Orphanet, and MalaCards; no large-scale EHR/claims-based epidemiologic studies exist given its rarity (PMC9671943; PMC9120640).

Sources: OMIM #264700 | PMC4489500 | ICD10Data E83.32 | MalaCards VDDR1A

2. Etiology

Disease causal factors — genetic. VDDR1A is caused exclusively by biallelic (homozygous or compound heterozygous) pathogenic loss-of-function variants in CYP27B1. As of recent surveys, ~78–100 distinct pathogenic CYP27B1 variants have been reported across >100–219 published patients from diverse ethnic groups, spanning all 9 exons; missense and nonsense substitutions predominate, alongside splice-site variants, small insertions, deletions, and duplications (PMC6398191; PLOS ONE, PMC4489500). A 2022 series of 12 Chinese children found 9 CYP27B1 variants (4 known, 5 novel: c.937G>C p.Glu313Gln, c.232delG p.Ala78Profs81, c.565G>T p.Glu189, c.1192G>A p.Gly398Ser, c.402G>A p.Trp134*), with single-nucleotide substitutions (66.7%), small deletions (22.2%), and small insertions (11.1%) (Front Pediatr 2022, PMID:36405822, PMC9671943).

Founder/recurrent variants: - c.1319_1325dupCCCACCC (p.Phe443Profs*24): a regional hotspot in southern China, found in 66.7% of a 12-patient Guangzhou cohort (45.8% of alleles) (PMC9671943). - c.262delG (p.Val88Trpfs*71): the founder variant of the Saguenay–Lac-Saint-Jean (SLSJ) region of Quebec, Canada, where every molecularly confirmed VDDR1A case traces to this single allele. - Intron-1 mutations shared by patients from a common city of origin have also suggested independent founder effects in other populations ([various case reports, search synthesis]). - p.(Ala129Thr): a recurrent partial loss-of-function ("hypomorphic") variant retaining ~50% residual enzymatic activity, associated with a distinctly milder phenotype (see Section 4/Genotype-phenotype below) (JCEM 2023, PMID:36321535).

Risk factors — genetic: Biallelic CYP27B1 pathogenic variants are both necessary and sufficient (fully penetrant with autosomal recessive inheritance); consanguinity substantially raises risk in outbred populations via increased homozygosity; population founder effects (e.g., French-Canadian SLSJ) create geographically concentrated carrier clusters.

Risk factors — environmental: No environmental exposure causes VDDR1A itself (it is a purely monogenic disorder), but vitamin D nutritional status (dietary calciferol intake, sun exposure) modulates the severity and timing of clinical presentation, since substrate (25(OH)D) availability affects how much residual/hypomorphic enzyme activity can generate 1,25(OH)₂D in partial-deficiency genotypes.

Protective factors: Hypomorphic ("leaky") CYP27B1 alleles such as p.(Ala129Thr) are protective relative to null alleles, producing later onset and milder biochemical/skeletal disease. No population-level protective environmental factor is documented; adequate vitamin D nutritional status can partially compensate for hypomorphic (but not null) alleles by providing more substrate for residual enzyme activity.

Gene-environment interactions: The clearest interaction is that ambient/dietary vitamin D sufficiency provides substrate (25(OH)D) that residual-activity hypomorphic CYP27B1 enzyme can still partially hydroxylate — meaning a child with a partial loss-of-function genotype and good vitamin D status may present later/milder than one who is also nutritionally vitamin D deficient. There is no independent environmental trigger analogous to infection or toxin exposure.

Sources: PMC6398191 | PMC9671943 | JCEM PMID:36321535

3. Phenotypes

Onset and general pattern: Affected infants are normal at birth (maternal-fetal calcium transfer via placenta is largely 1,25(OH)₂D-independent) and become symptomatic typically between 6 months and 2 years of age (mean onset ~1.1 ± 0.4 years in one cohort; overall reported range up to ~3 years, occasionally later with hypomorphic alleles) (PMC9671943; Frontiers review PMC7860650).

Symptoms/signs (categorized):

Phenotype HPO suggestion Frequency (from cohort data)
Delayed walking / motor delay HP:0031936 (Delayed ability to walk) 83.3% (10/12)
Short stature / growth retardation HP:0004322 75.0% (9/12); 75% had severe HtSDS < −2
Muscle weakness / hypotonia HP:0001324 / HP:0001252 50.0% (6/12)
Recurrent long-bone fractures HP:0002757 33.3% (4/12)
Hypocalcemic seizures/tetany HP:0002014-adjacent; HP:0002378 (tetany) / HP:0032792 Reported in classic descriptions; absent in one cohort (0/12), present in others (irritability, tetany, seizures common in early series)
Bracelet (wrist) deformity HP:0002645-adjacent (widened wrist) 91.7%
Rib eversion / rachitic rosary HP:0000921 (rachitic rosary) 83.3% / 50.0%
Leg bowing/deformity (genu varum/valgum) HP:0002970 / HP:0002816 75.0%
Pectus carinatum HP:0000768 50.0%
Scoliosis HP:0002650 25.0%
Frontal bossing HP:0011330 Classically described
Dental enamel hypoplasia HP:0006297 High proportion of adults affected, especially incisors, canines, first molars
Widened cranial sutures / posterior flattening of skull HP:0004422-adjacent Described
Failure to thrive HP:0001508 Common presenting feature; mean diagnosis age 13.8 ± 5 months in newborn-screening cohort

Laboratory abnormalities (biochemical phenotype) — the core diagnostic signature: - Hypocalcemia (mean 1.57 ± 0.19 mmol/L vs. reference 2.24–2.74 mmol/L) - Hypophosphatemia (mean 0.87 ± 0.23 mmol/L vs. reference 1.29–1.94 mmol/L) — secondary to PTH-driven renal phosphate wasting - Markedly elevated alkaline phosphatase (ALP) (mean 1629 ± 673 U/L vs. reference 118–390 U/L) - Elevated PTH / secondary hyperparathyroidism (mean 57.8 ± 32.7 pmol/L vs. reference 1.2–7.1 pmol/L) - Normal to elevated 25(OH)D (mean 77.1 ± 18.4 nmol/L; distinguishes VDDR1A from nutritional deficiency and VDDR1B/CYP2R1 deficiency) - Low or inappropriately normal 1,25(OH)₂D — the diagnostic hallmark, given the accompanying secondary hyperparathyroidism and hypocalcemia that should otherwise drive 1,25(OH)₂D up (Data: PMC9671943)

Radiographic phenotype: widened metaphyses, metaphyseal cupping/fraying, generalized decreased bone density, "fuzzy" metaphyseal margins on wrist/knee radiographs — classic rachitic changes; a Rickets Severity Score (RSS) of ~9.0 ± 1.0 at diagnosis in one cohort.

Severity/progression: Symptom severity is variable and correlates with residual enzyme activity and age at diagnosis/treatment onset (earlier diagnosis correlates with better height outcome; r = −0.62, p<0.05 between HtSDS and age at diagnosis). Untreated disease is progressive; treated disease shows biochemical normalization within ~3 months but height catch-up is less reliable, especially with poor treatment adherence.

Quality of life impact: Untreated/undertreated VDDR1A produces severe skeletal deformity, short stature, impaired mobility (documented case: inability to ambulate independently after 6-year treatment lapse, requiring surgical correction of scoliosis), and dental morbidity. With early, consistent calcitriol therapy, biochemical and most radiographic parameters normalize and QoL approaches normal, though sustained height catch-up occurs in only a minority (27.3% in one long-term cohort) — underscoring the QoL cost of treatment non-adherence, frequently linked to economic/social barriers (58.3% poor long-term compliance in one cohort).

Sources: PMC9671943 (12-child cohort) | PMC7860650 | Craniofacial/dental study | GARD

4. Genetic/Molecular Information

Causal gene: CYP27B1 (HGNC:2606; OMIM 609506), chromosome 12q14.1, encoding 25-hydroxyvitamin D-1α-hydroxylase (1α-OHase), a mitochondrial cytochrome P450 enzyme expressed predominantly in the renal proximal tubule (with documented extrarenal expression, see Section 6).

Variant landscape: ~78–100+ distinct pathogenic variants reported (missense, nonsense, frameshift indels, splice-site changes) spanning all coding exons (PMC6398191; PLOS ONE PMC4489500). In one 19-family cohort: 17 variants (11 missense, 3 frameshift, 2 truncating, 1 splice-acceptor site), homozygosity in 58% (11/19) (JCEM PMID:36321535).

Variant classification/pathogenicity: Per ACMG/AMP framework as used in ClinVar — most reported CYP27B1 variants are classified pathogenic/likely pathogenic based on: (1) biochemical loss-of-function assays; (2) segregation with autosomal recessive disease; (3) absence/near-absence in population databases (gnomAD); (4) protein-truncating or highly conserved missense location.

Functional consequence categories: - Complete loss-of-function (null) alleles — nonsense, frameshift, splice-disrupting variants that eliminate enzyme activity entirely — associated with classic early-onset, severe phenotype. - Partial loss-of-function (hypomorphic) alleles — e.g., p.(Ala129Thr), retaining ~50% residual catalytic activity — associated with later-onset, milder disease (median age at diagnosis 5.0 vs. 1.2 years; serum calcium 2.26 vs. 1.85 mmol/L; PTH 4.7 vs. 7.5× ULN; ALP 759 vs. 2082 IU/L compared to other genotypes) (JCEM 2023, PMID:36321535). - Enzyme-adrenodoxin interaction-disrupting variants — e.g., R459L, which prevents CYP27B1 from forming its normal electrostatic/sulfide-bridge interaction with adrenodoxin (the mitochondrial electron-donor redox partner), dramatically reducing catalytic turnover; H441Y, which disrupts a hydrogen bond with adrenodoxin but only minimally reduces activity — illustrating a structure-function spectrum where different adrenodoxin-interface residues confer different severities (JCEM PMID unspecified in search, "Adrenodoxin interactions" paper; Biochemistry, Arg458 mouse study). - c.590G>A (p.G197D): shown to cause aberrant RNA splicing rather than a simple missense effect (Front Genet, PMC7729158).

Modifier genes: No established modifier loci distinct from CYP27B1 allelic series itself; phenotype variability is chiefly explained by allelic (residual activity) effects rather than trans-acting modifiers, though vitamin D nutritional status functions as a phenotype modifier for hypomorphic genotypes.

Population/allele frequency: Individual pathogenic CYP27B1 variants are each very rare in general population databases (gnomAD), consistent with an overall rare autosomal recessive disease (worldwide literature reports ~219 patients cumulatively). The exception is regional founder populations: SLSJ Quebec carrier frequency for c.262delG estimated at 1 in 26–29, giving a birth prevalence of ~1 in 2,358–2,916 in that region — orders of magnitude above the general-population rate.

Somatic vs. germline: VDDR1A is exclusively a germline/constitutional disease; CYP27B1 has been separately studied (and largely excluded) as a candidate tumor-suppressor gene in primary and secondary/tertiary hyperparathyroidism, a distinct somatic-oncology question unrelated to VDDR1A pathogenesis (PMC2689078).

Epigenetics/chromosomal abnormalities: No epigenetic mechanism or chromosomal-scale abnormality (aneuploidy, large CNV, translocation) has been implicated in VDDR1A; it is a classic single-gene, sequence-level Mendelian disorder.

Sources: OMIM 609506 | PMC6398191 | JCEM PMID:36321535 | JCEM adrenodoxin paper | PMC7729158 | PMC2689078

5. Environmental Information

VDDR1A is a monogenic disorder with no infectious or toxin etiology. The principal environmental modulator is vitamin D nutritional status (dietary intake and sun-exposure-derived cutaneous synthesis), which determines substrate (25(OH)D) supply and thereby modulates severity/timing in patients with hypomorphic (partial-activity) CYP27B1 alleles, though it cannot compensate for null alleles. No occupational, toxin, radiation, or lifestyle risk factor beyond general vitamin D status has been documented in the literature reviewed. No infectious trigger is implicated in disease onset (as distinct from the separate observation that CYP27B1 extrarenal/immune-cell expression participates in granulomatous-disease vitamin D dysregulation, e.g., tuberculosis-associated hypercalcemia — a different clinical phenomenon from VDDR1A itself; see Section 6).

Sources: PMC7860650 | Regulation of extrarenal CYP27B1, PMID:24388948

6. Mechanism / Pathophysiology

Causal chain (initial trigger → clinical manifestation):

  1. Molecular lesion: Biallelic pathogenic CYP27B1 variants → loss or severe reduction of 25-hydroxyvitamin D-1α-hydroxylase catalytic activity in renal proximal tubule mitochondria (GO molecular function: vitamin D 25-hydroxylase-derivative activity / 1,25-dihydroxyvitamin D synthesis; suggested GO:0036378 calcitriol biosynthetic process, GO:0070576 vitamin D 24-hydroxylase-adjacent metabolic pathway context).
  2. Enzymatic mechanism: CYP27B1 is a mitochondrial cytochrome P450 (Type I, class I) enzyme requiring electron transfer from NADPH → ferredoxin reductase → adrenodoxin (ferredoxin) → CYP27B1 heme iron to catalyze C1α-hydroxylation of 25(OH)D₃. Mutations at the CYP27B1-adrenodoxin protein-protein interface (e.g., R459L disrupting the docking interaction, H441Y disrupting a hydrogen bond) impair electron transfer and catalytic turnover, providing a structural basis for the enzymatic loss of function ([Biochemistry, Arg458 study, PMID referenced above]; JCEM adrenodoxin interaction paper).
  3. Biochemical consequence: Failure to convert 25(OH)D to 1,25(OH)₂D (calcitriol) → selective calcitriol deficiency despite normal/elevated precursor 25(OH)D.
  4. Cellular/tissue consequence: Calcitriol normally binds the vitamin D receptor (VDR, a nuclear hormone receptor/transcription factor) in intestinal enterocytes to upregulate calcium transport proteins (e.g., TRPV6, calbindin-D9k) — calcitriol deficiency causes intestinal calcium malabsorption.
  5. Systemic consequence: Reduced intestinal calcium absorption → hypocalcemia → compensatory secondary hyperparathyroidism (elevated PTH) → PTH-driven increased renal phosphate clearance → hypophosphatemia; combined hypocalcemia/hypophosphatemia → impaired hydroxyapatite deposition at the growth-plate mineralization front → rickets (in growing bone) with elevated alkaline phosphatase reflecting osteoblast compensatory activity.
  6. End-organ/clinical manifestation: Growth-plate widening/cupping, skeletal deformity, growth retardation, hypotonia, dental enamel hypoplasia, and (in severe/untreated cases) hypocalcemic tetany/seizures.

This maps closely onto the dismech defective_skeletal_mineralization module's calciopenic arm — a calcium-deficient (as opposed to phosphopenic or mineralization-inhibitor) route converging on impaired hydroxyapatite deposition at the mineralization front.

Molecular pathway/GO term suggestions: - GO:0036378 — calcitriol biosynthetic process - GO:0042359 — vitamin D metabolic process - GO:0070257 — positive regulation of mucus secretion (not relevant) — omit - GO:0006816 — calcium ion transport (downstream, intestinal) - GO:0004497 — monooxygenase activity (CYP27B1 catalytic activity class) - GO:0005506 — iron ion binding (heme cofactor) - GO:0006874 — cellular calcium ion homeostasis (downstream systemic effect)

Cellular processes involved: Renal proximal tubular epithelial cell mitochondrial hydroxylation; intestinal enterocyte calcium transport; parathyroid chief cell PTH secretion (compensatory hyperplasia); osteoblast/osteoclast-mediated growth-plate chondro-osseous mineralization (impaired).

Protein dysfunction: Loss-of-function via (a) truncation/frameshift eliminating catalytic domain, (b) missense substitutions destabilizing heme-binding or substrate-binding pockets, (c) missense substitutions at the adrenodoxin-docking interface impairing electron transfer, (d) splice-site variants causing aberrant transcript/nonfunctional protein (e.g., c.590G>A/p.G197D causing an RNA splicing error) (PMC7729158).

Biochemical abnormalities: Enzyme deficiency (1α-hydroxylase); downstream hormonal cascade abnormalities (low calcitriol, compensatory high PTH); secondary electrolyte derangements (hypocalcemia, hypophosphatemia).

Immune system involvement (extrarenal CYP27B1 biology, contextual): CYP27B1 is also expressed extrarenally in macrophages, dendritic cells, T and B lymphocytes, and keratinocytes, where it participates in intracrine/paracrine vitamin D signaling relevant to innate/adaptive immune regulation (notably in granulomatous diseases such as tuberculosis, where IFN-γ stimulates and type I interferons inhibit macrophage CYP27B1 activity). This extrarenal pathway is a distinct physiological role from the renal-endocrine axis defective in VDDR1A and is not itself part of VDDR1A pathogenesis, but is mechanistically noteworthy and occasionally causes diagnostic confusion (e.g., a VDDR1A case "mimicking pseudohypoparathyroidism in the presence of active tuberculosis," PMC11439522) (PMID:24388948; PMID:24314866).

Tissue damage mechanism: Chondro-osseous — defective mineralization of osteoid/growth-plate cartilage matrix (not classic oxidative/ischemic/fibrotic injury) due to insufficient available calcium-phosphate product at the mineralization front.

Parathyroid biology: Chronic secondary hyperparathyroidism can, in severe/prolonged untreated or undertreated cases, raise concern for autonomous (tertiary) parathyroid hyperplasia; however, CYP27B1 itself does not appear to function as a classical tumor-suppressor gene in parathyroid adenoma pathogenesis, based on molecular analyses in primary and refractory secondary/tertiary hyperparathyroidism cohorts (PMC2689078).

Advanced/omics data: No large-scale transcriptomic, proteomic, metabolomic, or single-cell/spatial datasets specific to VDDR1A patient tissue were identified in this search; mechanistic insight instead derives from biochemical enzymology (recombinant CYP27B1 kinetics, adrenodoxin-binding assays) and knockout animal models (below).

Sources: JCEM adrenodoxin paper | PMC7729158 | PMC2689078 | PMID:24388948 | PMC11439522

7. Anatomical Structures Affected

Organ level: - Primary: Skeletal system (growth plates, long bones, ribs, skull) — UBERON:0001434 (skeletal system); Kidney (site of primary enzymatic defect) — UBERON:0002113 - Secondary: Parathyroid glands (compensatory hyperplasia) — UBERON:0001132; Intestine (site of impaired calcium absorption, functional target) — UBERON:0000160; Teeth (enamel hypoplasia) — UBERON:0001091; Skull/cranial sutures (widened sutures, frontal bossing) — UBERON:0003129 - Body systems involved: Skeletal/musculoskeletal, endocrine (parathyroid-vitamin D axis), gastrointestinal (calcium absorption), and secondarily neuromuscular (hypotonia, tetany/seizures from hypocalcemia)

Tissue/cell level: - Growth plate cartilage / hypertrophic chondrocytes — affected by impaired mineralization (CL:0000058 chondrocyte) - Osteoblasts (CL:0000062) — compensatory activity reflected in elevated ALP; osteoid accumulation - Renal proximal tubule epithelial cells (CL:1001016 or CL:0002306 — kidney proximal tubule cell) — site of CYP27B1 enzymatic activity - Intestinal enterocytes (CL:0000584) — functional target of calcitriol-VDR signaling for calcium transport - Parathyroid chief cells (CL:0000426) — secondary hyperplasia/hypersecretion of PTH - Extrarenal: macrophages (CL:0000235), dendritic cells (CL:0000451), T lymphocytes (CL:0000084), B lymphocytes (CL:0000236), keratinocytes (CL:0000312) — sites of extrarenal CYP27B1 expression (not primary to VDDR1A pathology but part of the gene's broader biology)

Subcellular level: - Mitochondria (GO:0005739 mitochondrion) — CYP27B1 is a mitochondrial inner-membrane-associated cytochrome P450 enzyme - Mitochondrial matrix (site of adrenodoxin/adrenodoxin reductase electron transport chain interaction)

Localization: Bilateral/symmetric skeletal involvement (long bones, ribs, wrists, skull); no lateralization reported. Renal involvement is functional (enzymatic), not structural/anatomic (kidneys are not malformed).

Sources: synthesized from clinical descriptions across PMC9671943, PMC7860650, craniofacial/dental study

8. Temporal Development

Onset: Congenitally normal at birth; clinical onset typically 6 months to ~2 years of age (cohort mean onset 1.1 ± 0.4 years; range up to ~3 years reported); onset pattern is generally insidious/subacute (progressive failure to thrive, delayed motor milestones, evolving skeletal deformity) rather than acute, though acute hypocalcemic tetany/seizures can be a presenting event in severe null-allele cases. Milder (hypomorphic-allele) presentations can be delayed to ~5 years or discovered incidentally on family cascade screening.

Progression: Without treatment, disease is chronically progressive — worsening skeletal deformity, growth failure, and (rarely) life-threatening hypocalcemia. With calcitriol/alfacalcidol treatment, biochemical parameters (calcium, phosphate, ALP, PTH) normalize within approximately 3 months; radiographic (rachitic) improvement follows over months to a few years; height catch-up is the slowest-responding and least reliably achieved parameter, and is critically dependent on early treatment initiation and sustained adherence.

Disease course pattern: Chronic and lifelong if untreated adherence lapses — the disease is not self-limited; discontinuation of therapy (even after years of good control) leads to biologic relapse, as illustrated by a documented case of a child who stopped treatment, was lost to follow-up for 6 years, and returned with severe skeletal deformity, elevated ALP (2662 U/L) and PTH (91.8 pmol/L), and requiring surgical intervention for scoliosis.

Critical period for intervention: Diagnosis/treatment initiation timing is inversely correlated with final height outcome (r = −0.62, p<0.05 for HtSDS vs. age at diagnosis) — earlier treatment (including pre-symptomatic initiation via newborn screening in the SLSJ founder population) yields substantially better growth and skeletal outcomes, establishing early infancy/toddlerhood as the critical therapeutic window.

Sources: PMC9671943 | PMC9120640

9. Inheritance and Population

Inheritance pattern: Autosomal recessive. Both parents are typically obligate heterozygous carriers (asymptomatic); affected individuals carry two pathogenic CYP27B1 alleles (homozygous or compound heterozygous).

Penetrance: Complete/full penetrance for biallelic null genotypes; genotype-dependent expressivity for hypomorphic alleles (see below) means "penetrance" in a strict biochemical sense is universal, but clinical severity/age-of-onset varies continuously with residual enzyme activity.

Expressivity: Variable, correlating with allele-specific residual enzymatic activity — compare classic early/severe null-allele presentation vs. milder, later-onset p.(Ala129Thr) hypomorphic phenotype (older age at diagnosis, higher calcium, lower PTH/ALP, absence of hypotonia/seizures).

Genetic anticipation: Not reported/applicable (no repeat-expansion mechanism).

Germline mosaicism: Not specifically documented in the reviewed literature for CYP27B1, though theoretically possible for any recessive Mendelian disorder; recurrence-risk counseling follows standard autosomal recessive principles (25% recurrence risk per pregnancy for carrier × carrier couples).

Founder effects: Well-documented — the Saguenay–Lac-Saint-Jean (SLSJ) region of Quebec, Canada exhibits a strong founder effect for the c.262delG (p.Val88Trpfs*71) variant, with a carrier frequency of 1 in 26–29 and a birth prevalence of ~1 in 2,358–2,916 (i.e., roughly one affected child born annually in the region) — dramatically higher than the general worldwide rate. Independent founder/common-ancestor patterns (e.g., shared intron-1 mutations among patients from a single city) have also been suggested in other populations, and a regional Chinese hotspot allele (c.1319_1325dupCCCACCC) has been reported in southern China.

Consanguinity: A significant contributor in outbred, non-founder populations — the high proportion of homozygous (as opposed to compound heterozygous) genotypes in several case series (41.7–58%) is consistent with parental consanguinity in many reported families, particularly from regions/cultures with higher consanguinity rates.

Carrier frequency: ~1 in 26–29 in the SLSJ founder population (markedly elevated); general-population carrier frequency is not well established given overall rarity but is presumably very low (<<1%) outside founder clusters.

Epidemiology (prevalence/incidence): - Overall exceedingly rare worldwide: ~219 patients reported in the cumulative literature (per one synthesis). - Denmark: prevalence among children <15 years estimated at 1/250,000. - SLSJ, Quebec: prevalence at birth estimated at 1 in 2,358 (regional founder-effect outlier). - No formal Global Burden of Disease (GBD) or large national-registry incidence estimate exists given the disease's rarity; most epidemiologic knowledge is derived from case-series aggregation and the SLSJ founder registry.

Population demographics: No strong sex predilection is reported (autosomal recessive; one cohort reported exactly 1:1 male:female ratio, 6/6). Ethnic/geographic clustering reflects founder populations (French-Canadian SLSJ; regional hotspots in southern China) and consanguineous communities (e.g., Middle Eastern, Central/South Asian populations, based on the geographic spread of case reports including Uzbekistan, Vietnam, and others cited in the literature search).

Sources: OMIM #264700 | Orphanet ORPHA289157 | PMC9120640 | PMC9671943 | Cruz Marino 2023, AJMG-A

10. Diagnostics

Core biochemical panel (LOINC-codeable): - Serum calcium (low) — LOINC 17861-6 - Serum phosphate (low) - Serum alkaline phosphatase (markedly elevated) - Serum intact PTH (markedly elevated) - 25-hydroxyvitamin D (normal or elevated — key discriminator from nutritional deficiency and VDDR1B) - 1,25-dihydroxyvitamin D (calcitriol) — low or inappropriately normal given the concurrent hypocalcemia/hyperparathyroidism that should otherwise drive it up; this is the single most discriminating biochemical test - Urinary calcium/creatinine ratio (for monitoring hypercalciuria risk during treatment)

Imaging: - Wrist and knee radiographs — widened epiphyses/metaphyses, metaphyseal cupping and fraying, generalized decreased bone density; graded via a Rickets Severity Score (RSS) - Renal ultrasound — baseline and monitoring for nephrocalcinosis (a treatment-related risk), performed at diagnosis and every 1–2 years thereafter (more frequently if hypercalciuria develops) - Skull imaging may show widened sutures, posterior flattening

Genetic testing: - Single-gene CYP27B1 sequencing (Sanger or targeted NGS) is the definitive diagnostic test given the disorder's clean genotype-phenotype relationship; a skeletal dysplasia/rickets gene panel (including CYP27B1, CYP2R1, VDR, PHEX, DMP1, FGF23, ENPP1, SLC34A3, etc.) is commonly used clinically to differentiate the vitamin D-dependent and hypophosphatemic rickets spectrum. Whole-exome sequencing is increasingly used, especially in atypical or apparently sporadic presentations. - Biochemical phenotype (low/inappropriately-normal 1,25(OH)₂D with normal/high 25(OH)D) strongly predicts CYP27B1 involvement prior to sequencing.

Newborn screening: A prospective newborn genetic screening program has been implemented in the SLSJ founder population (targeting the c.262delG founder allele), demonstrated to be safe, feasible, and efficient; pre-symptomatic identification allows calcitriol initiation before clinical manifestations develop, improving growth/skeletal outcomes (PMC9120640).

Differential diagnosis: | Condition | Distinguishing feature vs. VDDR1A | |---|---| | Nutritional vitamin D deficiency rickets | Low 25(OH)D (vs. normal/high in VDDR1A); responds to standard vitamin D supplementation | | VDDR1B (CYP2R1 deficiency, 25-hydroxylase) | Deficient 25(OH)D (upstream hydroxylation defect); may show gene-dosage/heterozygous partial phenotypes improving with age; can respond to calcifediol bypassing the block | | VDDR2A (VDR mutations, hereditary vitamin D-resistant rickets) | Markedly elevated 1,25(OH)₂D (end-organ resistance, not deficiency); alopecia in ~50% of cases (absent in VDDR1A); requires massive calcitriol doses or IV calcium; may show dramatic post-pubertal improvement in calcium absorption | | X-linked hypophosphatemic rickets (PHEX)/other FGF23-mediated hypophosphatemic rickets | Normal PTH and normal/low-normal calcium (vs. VDDR1A's elevated PTH and low calcium); phosphopenic rather than calciopenic mechanism | | Hypoparathyroidism/pseudohypoparathyroidism | Low or inappropriately normal PTH (hypoPTH) or PTH resistance with characteristic Albright hereditary osteodystrophy features (pseudoHP) — VDDR1A shows appropriately elevated PTH; misdiagnosis as normocalcemic primary hyperparathyroidism or pseudohypoparathyroidism has been reported due to overlapping biochemistry in atypical presentations |

Diagnostic pitfalls documented in the literature: VDDR1A has been misdiagnosed as nutritional rickets, hypophosphatemic rickets, pseudohypoparathyroidism (including in the setting of concurrent active tuberculosis, where extrarenal CYP27B1 activity in granulomas confounds vitamin D metabolite interpretation), and normocalcemic primary hyperparathyroidism — underscoring the value of genetic confirmation.

Sources: PMC11439522 | JCEM Case Reports, PMID misdiagnosis paper | PMC9120640 | Frontiers diagnosis/management review

11. Outcome/Prognosis

Survival/mortality: With timely diagnosis and appropriate calcitriol replacement, VDDR1A is not a life-shortening condition; mortality risk is essentially confined to acute, severe, untreated hypocalcemia (tetany/seizures/cardiac effects) in infancy, which is preventable with treatment. No formal survival/life-expectancy statistics were identified, consistent with the expectation of near-normal life expectancy on treatment.

Morbidity/functional outcomes: - Biochemical normalization is generally achieved within ~3 months of appropriate calcitriol/calcium therapy. - Radiographic (rachitic) improvement follows, with RSS improving significantly with good adherence (e.g., from 8.6 ± 1.0 to 3.7 ± 3.4 in one cohort, p<0.05). - Growth/height outcome is the most treatment-resistant domain: initial catch-up growth occurs in ~91% of patients in the first few years, but sustained catch-up to normal height was maintained in only ~27% at last follow-up in one long-term cohort; persistent short stature (HtSDS < −2) affected 63.6% at last visit. Biochemical normalization does not guarantee height recovery. - Renal outcomes: No nephrocalcinosis was observed in a 12-patient cohort with appropriate calcitriol dosing over a mean 6.2-year follow-up (one patient had enhanced kidney echogenicity only), suggesting that with careful monitoring the treatment-related hypercalciuria/nephrocalcinosis risk (a concern for all calcitriol-treated rachitic disorders) can be managed effectively.

Complications: Severe/relapsed disease (from treatment discontinuation) can require orthopedic surgical intervention (e.g., for severe scoliosis); dental enamel hypoplasia is a persistent complication even with adequate systemic treatment; secondary/occasionally severe hyperparathyroidism can develop with chronic undertreatment, raising a theoretical (though apparently uncommon) concern for progression toward parathyroid autonomy.

Prognostic factors: The dominant modifiable prognostic factor is age at diagnosis/treatment initiation (earlier = better height outcome) and long-term treatment adherence (the primary determinant of sustained skeletal/growth benefit — cited reasons for poor adherence include economic constraints, social problems, inadequate medical education, and adolescent psychosocial issues). Genotype (null vs. hypomorphic allele, e.g., p.(Ala129Thr)) is a non-modifiable prognostic factor correlating with baseline severity and, indirectly, with the degree of catch-up needed.

Sources: PMC9671943 | JCEM PMID:36321535

12. Treatment

Pharmacotherapy — mainstay of treatment: - Calcitriol (1,25-dihydroxyvitamin D₃) is the first-line, definitive replacement therapy, since it bypasses the defective 1α-hydroxylation step entirely. - Initial/loading dose: commonly 1–2 μg/day (some protocols 1–1.5 μg twice daily); pediatric cohort dosing reported as low as 0.25–0.5 μg/day depending on severity and body size, titrated to response. - Maintenance dose: typically 0.25–1 μg/day (ranges cited 0.3–2 μg/day), given in divided (twice-daily) doses owing to calcitriol's short biological half-life. - Calcium supplementation is co-administered, especially during the initial "hungry bone" remineralization phase (guidance cited: ~50 mg/kg/day elemental calcium in children; cohort doses of 500–1000 mg/day). - Alternative agents: 1α-hydroxyvitamin D (alfacalcidol/1α-OH-D₃) — a prodrug requiring only hepatic 25-hydroxylation (which is intact in VDDR1A) to become active — offers a longer half-life allowing once-daily dosing and is widely used, particularly in European cohorts (e.g., the 19-family JCEM genotype-phenotype cohort was treated with alfacalcidol). Eldecalcitol has shown superior osteogenic promotion versus alfacalcidol in the Cyp27b1-knockout mouse model (preclinical, not yet standard human therapy). - Therapeutic agent ontology: calcitriol (CHEBI:17823), alfacalcidol (CHEBI equivalent), calcium carbonate/citrate (elemental calcium supplementation). - NCIT treatment term suggestions: NCIT:C15986 (Pharmacotherapy) as the generic action, with therapeutic_agent bound to calcitriol/alfacalcidol.

Treatment goals: Achieve normocalcemia, maintain PTH within normal limits, avoid hypercalciuria/nephrocalcinosis, and normalize radiographic/growth parameters.

Monitoring protocol: Serum calcium, phosphorus, PTH, alkaline phosphatase, creatinine, and vitamin D metabolites every 3–6 months; 24-hour urinary calcium or spot calcium:creatinine ratio; renal ultrasound every 1–2 years (more frequently if hypercalciuria present); annual wrist/knee radiographs during active growth.

Duration: Lifelong — "treatment must be continued indefinitely"; discontinuation reliably leads to biochemical and skeletal relapse (documented case of a 6-year treatment lapse producing severe deformity requiring surgery).

Surgical/interventional care: Orthopedic surgical correction may be required for severe, established skeletal deformities (e.g., scoliosis) in patients with delayed diagnosis or prolonged non-adherence.

Supportive/rehabilitative care: Nutritional counseling to support adequate dietary calcium/vitamin D intake; physical therapy may be used adjunctively for motor delay/deformity-related functional limitation (NCIT:C15302, Physical Therapy), though this is not emphasized as a primary modality in the literature reviewed.

Genetic counseling: Recommended for families given autosomal recessive inheritance and (in founder populations) availability of targeted carrier/newborn screening; NCIT:C15240 (Genetic Counseling).

Experimental/investigational therapies: No gene therapy, RNA-based therapy, or novel targeted biologic specific to VDDR1A was identified in this search — enzyme-replacement is achieved pragmatically via direct hormone (calcitriol) replacement rather than protein or gene-based correction, which is feasible precisely because the deficient product (calcitriol) itself is an inexpensive, orally bioavailable small molecule.

Treatment response/outcomes: Excellent biochemical and radiographic response rates with adherent therapy; the principal "failure mode" is non-adherence rather than pharmacologic non-response — reinforcing that VDDR1A is, mechanistically, a highly treatable condition once diagnosed.

Sources: PMC9671943 | Frontiers diagnosis/management review | JCEM PMID:36321535 | Calcitriol treatment, ScienceDirect | Eldecalcitol vs alfacalcidol mouse study, PMC6169848

13. Prevention

Primary prevention: Not applicable in the classic sense (this is a genetic, not an acquired/exposure-based disease), but pre-symptomatic treatment initiation via newborn/carrier screening in founder populations effectively prevents the clinical manifestations of the disease from ever developing — the SLSJ program demonstrates that daily calcitriol initiated before symptom onset can prevent the phenotype entirely.

Secondary prevention/screening: - Targeted newborn genetic screening for the founder c.262delG variant in the SLSJ Quebec population — shown safe, feasible, and effective at enabling pre-symptomatic treatment. - Carrier screening / cascade family testing is recommended in founder populations and in families with an index case, given the high carrier frequency locally (1/26–29 in SLSJ) and the straightforward single-gene test. - General population newborn screening for VDDR1A is not standard practice outside founder/high-prevalence populations, given the disease's overall rarity.

Tertiary prevention: Once diagnosed, ongoing monitoring (per Section 12) prevents complications (nephrocalcinosis, severe deformity, growth failure) and enables early detection/correction of relapse from non-adherence.

Genetic counseling: Central to prevention strategy in affected families and in founder communities — informing reproductive risk (25% recurrence for carrier couples) and enabling prenatal or preimplantation genetic testing where desired.

Public health interventions: No population-wide public health intervention (e.g., water fortification, mass supplementation) is applicable, since VDDR1A is refractory to standard vitamin D supplementation (the defect is downstream of 25(OH)D availability) — this is an important practical distinction from nutritional rickets prevention programs.

Prophylaxis: N/A beyond the therapeutic calcitriol regimen itself, which functions simultaneously as treatment and (when started pre-symptomatically) as prevention of phenotypic expression.

Sources: PMC9120640

14. Other Species / Natural Disease

Naturally occurring VDDR1A in companion animals — a well-characterized comparative model: - Dogs (Canis lupus familiaris, NCBI Taxon:9615): Naturally occurring CYP27B1-mutation vitamin D-dependent rickets type IA has been documented in pugs and Saint Bernards, catalogued in OMIA:000837-9615 (OMIA). A 2023 study identified a stop-gain mutation (chr10:2182971G>T) in CYP27B1 in affected pugs, causing premature truncation at codon 87 (loss of ~83% of the protein), producing a clinical phenotype "indistinguishable" from nutritional vitamin D deficiency and life-threatening if untreated in young pugs (J Vet Intern Med 2023, PMID:37293695; PMC10365047). - Breed relevance (VBO): Pug and Saint Bernard breeds are specifically documented; this represents genuine veterinary clinical importance (a naturally arising, breed-associated inherited disease) rather than only a laboratory-induced model.

Comparative biology: The canine phenotype recapitulates the core human biochemical and skeletal signature (hypocalcemia, secondary hyperparathyroidism, rachitic bone disease), supporting deep evolutionary conservation of the CYP27B1-vitamin D endocrine axis across mammals. No zoonotic or transmission relevance applies — this is a purely genetic, non-communicable disease in both species.

No non-mammalian natural disease models identified in this search (the vitamin D endocrine/calcitriol-VDR axis is a vertebrate, largely mammalian/avian physiological system, but naturally occurring CYP27B1-deficiency disease was not found reported outside canines in the literature surveyed).

Sources: OMIA:000837-9615 | J Vet Intern Med, PMID:37293695 | PMC10365047

15. Model Organisms

Mouse (Mus musculus) — Cyp27b1 knockout: - Model type: Targeted gene-knockout (constitutive), the principal genetic animal model of VDDR1A/pseudo-vitamin-D-deficiency rickets. - Phenotype recapitulation: Cyp27b1-knockout mice develop hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and short, deformed bones with dysmorphic growth plates — closely mirroring the human biochemical and skeletal phenotype. After weaning, mice show marked hypocalcemia and high PTH with decreased growth, osteodystrophy (bone hypocalcification), and growth-plate cartilage hypertrophy. - Rescue experiments: Treatment with exogenous 1,25-dihydroxyvitamin D₃ (calcitriol) rescues the pseudo-vitamin-D-deficiency-rickets phenotype in Cyp27b1-deficient mice — confirmed via biochemical, histomorphometric, and biomechanical analyses (PMID:12674324) — directly validating calcitriol replacement as mechanistically corrective, mirroring the human standard-of-care. - Comparative model characteristics: The mineral/skeletal phenotype of Cyp27b1-KO mice is more severe than that of Vdr-KO mice (VDDR2A model) and, notably, cannot be fully rescued by a "rescue diet" high in calcium, phosphate, and lactose — a diet strategy that does substantially normalize the Vdr-KO phenotype — highlighting a biologically meaningful difference between the ligand-deficiency (VDDR1A) and receptor-resistance (VDDR2A) mechanisms even though both converge on impaired VDR signaling output (Bone Research 2024). - Model limitations: As with all knockout models, developmental compensation and species-specific differences in mineral handling/diet (rodent vs. human) limit direct translational fidelity, particularly regarding the precise growth/height catch-up dynamics seen in human patients on treatment. - Applications: Studying calcitriol-VDR axis physiology, comparing therapeutic vitamin D analogs (e.g., eldecalcitol vs. alfacalcidol — eldecalcitol showed superior osteogenic promotion in Cyp27b1-KO mice, PMC6169848), and dissecting genetic vs. dietary rescue strategies.

Rat (Rattus norvegicus): Novel genetically modified rat models (including Vdr-KO rats) have been generated to further probe molecular mechanisms of vitamin D action; Vdr-KO rats notably show alopecia (as in human VDDR2A) — a feature that, by contrast, is absent in CYP27B1-deficient animals (and in human VDDR1A), reinforcing alopecia as a VDR-signaling/receptor-pathway-specific (not ligand-deficiency) feature (Sci Rep, PMC7105495).

Naturally occurring large-animal model: The pug/Saint Bernard dog model (Section 14) functions additionally as a valuable spontaneous (non-engineered) genetic model, complementing the engineered mouse knockout, particularly for large-animal/companion-animal translational and veterinary-clinical study.

Cellular/in vitro models: Recombinant CYP27B1 expression systems (e.g., in bacterial or mammalian expression systems) have been used extensively for structure-function mutagenesis studies (e.g., Arg458/Arg459 adrenodoxin-interaction mutants) to dissect enzyme kinetics and electron-transfer partner interactions at the molecular level, though these are biochemical rather than whole-cell disease models.

Model databases: MGI (Mouse Genome Informatics) for Cyp27b1 mouse alleles; OMIA for the canine model; no zebrafish, Drosophila, C. elegans, or yeast VDDR1A-specific model was identified (unsurprising, given the mammalian-specific renal-endocrine vitamin D axis).

Sources: Bone Research 2024, Nature | PMID:12674324 (rescue study) | PMC6169848 (eldecalcitol study) | PMC7105495 (rat models) | OMIA:000837-9615

Summary Ontology Term Suggestions

Category Suggested terms
MONDO/Disease ORPHA:289157; consider MONDO term for VDDR1A specifically (verify exact MONDO CURIE via OAK before curating)
HGNC gene hgnc:2606 (CYP27B1)
HP phenotypes HP:0002748 (Rickets, if using generic term) or defer to defective_skeletal_mineralization module conformance; HP:0002014-adjacent hypocalcemia terms; HP:0004322 (Short stature); HP:0001324 (Muscle weakness); HP:0001252 (Hypotonia); HP:0002757 (Recurrent fractures); HP:0000921 (Rachitic rosary); HP:0011330 (Frontal bossing); HP:0006297 (Dental enamel hypoplasia); HP:0002650 (Scoliosis); HP:0000768 (Pectus carinatum)
GO biological process GO:0036378 (calcitriol biosynthetic process); GO:0042359 (vitamin D metabolic process); GO:0006874 (cellular calcium ion homeostasis)
GO cellular component GO:0005739 (mitochondrion)
CL cell types CL:0002306 (kidney proximal tubule cell — verify exact ID); CL:0000584 (enterocyte); CL:0000426 (parathyroid chief cell); CL:0000058 (chondrocyte); CL:0000062 (osteoblast)
UBERON UBERON:0002113 (kidney); UBERON:0001434 (skeletal system); UBERON:0001132 (parathyroid gland); UBERON:0000160 (intestine)
CHEBI Calcitriol; alfacalcidol; calcium (verify exact CHEBI CURIEs via OAK)
NCIT treatment NCIT:C15986 (Pharmacotherapy) + therapeutic_agent (calcitriol)
NCBITaxon (models) NCBITaxon:10090 (Mus musculus); NCBITaxon:9615 (Canis lupus familiaris)

(Per dismech convention, all suggested ontology terms should be independently verified via OAK — runoak -i sqlite:obo:<ontology> info <CURIE> -O obo — before use in curation, to guard against label mismatch or hallucination.)

Master Source List

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 21
On topic 14
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMC:PMC11439522 (abstract only): "mimicking pseudohypoparathyroidism in the presence of active tuberculosis,"
  • closest text in source: "This report describes a case of vitamin D-dependent rickets type 1A, mimicking pseudohypoparathyroidism owing to presence of concurrent illness like extrapulmonary tuberculosis."