Vitamin D-Dependent Rickets Type 2B

Metabolic Disorder MONDO:0010931 Pathograph 17 Show in embeddings browser Metabolic Bone Disorders

MONDO:0010931 is curated here as an unresolved umbrella. Two principal evidence strata modeled in this entry have not been genetically or epidemiologically connected. One is a 1995 rural-Cauca cluster of more than 200 children with lower-limb deformities, receptor-positive vitamin D resistance, normal VDR cDNA sequence, and no alopecia. The other is a single alopecic child first reported in 1993: the child's endogenous VDR bound calcitriol but failed to localize normally to the nucleus, whereas the normal VDR coding sequence functioned after transfer to a heterologous cell context. Follow-up studies of cells from that index case identified overexpressed HNRNPC C1/C2 competing with VDR-RXR at vitamin D response elements and broadly suppressing vitamin-D-responsive transcription. HNRNPC is therefore represented only as a molecular actor in the index-case mechanism, not as a disease-causal gene. No causal germline lesion, inheritance pattern, or shared molecular basis for the two strata is established. The historical label "HVDRR type III" used for the index case predates and is not equivalent to modern CYP3A4-related vitamin D-dependent rickets type 3.

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6
Pathophys.
5
Phenotypes
2
Gaps
17
Pathograph
1
Medical Actions
2
Differentials
1
Datasets
6
Models
13
References
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Discussions and Knowledge Gaps

2
Do the Cauca cluster, the alopecic HNRNPC/VDRE index case, and other historical receptor-positive postreceptor cases represent one disease entity or several mechanistically distinct forms of vitamin D resistance?
CONTROVERSY OPEN controversy_vddr2b_entity_boundary
Attached to
pathophysiology#Cauca-Cohort Receptor-Positive Vitamin D Resistance pathophysiology#Index-Case Endogenous VDR Nuclear-Localization Failure pathophysiology#Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
The evidence strata are not connected by pedigree, genotype, or a shared molecular assay. The 1983 postreceptor case had normal cytosolic and nuclear ligand binding but impaired 24-hydroxylase induction. The 1993 alopecic index case instead lacked normal endogenous VDR nuclear localization, and only its later cell lineage was tied to HNRNPC C1/C2 competition. The Cauca cohort had no alopecia, low-normal calcium, normal phosphate, and no HNRNPC study. MONDO currently combines a postreceptor/HNRNPC description, no-alopecia synonyms, and "Sporadic" metadata that do not jointly fit the primary strata; those ontology assertions are treated as an unresolved source mismatch, not as proof of one entity or a demonstrated inheritance mode. Modern classification has not resolved the mismatch: the 2023 skeletal-disorder nosology table labels the entity HNRNPC-related and "AD?" while qualifying the proposed HNRNPC dominant-negative basis as coming from a single patient, and the 2024 review recounts the index case and Cauca cluster separately, calls VDDR2B less well defined, and notes that the cluster phosphorus pattern lacks replication. These later summaries are treated as classification context, not as new causal-gene or inheritance evidence.
Proposed experiments
Prospective resolution of receptor-positive vitamin D-resistance strata
exp_vddr2b_stratum_resolution
Ascertain VDR-coding-negative patients prospectively and record alopecia, mineral biochemistry, endogenous VDR localization, calcitriol-responsive transcription, HNRNPC abundance, and VDRE occupancy under a common protocol, followed by genome and transcriptome sequencing.
Decision criterion
Recurrent shared molecular and genetic findings across phenotypic strata would support lumping; reproducible stratum-specific mechanisms would support splitting the umbrella concept.
Show evidence (6 references)
PMID:6313754 SUPPORT Human Clinical
"This patient, therefore, appeared to have a receptor-positive form of resistance to 1,25-(OH)2D3."
Establishes a historical receptor-positive case that predates the later alopecic HNRNPC index lineage.
PMID:6313754 SUPPORT In Vitro
"We conclude that impaired induction of 24-hydroxylase in the presence of normal receptor binding is evidence for postreceptor resistance to the action of 1,25-(OH)2D3."
Defines that case's distinct measured postreceptor phenotype without assigning the HNRNPC mechanism.
PMID:8287584 SUPPORT In Vitro
"VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear localization resulting in an absence of functional response to 1,25(OH)2D3."
Shows the contrasting localization phenotype in the alopecic index lineage.
+ 3 more references
What caused HNRNPC C1/C2 overexpression in the single index case, and how is VDRE competition related to the earlier endogenous VDR localization failure?
KNOWLEDGE GAP OPEN knowledge_gap_vddr2b_hnrnpc_cause
Attached to
pathophysiology#Index-Case Endogenous VDR Nuclear-Localization Failure pathophysiology#Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
Reciprocal overexpression and siRNA experiments support HNRNPC C1/C2 as a transcriptional actor, but no causal germline lesion or upstream regulatory event was identified. The earlier localization result and the later occupancy result were not placed in one experimentally tested causal sequence. Germline HNRNPC haploinsufficiency has since been associated with a distinct neurodevelopmental disorder, not with this rachitic phenotype, so it cannot be imported as evidence for VDDR2B inheritance.
Proposed experiments
Causal analysis of HNRNPC regulation in the index lineage
exp_vddr2b_genome_sequencing_hnrnpc_regulation
Perform genome, transcriptome, copy-number, chromatin, and allele-specific expression analysis on archived index-lineage material; perturb candidate regulatory events and normalize HNRNPC expression to test rescue of VDRE occupancy, VDR localization, and calcitriol-responsive transcription.
Show evidence (3 references)
PMID:17071612 SUPPORT In Vitro
"When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1 and hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%, respectively; both p < 0.005)."
Supports the actor-level mechanism without establishing its upstream cause.
PMID:32596195 SUPPORT Other
"No gene has yet been identified as the cause of VDDR2b so it is impossible to state with precision the number of affected subjects."
Explicitly documents the absent causal-gene assignment.
PMID:37541189 SUPPORT Human Clinical
"Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants."
Demonstrates that established germline HNRNPC disease has a distinct neurodevelopmental phenotype and does not validate HNRNPC inheritance for this rickets umbrella.
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Pathophysiology

6
Cauca-Cohort Receptor-Positive Vitamin D Resistance
The 1995 Cauca study described more than 200 children with lower-limb deformities, elevated calcitriol, normal 25-hydroxyvitamin D, and a normal VDR cDNA sequence. The authors called this a distinct receptor-positive form of vitamin D resistance. HNRNPC abundance, VDRE occupancy, and the index-case cellular mechanism were not studied in this cohort, so its proximal molecular block remains unknown.
Downstream
Defective Skeletal Mineralization The cluster's biochemical resistance was associated with lower-limb deformities, but calcium remained within the low-normal range and phosphate was normal. The causal mineral intermediates were not resolved.
Show evidence (2 references)
PMID:7586652 SUPPORT Human Clinical
"More than 200 patients with different types of lower limb deformities were detected in a rural area of the Cauca department in the southwest part of Colombia."
Defines the size, geography, and skeletal presentation of the cluster stratum without linking it to the later index case.
PMID:7586652 SUPPORT Human Clinical
"The cDNA analysis showed normal nucleotide sequence. We suggest that our patients represent a distinct form of receptor-positive resistance to vitamin D."
Supports receptor-positive resistance and a normal VDR coding sequence, but does not identify the molecular cause.
Index-Case Endogenous VDR Nuclear-Localization Failure
In cells from the single alopecic child, endogenous VDR bound calcitriol but failed to show normal nuclear localization or a functional response. The VDR coding sequence was normal, and transfer of the patient's VDR cDNA into a different cellular context restored normal transactivation. This establishes a cell-contextual receptor-handling phenotype, not a causal VDR variant.
Experimental models
Index-case skin fibroblast culture PRIMARY CELL CULTURE Patient-derived cells directly reproduce ligand binding with absent normal nuclear localization in the index case's own cellular context.
Downstream
Index-Case Loss of Vitamin D-Responsive Transcription Failure of endogenous ligand-bound VDR to localize normally was accompanied by absent calcitriol-responsive 24-hydroxylase activity in the same cells.
Show evidence (2 references)
PMID:8287584 SUPPORT In Vitro
"VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear localization resulting in an absence of functional response to 1,25(OH)2D3."
Directly records the abnormal endogenous localization and functional response observed in patient cells.
PMID:8287584 SUPPORT In Vitro
"Sequencing revealed that the VDR coding region was normal. Expression studies of the patient's VDR showed functionally normal VDR as evidenced by normal transactivation in the presence of 1,25(OH)2D3."
Separates the patient-cell phenotype from an intrinsic coding or functional defect of the VDR molecule.
Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
Follow-up work on the index-case cells first detected an overexpressed response-element-binding protein and provisionally assigned it to the hnRNPA family. The protein was subsequently purified and cloned as HNRNPC C1/C2. Overexpressed HNRNPC competed with VDR-RXR for VDRE occupancy, disrupted the normal reciprocal occupancy cycle, and suppressed vitamin-D-directed transcription. HNRNPC is annotated here as the experimentally implicated actor; these studies did not identify a germline HNRNPC lesion.
HNRNPC hgnc:5035 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HNRNPC (hgnc:5035). hgnc:5035 is a gene from the HUGO Gene Nomenclature Committee.
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
Vitamin D response-element binding by HNRNPC C1/C2 GO:0000976 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased Vitamin D response-element binding by HNRNPC C1/C2, annotated with transcription cis-regulatory region binding (GO:0000976). GO:0000976 is a molecular function from the Gene Ontology. ↑ INCREASED
Experimental models
Index-case EBV-transformed B-cell line CELL LINE The patient line carries the elevated VDRE-binding-protein state used to characterize competitive occupancy.
HKC-8 HNRNPC C1/C2 overexpression system CELL LINE Isoform overexpression suppresses VDR-VDRE transactivation, testing sufficiency of increased HNRNPC activity in this engineered context.
ROS 17/2.8 HNRNPC C1/C2 siRNA system CELL LINE Knockdown relieves endogenous repression of VDR transactivation in a responsive rat cell line.
MG63 osteoblast-like HNRNPC perturbation model CELL LINE Isoform overexpression and knockdown separately probe HNRNPC control of vitamin D-directed transcription and RNA processing in a human bone-lineage context.
Downstream
Index-Case Loss of Vitamin D-Responsive Transcription Competitive VDRE occupancy limits VDR-RXR access and suppresses target-gene transactivation in index-case and engineered cell systems.
Show evidence (3 references)
PMID:12716975 SUPPORT In Vitro
"Ab blocking in electrophoretic mobility-shift assays indicated that this dominant-negative acting protein was in the hnRNPA family of nucleic acid-binding proteins."
Preserves the 2003 intermediate assignment; PARTIAL marks that the study had not yet identified the later HNRNPC C1/C2 molecular species.
PMID:17071612 SUPPORT In Vitro
"Here we describe the purification, molecular cloning, and expression of this vitamin D resistance-causing, competitive response element-binding protein (REBiP) hnRNP C1/C2."
Supplies the later molecular identification that superseded the preliminary hnRNPA-family assignment.
PMID:17071612 SUPPORT In Vitro
"When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1 and hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%, respectively; both p < 0.005)."
Reconstitutes transcriptional suppression by HNRNPC C1 or C2 overexpression.
Index-Case Loss of Vitamin D-Responsive Transcription
Patient-derived cells were broadly insensitive to calcitriol-responsive gene regulation. The later transcriptomic study found that 113 of 114 genes regulated by calcitriol in control cells became insensitive in the VDRE-binding-protein-overexpressing patient cells.
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
Experimental models
Index-case skin fibroblast culture PRIMARY CELL CULTURE Calcitriol-responsive 24-hydroxylase activity and cotransfection in patient cells provide functional readouts of the suppressive patient-cell context.
Heterologous CV-1 transfer of index-case VDR cDNA CELL LINE Normal reporter transactivation after transfer fails to reproduce the transcriptional loss and demonstrates intrinsic function of the patient's VDR coding product outside the suppressive patient context.
Index-case EBV-transformed B-cell line CELL LINE The microarray measures the breadth of calcitriol-responsive transcription lost in the patient line relative to control.
Downstream
Index-Case Hypocalcemic Mineral Disturbance The cellular transcriptional resistance is consistent with the index child's hypocalcemic rickets, but intestinal calcium transport and the intervening organism-level steps were not directly measured in these mechanistic studies.
Show evidence (1 reference)
PMID:21123297 SUPPORT In Vitro
"DNA array analysis showed that of 114 genes regulated by 1,25(OH)(2)D(3) in control cells, almost all (113) were rendered insensitive to the hormone in VDRE-BP-overexpressing HVDRR cells."
Quantifies the breadth of the transcriptional resistance in the index-case cell system.
Index-Case Hypocalcemic Mineral Disturbance
The index child had albumin-corrected calcium of 2.03 mmol/L against a stated reference interval of 2.25-2.55 mmol/L, elevated alkaline phosphatase, and elevated calcitriol. This stratum-specific node does not absorb the Cauca cohort, whose calcium was low-normal and whose phosphate was normal, and it avoids asserting directly measured intestinal malabsorption.
Downstream
Hypocalcemia The measured low serum calcium is the defining clinical phenotype of this stratum-specific mineral disturbance.
Defective Skeletal Mineralization Reduced calcium availability can impair skeletal mineralization. The exact intermediate physiology, including the growth-plate route, was not fully measured in the index-case mechanistic studies.
Defective Skeletal Mineralization
Failure of growth-plate and bone mineralization manifests as rickets in the index child and as diverse lower-limb deformities in the Cauca cluster. This is the only asserted convergence of the two evidence strata.
Osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
Bone Mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Bone Mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↓ DECREASED
Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bone, annotated with bone element (UBERON:0001474). UBERON:0001474 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Rickets Impaired growth-plate mineralization manifests as rickets in the alopecic index child.
Abnormality of the lower limb Defective skeletal mineralization is associated with the diverse lower-limb deformities used to ascertain the Cauca cluster, but the abstract does not resolve the intervening skeletal morphology.
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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 2B 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

5
Integument 1
Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Alopecia is deliberately left without a pathophysiology edge because no study tested a causal link between hair loss and the index-case localization or HNRNPC/VDRE mechanisms.
Show evidence (2 references)
PMID:8287584 SUPPORT Human Clinical
"A child with alopecia diagnosed as having rickets due to resistance to 1,25(OH)2D3."
Directly records alopecia in the index case.
PMID:7586652 SUPPORT Human Clinical
"None of them presented alopecia, myopathy, seizures or aminoaciduria."
Directly records absence of alopecia in the Cauca cohort; this is a stratum-specific negative observation, not a global frequency estimate.
Metabolism 1
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.
The full text of PMID:12716975 (PMCID:PMC156334) reports albumin-corrected calcium of 2.03 mmol/L against a stated 2.25-2.55 mmol/L reference interval. The sanctioned PMID cache is abstract-only, so no unverifiable snippet is attached here. Other historical receptor-positive/postreceptor HVDRR reports are not assumed to belong to this index-case lineage.
Musculoskeletal 1
Rickets HP:0002748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:8287584 SUPPORT Human Clinical
"A child with alopecia diagnosed as having rickets due to resistance to 1,25(OH)2D3."
Directly documents rickets in the index child.
PMID:7586652 SUPPORT Human Clinical
"More than 200 patients with different types of lower limb deformities were detected in a rural area of the Cauca department in the southwest part of Colombia."
Records the cluster's skeletal presentation; PARTIAL avoids treating the broad deformity phrase as standardized case-level rickets ascertainment.
Other 2
Abnormality of the lower limb HP:0002814 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the lower limb (HP:0002814). HP:0002814 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:7586652 SUPPORT Human Clinical
"More than 200 patients with different types of lower limb deformities were detected in a rural area of the Cauca department in the southwest part of Colombia."
Directly supports a broad lower-limb abnormality in the cluster stratum.
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.
The index-case value is in the full text of PMID:12716975; its sanctioned cache is abstract-only, so the exact value is not presented as a verified snippet.
Show evidence (1 reference)
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."
Directly reports high alkaline phosphatase in the cluster.
💊

Medical Actions

1
Index-Case High-Dose Calcitriol Plus Calcium
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. calcium(2+) CHEBI:29108 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcium(2+) (CHEBI:29108). CHEBI:29108 is a therapeutic agent from Chemical Entities of Biological Interest.
In the single alopecic index child, a regimen of calcitriol at 12 micrograms per day plus calcium at 1 gram per day was reported to correct rachitic bone disease, while alopecia persisted. This is an observed n=1 combined regimen, not evidence that either component was sufficient alone and not a general dosing recommendation for the unresolved umbrella entity.
Mechanism Target:
RESTORES Defective Skeletal Mineralization — The rachitic bone disease was reported corrected during the combined regimen. RESTORES describes that observed skeletal outcome and does not isolate the contribution of high-dose calcitriol from calcium or imply a treatment response in the Cauca stratum.
Target Phenotypes: Rickets HP:0002748 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology.
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Biochemical Markers

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1,25-dihydroxyvitamin D (calcitriol) (Elevated)
Context: Elevated calcitriol was measured in both principal strata. The Cauca cohort source interpreted it as evidence of target-organ resistance; index-case full text reports 466-650 pmol/L against a stated 48-156 pmol/L interval. No pooled cross-stratum distribution is assigned.
Show evidence (1 reference)
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."
Directly reports high circulating calcitriol in the cluster.
25-hydroxyvitamin D (calcidiol) (Normal)
Context: Normal 25-hydroxyvitamin D3 was reported in the Cauca cohort alongside high calcitriol. This finding is stratum-specific; no global distribution is assigned.
Show evidence (1 reference)
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."
Directly reports normal 25-hydroxyvitamin D3 in the cluster.
Serum calcium (Stratum-specific abnormality)
Context: The index child was hypocalcemic at 2.03 mmol/L (stated interval 2.25-2.55 mmol/L). In the Cauca cohort, calcium was significantly below related controls but remained within the low-normal range. These distinct observations are not collapsed into a single global severity or frequency.
Show evidence (1 reference)
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."
Directly supports the cluster-specific low-normal calcium observation.
Serum phosphate (Normal in the Cauca cohort)
Context: Serum phosphate was normal in the Cauca cohort. The primary abstract does not establish a corresponding index-case value, so this is not generalized.
Show evidence (1 reference)
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."
Directly reports normal serum phosphorus in the cluster.
🔬

Diagnosis

3
Clinical and biochemical assessment of receptor-positive vitamin D resistance
Rickets or lower-limb deformity together with relatively low calcium, high alkaline phosphatase, normal 25-hydroxyvitamin D, and elevated calcitriol can support suspicion of target-organ vitamin D resistance. The documented pattern comes from the Cauca cohort and does not by itself establish that an individual has the index-case HNRNPC mechanism.
Clinical Evaluation NCIT:C124351 NCI Thesaurus (NCIT)
Results: A vitamin-D-resistant rachitic biochemical pattern supports further evaluation but is not specific for VDDR2B or either evidence stratum.
Show evidence (1 reference)
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."
Defines the directly observed cluster biochemical pattern.
VDR coding-sequence analysis as an exclusionary test
Demonstrating a normal VDR coding sequence helps distinguish these reports from VDR-related vitamin D-dependent rickets type 2A. A negative VDR result does not confirm VDDR2B, identify HNRNPC dysregulation, or prove that the two evidence strata share a disorder.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A normal VDR coding sequence is exclusionary for a coding lesion in VDR; it is not a positive molecular test for VDDR2B.
Show evidence (2 references)
PMID:8287584 SUPPORT Human Clinical
"Sequencing revealed that the VDR coding region was normal. Expression studies of the patient's VDR showed functionally normal VDR as evidenced by normal transactivation in the presence of 1,25(OH)2D3."
Directly supports normal VDR coding and transferred function in the index case.
PMID:7586652 SUPPORT Human Clinical
"The cDNA analysis showed normal nucleotide sequence."
Directly supports a normal VDR cDNA sequence in the Cauca cohort.
HNRNPC-VDRE functional assays (research only)
VDRE mobility-shift, chromatin-occupancy, transactivation, HNRNPC overexpression, and siRNA assays characterized the index-case mechanism. These are research assays with no validated clinical threshold or evidence of diagnostic sensitivity or specificity.
Results: Excess HNRNPC C1/C2 occupancy with impaired VDR transactivation can reproduce the index-case cellular phenotype but is not a validated confirmatory test.
Show evidence (1 reference)
PMID:17071612 SUPPORT In Vitro
"By contrast, transient expression of an hnRNP C1/C2 small interfering RNA increased VDR transactivation by 39% (p < 0.005)."
Documents one of the reciprocal functional perturbations; it supports mechanism research, not clinical validation.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Vitamin D-Dependent Rickets Type 2B:

Vitamin D-Dependent Rickets Type 2A MONDO:0010186
Overlapping Features Type 2A can share rickets, elevated calcitriol, hypocalcemia, and alopecia, but it is caused by biallelic loss-of-function variants in VDR.
Distinguishing Features
  • A pathogenic biallelic VDR genotype supports type 2A rather than this receptor-positive umbrella.
  • A normal VDR coding sequence only excludes a coding lesion; it does not confirm type 2B.
Show evidence (1 reference)
PMID:32596195 SUPPORT Other
"VDDR2a (OMIM 277440) is due to biallelic loss-of-function mutations in the gene encoding the vitamin D receptor (VDR; 601769) on chromosome 12q13.11, and therefore represents a bona fide form of tissue resistance to vitamin D."
Establishes the causal VDR genotype that distinguishes type 2A.
Vitamin D-Dependent Rickets Type 3 MONDO:0033640
Overlapping Features Modern VDDR3 is a distinct, dominantly acting CYP3A4 p.Ile301Thr gain-of-function disorder with accelerated inactivation and low 25-hydroxyvitamin D and calcitriol. Conventional dosing can be inadequate, although the original subjects maintained normal mineral biochemistry with sufficiently high calcitriol or vitamin D dosing. It must not be inferred from the historical phrase "HVDRR type III" used for the receptor-positive index case before modern VDDR3 was defined.
Distinguishing Features
  • Modern VDDR3 has a heterozygous CYP3A4 p.Ile301Thr gain-of-function variant; de novo occurrence in the original subjects is not asserted as universal.
  • Both major circulating vitamin D metabolites are reduced rather than the elevated calcitriol reported in the Cauca receptor-positive cluster.
Show evidence (2 references)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Defines the modern type 3 clinical and biochemical pattern.
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)."
Establishes the molecular identity of modern VDDR3 and scopes de novo occurrence to the two original subjects rather than the whole disorder.
📊

Related Datasets

1
Analysis of vitamin D response element binding protein target genes reveals a role for vitamin D in osteoblast mTOR signaling geo:GSE22523
Human expression microarray comparing EBV-transformed B-cell lines from the single VDDR2B index patient and a matched control, each with vehicle or 1,25-dihydroxyvitamin D exposure in biological duplicate. The resource tests the index-case cellular transcriptional response; it is not a cohort of the Cauca cluster.
human MICROARRAY n=8 GPL6244
EBV-transformed B-cell line CL:0000236 Cell Ontology (CL) Relation: this dataset samples this sample type This dataset samples EBV-transformed B-cell line, annotated with B cell (CL:0000236). CL:0000236 is a sample type from the Cell Ontology.
Conditions: Index-patient EBV B cells with vehicle Index-patient EBV B cells with 1,25-dihydroxyvitamin D Matched-control EBV B cells with vehicle Matched-control EBV B cells with 1,25-dihydroxyvitamin D
PMID:21123297
Official NCBI GEO metadata verified on 2026-08-20: eight human samples, platform GPL6244, two biological replicates per four condition groups, and PMID:21123297. GSE63086 is deliberately omitted because it is an MG63 mechanistic perturbation dataset rather than a patient VDDR2B resource.
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Experimental Models

6
Index-case skin fibroblast culture PRIMARY_CELL_CULTURE
Skin fibroblast cultures from the alopecic index child and controls were used to measure calcitriol binding, endogenous VDR nuclear association, 24-hydroxylase response, VDR coding sequence, and suppression of wild-type VDR transactivation in the patient-cell context.
Alopecic index-case fibroblasts Control fibroblasts 1,25-dihydroxyvitamin D3 exposure
skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses skin fibroblast (CL:0002620). CL:0002620 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
Skin fibroblasts from the single index child and controls
Culture
Patient and control fibroblast monolayers
Publication
PMID:8287584
Pathograph links
Index-Case Endogenous VDR Nuclear-Localization Failure recapitulates fidelity: high Patient-derived cells directly reproduce ligand binding with absent normal nuclear localization in the index case's own cellular context.
Limitations: This is a culture from one patient and is not the intestinal target tissue; it cannot establish that the finding is shared by the Cauca cohort or other receptor-positive cases.
Show evidence (1 reference)
PMID:8287584 SUPPORT In Vitro
"VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear localization resulting in an absence of functional response to 1,25(OH)2D3."
Directly supports the localization phenotype in the patient-derived culture.
Index-Case Loss of Vitamin D-Responsive Transcription measures fidelity: high Calcitriol-responsive 24-hydroxylase activity and cotransfection in patient cells provide functional readouts of the suppressive patient-cell context.
Limitations: The assays measure selected vitamin D responses in fibroblasts and do not reproduce whole-body mineral physiology.
Show evidence (1 reference)
PMID:12716975 SUPPORT In Vitro
"Initial cotransfection studies showed that the cells of the patient suppressed basal and hormone-induced transactivation by wild-type VDR."
Directly supports a suppressive transcriptional phenotype in patient cells without conflating it with heterologous CV-1 transfer.
Show evidence (1 reference)
PMID:8287584 SUPPORT In Vitro
"Patient and control cell lines prepared from skin fibroblasts and peripheral blood lymphocytes were used to measure binding of 1,25(OH)2D3 and to isolate vitamin D receptor mRNA."
Defines the patient-derived and control cellular systems.
Heterologous CV-1 transfer of index-case VDR cDNA CELL_LINE
The index patient's VDR cDNA was transferred into VDR-deficient CV-1 cells and tested with a cotransfected reporter. Normal calcitriol-dependent transactivation in this heterologous context demonstrates that the VDR coding product itself was functional; it does not reproduce the patient-cell defect.
Index-patient VDR cDNA transfer VDR-deficient CV-1 recipient cells 1,25-dihydroxyvitamin D3 exposure
Organism
African green monkey NCBITaxon:9534 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in African green monkey, annotated with Chlorocebus aethiops (NCBITaxon:9534). NCBITaxon:9534 is an organism from the NCBI Taxonomy.
Cell source
VDR-deficient CV-1 cells receiving index-patient VDR cDNA
Culture
Heterologous cotransfection reporter system
Publication
PMID:8287584
Pathograph links
Index-Case Loss of Vitamin D-Responsive Transcription fails to recapitulate fidelity: low Normal reporter transactivation after transfer fails to reproduce the transcriptional loss and demonstrates intrinsic function of the patient's VDR coding product outside the suppressive patient context.
Limitations: The heterologous recipient lacks the patient's cellular environment, so the assay cannot reproduce the localization or HNRNPC/VDRE phenotype and should not be treated as a rescue of the patient state.
Show evidence (1 reference)
PMID:8287584 SUPPORT In Vitro
"Expression studies of the patient's VDR showed functionally normal VDR as evidenced by normal transactivation in the presence of 1,25(OH)2D3."
Directly supports normal function of the transferred VDR cDNA in CV-1.
Show evidence (1 reference)
PMID:8287584 SUPPORT In Vitro
"VDR cDNA was also transfected into VDR-deficient CV-1 cells and functional response to 1,25(OH)2D3 assessed by co-transfection with a chloramphenicol acetyltransferase (CAT) reporter plasmid."
Defines the heterologous recipient and reporter assay.
Index-case EBV-transformed B-cell line CELL_LINE
EBV-transformed B-cell lines from the index patient and a matched control were used for VDRE-binding-protein studies and the GSE22523 calcitriol-response microarray. This is the direct patient-cell transcriptomic resource for the HNRNPC/VDRE mechanism.
Index-patient EBV-transformed B cells Matched-control EBV-transformed B cells Vehicle and 1,25-dihydroxyvitamin D3 exposure
B cell CL:0000236 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses B cell (CL:0000236). CL:0000236 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
Index-patient and matched-control peripheral B cells
Culture
Epstein-Barr-virus-transformed B-cell lines
Publication
PMID:21123297
Pathograph links
Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements recapitulates fidelity: moderate The patient line carries the elevated VDRE-binding-protein state used to characterize competitive occupancy.
Limitations: It is one transformed B-cell line from one patient; viral transformation, cell lineage, and long-term culture limit transfer to intestine or bone and provide no evidence for the Cauca cohort.
Show evidence (1 reference)
PMID:17071612 SUPPORT In Vitro
"The temporal and reciprocal pattern of VDR and hnRNPC1/C2 interaction with the VDRE was lost in HVDRR cells overexpressing the hnRNP C1/C2 REBiP."
Directly supports disrupted reciprocal occupancy in the patient-cell system.
Index-Case Loss of Vitamin D-Responsive Transcription measures fidelity: moderate The microarray measures the breadth of calcitriol-responsive transcription lost in the patient line relative to control.
Limitations: Expression response in transformed B cells is a cellular readout, not a direct skeletal or intestinal phenotype.
Show evidence (1 reference)
PMID:21123297 SUPPORT In Vitro
"DNA array analysis showed that of 114 genes regulated by 1,25(OH)(2)D(3) in control cells, almost all (113) were rendered insensitive to the hormone in VDRE-BP-overexpressing HVDRR cells."
Provides the direct transcriptomic readout for this model.
EBV transformation, the matched-control design, and the four duplicate conditions were verified against the official GSE22523 record.
HKC-8 HNRNPC C1/C2 overexpression system CELL_LINE
Human HKC-8 cells were engineered to overexpress HNRNPC C1 or C2. Each isoform suppressed VDR-VDRE transactivation, testing an actor-level perturbation without reproducing the complete patient state.
HNRNPC C1 overexpression HNRNPC C2 overexpression Control transfection Transient CYP24-VDRE luciferase reporter 10 nM calcitriol stimulation
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
HKC-8 human renal epithelial cell line
Culture
Transient cDNA overexpression and CYP24-VDRE luciferase reporter assay
Publication
PMID:17071612
Pathograph links
Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements perturbs fidelity: moderate Isoform overexpression suppresses VDR-VDRE transactivation, testing sufficiency of increased HNRNPC activity in this engineered context.
Limitations: Engineered expression magnitude and a renal epithelial line may not match the patient B-cell or fibroblast state. The model does not establish a germline cause or applicability to the Cauca cohort.
Show evidence (1 reference)
PMID:17071612 SUPPORT In Vitro
"When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1 and hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%, respectively; both p < 0.005)."
Directly reports the overexpression perturbation.
ROS 17/2.8 HNRNPC C1/C2 siRNA system CELL_LINE
Rat ROS 17/2.8 cells were transfected with HNRNPC C1/C2 siRNA. Increased VDR transactivation after knockdown shows that endogenous HNRNPC restrains the response in this rat cell context; it was not a rescue of patient-derived cells.
HNRNPC C1/C2 siRNA Control transfection Stable CYP24-VDRE luciferase reporter 10 nM calcitriol stimulation
Organism
rat NCBITaxon:10116 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in rat, annotated with Rattus norvegicus (NCBITaxon:10116). NCBITaxon:10116 is an organism from the NCBI Taxonomy.
Cell source
ROS 17/2.8 rat osteosarcoma-derived cell line
Culture
Transient siRNA knockdown with stable CYP24-VDRE luciferase reporter
Publication
PMID:17071612
Pathograph links
Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements perturbs fidelity: low Knockdown relieves endogenous repression of VDR transactivation in a responsive rat cell line.
Limitations: This is a cross-species wild-type cell system, not patient material. It tests normal endogenous regulation rather than reversal of the index-case HNRNPC-overexpression state.
Show evidence (1 reference)
PMID:17071612 SUPPORT In Vitro
"By contrast, transient expression of an hnRNP C1/C2 small interfering RNA increased VDR transactivation by 39% (p < 0.005)."
Directly reports the siRNA perturbation without treating it as a patient rescue.
MG63 osteoblast-like HNRNPC perturbation model CELL_LINE
Human MG63 osteoblast-like cells were used to test HNRNPC isoform overexpression and later knockdown effects on vitamin-D-directed transcription and RNA processing. This is a mechanistic osteoblast-line model, not a patient-derived VDDR2B model or disease dataset.
HNRNPC C1 overexpression HNRNPC C2 overexpression Combined HNRNPC C1 and C2 overexpression HNRNPC C1/C2 knockdown 1,25-dihydroxyvitamin D exposure
osteoblast CL:0000062 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses osteoblast (CL:0000062). CL:0000062 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
MG63 human osteosarcoma-derived osteoblast-like cell line
Culture
Adherent transformed cell-line culture
Publication
PMID:25506471
Pathograph links
Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements perturbs fidelity: low Isoform overexpression and knockdown separately probe HNRNPC control of vitamin D-directed transcription and RNA processing in a human bone-lineage context.
Limitations: MG63 is a transformed osteosarcoma line with endogenous HNRNPC and no patient background. Species-specific HNRNPC heterodimerization means the paired human/mouse experiments cannot be transferred without qualification.
Show evidence (2 references)
PMID:25506471 SUPPORT In Vitro
"By contrast, overexpression of either huC1 or huC2 was sufficient to suppress 1,25(OH)2D-induced gene expression in human MG-63 osteoblast-like cells, with combined over-expression of huC1 and huC2 having an additive suppressive effect (Figure 1b)."
Directly supports isoform perturbation in the human MG63 system.
+ 1 more reference
Show evidence (1 reference)
PMID:27672039 SUPPORT In Vitro
"In MG63 osteoblastic cells, increased expression of the 1,25(OH)2D target gene CYP24A1 involved immunoprecipitation of hnRNPC1/C2 with CYP24A1 chromatin and RNA."
Confirms parallel chromatin- and RNA-association readouts in the cell system; it does not establish that the two actions are coupled through vitamin-D-induced transcription.
{ }

Source YAML

click to show 
name: Vitamin D-Dependent Rickets Type 2B
synonyms:
- VDDR2B
- Hereditary vitamin D-resistant rickets with normal vitamin D receptor
- Receptor-positive vitamin D-resistant rickets
creation_date: "2026-08-19T00:00:00Z"
category: Metabolic Disorder
description: >-
  MONDO:0010931 is curated here as an unresolved umbrella. Two principal
  evidence strata modeled in this entry have not been genetically or
  epidemiologically connected.
  One is a 1995 rural-Cauca cluster of more than 200 children with lower-limb
  deformities, receptor-positive vitamin D resistance, normal VDR cDNA sequence,
  and no alopecia. The other is a single alopecic child first reported in 1993:
  the child's endogenous VDR bound calcitriol but failed to localize normally to
  the nucleus, whereas the normal VDR coding sequence functioned after transfer
  to a heterologous cell context. Follow-up studies of cells from that index case
  identified overexpressed HNRNPC C1/C2 competing with VDR-RXR at vitamin D
  response elements and broadly suppressing vitamin-D-responsive transcription.

  HNRNPC is therefore represented only as a molecular actor in the index-case
  mechanism, not as a disease-causal gene. No causal germline lesion, inheritance
  pattern, or shared molecular basis for the two strata is established. The
  historical label "HVDRR type III" used for the index case predates and is not
  equivalent to modern CYP3A4-related vitamin D-dependent rickets type 3.
disease_term:
  preferred_term: vitamin D-dependent rickets, type 2B
  term:
    id: MONDO:0010931
    label: vitamin D-dependent rickets, type 2B
parents:
- Metabolic Bone Disorders
inheritance: []
genetic: []
pathophysiology:
- name: Cauca-Cohort Receptor-Positive Vitamin D Resistance
  description: >-
    The 1995 Cauca study described more than 200 children with lower-limb
    deformities, elevated calcitriol, normal 25-hydroxyvitamin D, and a normal VDR
    cDNA sequence. The authors called this a distinct receptor-positive form of
    vitamin D resistance. HNRNPC abundance, VDRE occupancy, and the index-case
    cellular mechanism were not studied in this cohort, so its proximal molecular
    block remains unknown.
  role: trigger
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  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: >-
      More than 200 patients with different types of lower limb deformities were
      detected in a rural area of the Cauca department in the southwest part of
      Colombia.
    explanation: >-
      Defines the size, geography, and skeletal presentation of the cluster
      stratum without linking it to the later index case.
  - 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: >-
      The cDNA analysis showed normal nucleotide sequence. We suggest that our
      patients represent a distinct form of receptor-positive resistance to
      vitamin D.
    explanation: >-
      Supports receptor-positive resistance and a normal VDR coding sequence, but
      does not identify the molecular cause.
  downstream:
  - target: Defective Skeletal Mineralization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cluster's biochemical resistance was associated with lower-limb
      deformities, but calcium remained within the low-normal range and phosphate
      was normal. The causal mineral intermediates were not resolved.
    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: >-
        More than 200 patients with different types of lower limb deformities were
        detected in a rural area of the Cauca department in the southwest part of
        Colombia.
      explanation: >-
        Documents the associated skeletal endpoint. PARTIAL marks that this
        sentence does not itself establish the resistance-to-mineralization link
        or an unmeasured calciopenic intermediate.
- name: Index-Case Endogenous VDR Nuclear-Localization Failure
  description: >-
    In cells from the single alopecic child, endogenous VDR bound calcitriol but
    failed to show normal nuclear localization or a functional response. The VDR
    coding sequence was normal, and transfer of the patient's VDR cDNA into a
    different cellular context restored normal transactivation. This establishes
    a cell-contextual receptor-handling phenotype, not a causal VDR variant.
  role: trigger
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear
      localization resulting in an absence of functional response to
      1,25(OH)2D3.
    explanation: >-
      Directly records the abnormal endogenous localization and functional
      response observed in patient cells.
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Sequencing revealed that the VDR coding region was normal. Expression
      studies of the patient's VDR showed functionally normal VDR as evidenced by
      normal transactivation in the presence of 1,25(OH)2D3.
    explanation: >-
      Separates the patient-cell phenotype from an intrinsic coding or functional
      defect of the VDR molecule.
  downstream:
  - target: Index-Case Loss of Vitamin D-Responsive Transcription
    causal_link_type: DIRECT
    description: >-
      Failure of endogenous ligand-bound VDR to localize normally was accompanied
      by absent calcitriol-responsive 24-hydroxylase activity in the same cells.
    evidence:
    - reference: PMID:8287584
      reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear
        localization resulting in an absence of functional response to
        1,25(OH)2D3.
      explanation: >-
        The authors explicitly connect failed localization to the absent
        functional response.
- name: Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
  description: >-
    Follow-up work on the index-case cells first detected an overexpressed
    response-element-binding protein and provisionally assigned it to the hnRNPA
    family. The protein was subsequently purified and cloned as HNRNPC C1/C2.
    Overexpressed HNRNPC competed with VDR-RXR for VDRE occupancy, disrupted the
    normal reciprocal occupancy cycle, and suppressed vitamin-D-directed
    transcription. HNRNPC is annotated here as the experimentally implicated
    actor; these studies did not identify a germline HNRNPC lesion.
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  gene:
    preferred_term: HNRNPC
    term:
      id: hgnc:5035
      label: HNRNPC
  molecular_functions:
  - preferred_term: Vitamin D response-element binding by HNRNPC C1/C2
    term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    modifier: INCREASED
  biological_processes:
  - preferred_term: Vitamin D receptor signaling
    term:
      id: GO:0070561
      label: vitamin D receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:12716975
    reference_title: 'Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ab blocking in electrophoretic mobility-shift assays indicated that this
      dominant-negative acting protein was in the hnRNPA family of nucleic
      acid-binding proteins.
    explanation: >-
      Preserves the 2003 intermediate assignment; PARTIAL marks that the study had
      not yet identified the later HNRNPC C1/C2 molecular species.
  - reference: PMID:17071612
    reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we describe the purification, molecular cloning, and expression of
      this vitamin D resistance-causing, competitive response element-binding
      protein (REBiP) hnRNP C1/C2.
    explanation: >-
      Supplies the later molecular identification that superseded the preliminary
      hnRNPA-family assignment.
  - reference: PMID:17071612
    reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1 and
      hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%,
      respectively; both p < 0.005).
    explanation: >-
      Reconstitutes transcriptional suppression by HNRNPC C1 or C2
      overexpression.
  downstream:
  - target: Index-Case Loss of Vitamin D-Responsive Transcription
    causal_link_type: DIRECT
    description: >-
      Competitive VDRE occupancy limits VDR-RXR access and suppresses target-gene
      transactivation in index-case and engineered cell systems.
    evidence:
    - reference: PMID:17071612
      reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Hormone resistance resulted from constitutive overexpression of
        heterogeneous nuclear ribonucleoprotein (hnRNP) that competed with a
        normally functioning VDR-retinoid X receptor (RXR) dimer for binding to
        the vitamin D response element (VDRE).
      explanation: >-
        Directly links HNRNPC overexpression and competitive VDRE occupancy to
        the transcriptional hormone-resistance phenotype.
- name: Index-Case Loss of Vitamin D-Responsive Transcription
  description: >-
    Patient-derived cells were broadly insensitive to calcitriol-responsive gene
    regulation. The later transcriptomic study found that 113 of 114 genes
    regulated by calcitriol in control cells became insensitive in the
    VDRE-binding-protein-overexpressing patient cells.
  role: central_effector
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: Vitamin D receptor signaling
    term:
      id: GO:0070561
      label: vitamin D receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:21123297
    reference_title: Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DNA array analysis showed that of 114 genes regulated by
      1,25(OH)(2)D(3) in control cells, almost all (113) were rendered insensitive
      to the hormone in VDRE-BP-overexpressing HVDRR cells.
    explanation: >-
      Quantifies the breadth of the transcriptional resistance in the index-case
      cell system.
  downstream:
  - target: Index-Case Hypocalcemic Mineral Disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cellular transcriptional resistance is consistent with the index
      child's hypocalcemic rickets, but intestinal calcium transport and the
      intervening organism-level steps were not directly measured in these
      mechanistic studies.
    evidence:
    - reference: PMID:17071612
      reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We recently described a human with the classical HVDRR phenotype but
        normal VDR function.
      explanation: >-
        Links the studied cells to the human HVDRR phenotype; PARTIAL marks that
        the mineral intermediary was not assayed in this paper.
- name: Index-Case Hypocalcemic Mineral Disturbance
  description: >-
    The index child had albumin-corrected calcium of 2.03 mmol/L against a stated
    reference interval of 2.25-2.55 mmol/L, elevated alkaline phosphatase, and
    elevated calcitriol. This stratum-specific node does not absorb the Cauca
    cohort, whose calcium was low-normal and whose phosphate was normal, and it
    avoids asserting directly measured intestinal malabsorption.
  role: central_effector
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  conforms_to: "defective_skeletal_mineralization#Calciopenic Substrate Deficiency"
  notes: >-
    Exact index-case laboratory values are reported in the full text of
    PMID:12716975 (PMCID:PMC156334). The sanctioned PMID cache is abstract-only,
    so no purportedly verbatim snippet is attached to this node.
  downstream:
  - target: Hypocalcemia
    causal_link_type: DIRECT
    description: >-
      The measured low serum calcium is the defining clinical phenotype of this
      stratum-specific mineral disturbance.
  - target: Defective Skeletal Mineralization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced calcium availability can impair skeletal mineralization. The exact
      intermediate physiology, including the growth-plate route, was not fully
      measured in the index-case mechanistic studies.
    evidence:
    - reference: PMID:32596195
      reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
      supports: SUPPORT
      directness: INDIRECT
      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: >-
        Supplies a general calcium-or-phosphorus mechanism for impaired skeletal
        mineralization. INDIRECT marks that it is narrative-review evidence, does
        not establish the index child's growth-plate intermediate, and is not a
        stratum-specific measurement.
    - reference: PMID:8287584
      reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A child with alopecia diagnosed as having rickets due to resistance to
        1,25(OH)2D3.
      explanation: >-
        Documents the index child's skeletal endpoint; INDIRECT marks that it does
        not establish the causal mineral-ion step.
- name: Defective Skeletal Mineralization
  description: >-
    Failure of growth-plate and bone mineralization manifests as rickets in the
    index child and as diverse lower-limb deformities in the Cauca cluster. This
    is the only asserted convergence of the two evidence strata.
  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
  downstream:
  - target: Rickets
    causal_link_type: DIRECT
    description: >-
      Impaired growth-plate mineralization manifests as rickets in the alopecic
      index child.
    evidence:
    - reference: PMID:8287584
      reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A child with alopecia diagnosed as having rickets due to resistance to
        1,25(OH)2D3.
      explanation: >-
        Documents the rickets endpoint; PARTIAL marks that the sentence does not
        itself measure growth-plate mineralization.
  - target: Abnormality of the lower limb
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Defective skeletal mineralization is associated with the diverse lower-limb
      deformities used to ascertain the Cauca cluster, but the abstract does not
      resolve the intervening skeletal morphology.
    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: >-
        More than 200 patients with different types of lower limb deformities were
        detected in a rural area of the Cauca department in the southwest part of
        Colombia.
      explanation: >-
        Documents the lower-limb endpoint; PARTIAL marks that the intermediate
        mineralization-to-deformity route was not measured.
phenotypes:
- category: Skeletal
  name: Rickets
  description: >-
    Rickets was diagnosed in the single alopecic index child. The Cauca report
    described a large cluster under the same diagnostic label with lower-limb
    deformities, but did not provide case-level skeletal phenotyping in the
    abstract.
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A child with alopecia diagnosed as having rickets due to resistance to
      1,25(OH)2D3.
    explanation: >-
      Directly documents rickets in the index child.
  - 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: >-
      More than 200 patients with different types of lower limb deformities were
      detected in a rural area of the Cauca department in the southwest part of
      Colombia.
    explanation: >-
      Records the cluster's skeletal presentation; PARTIAL avoids treating the
      broad deformity phrase as standardized case-level rickets ascertainment.
- category: Integumentary
  name: Alopecia
  description: >-
    Alopecia was present in the single index child but explicitly absent from the
    more-than-200-child Cauca cluster. No overall frequency is assigned because
    pooling these unconnected strata would manufacture a denominator.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  notes: >-
    Alopecia is deliberately left without a pathophysiology edge because no study
    tested a causal link between hair loss and the index-case localization or
    HNRNPC/VDRE mechanisms.
  evidence:
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A child with alopecia diagnosed as having rickets due to resistance to
      1,25(OH)2D3.
    explanation: >-
      Directly records alopecia in the index case.
  - 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: >-
      None of them presented alopecia, myopathy, seizures or aminoaciduria.
    explanation: >-
      Directly records absence of alopecia in the Cauca cohort; this is a
      stratum-specific negative observation, not a global frequency estimate.
- category: Skeletal
  name: Abnormality of the lower limb
  description: >-
    Diverse lower-limb deformities were the ascertainment feature of the Cauca
    cluster. The source does not justify assigning a more specific deformity or a
    frequency distribution.
  phenotype_term:
    preferred_term: Abnormality of the lower limb
    term:
      id: HP:0002814
      label: Abnormality of the lower limb
  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: >-
      More than 200 patients with different types of lower limb deformities were
      detected in a rural area of the Cauca department in the southwest part of
      Colombia.
    explanation: >-
      Directly supports a broad lower-limb abnormality in the cluster stratum.
- category: Biochemical
  name: Hypocalcemia
  description: >-
    Hypocalcemia was reported for the single index child and was described as
    responsive to high-dose calcitriol in a regimen that also included calcium.
    The Cauca cohort instead had calcium below related controls but still within
    the low-normal range, so this phenotype is not generalized to that cohort.
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  notes: >-
    The full text of PMID:12716975 (PMCID:PMC156334) reports albumin-corrected
    calcium of 2.03 mmol/L against a stated 2.25-2.55 mmol/L reference interval.
    The sanctioned PMID cache is abstract-only, so no unverifiable snippet is
    attached here. Other historical receptor-positive/postreceptor HVDRR reports
    are not assumed to belong to this index-case lineage.
- category: Biochemical
  name: Elevated circulating alkaline phosphatase concentration
  description: >-
    Elevated alkaline phosphatase was reported in both principal strata. The
    cache-backed cluster evidence is below; the index-case full text gives 1101
    U/L against a stated normal value below 300 U/L.
  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 clinical laboratory correlate
      of rachitic skeletal disease, but without isoenzyme fractionation it is not
      bone-specific and does not by itself measure mineralization.
  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.
    explanation: >-
      Directly reports high alkaline phosphatase in the cluster.
  notes: >-
    The index-case value is in the full text of PMID:12716975; its sanctioned
    cache is abstract-only, so the exact value is not presented as a verified
    snippet.
biochemical:
- name: 1,25-dihydroxyvitamin D (calcitriol)
  presence: Elevated
  biomarker_term:
    preferred_term: 1,25-Dihydroxyvitamin D3 Measurement
    term:
      id: NCIT:C179754
      label: 1,25-Dihydroxyvitamin D3 Measurement
  context: >-
    Elevated calcitriol was measured in both principal strata. The Cauca cohort
    source interpreted it as evidence of target-organ resistance; index-case
    full text reports 466-650 pmol/L against a stated 48-156 pmol/L interval. No
    pooled cross-stratum distribution is assigned.
  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.
    explanation: >-
      Directly reports high circulating calcitriol in the cluster.
  notes: >-
    The index-case range is in the full text of PMID:12716975; its sanctioned
    cache is abstract-only, so the exact value is not presented as a verified
    snippet.
- name: 25-hydroxyvitamin D (calcidiol)
  presence: Normal
  context: >-
    Normal 25-hydroxyvitamin D3 was reported in the Cauca cohort alongside high
    calcitriol. This finding is stratum-specific; no global distribution is
    assigned.
  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.
    explanation: >-
      Directly reports normal 25-hydroxyvitamin D3 in the cluster.
- name: Serum calcium
  presence: Stratum-specific abnormality
  context: >-
    The index child was hypocalcemic at 2.03 mmol/L (stated interval
    2.25-2.55 mmol/L). In the Cauca cohort, calcium was significantly below
    related controls but remained within the low-normal range. These distinct
    observations are not collapsed into a single global severity or frequency.
  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.
    explanation: >-
      Directly supports the cluster-specific low-normal calcium observation.
  notes: >-
    The index-case value is in the full text of PMID:12716975; its sanctioned
    cache is abstract-only, so no index-case snippet is attached.
- name: Serum phosphate
  presence: Normal in the Cauca cohort
  context: >-
    Serum phosphate was normal in the Cauca cohort. The primary abstract does not
    establish a corresponding index-case value, so this is not generalized.
  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.
    explanation: >-
      Directly reports normal serum phosphorus in the cluster.
treatments:
- name: Index-Case High-Dose Calcitriol Plus Calcium
  action_category: THERAPEUTIC
  description: >-
    In the single alopecic index child, a regimen of calcitriol at 12 micrograms
    per day plus calcium at 1 gram per day was reported to correct rachitic bone
    disease, while alopecia persisted. This is an observed n=1 combined regimen,
    not evidence that either component was sufficient alone and not a general
    dosing recommendation for the unresolved umbrella entity.
  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
    - preferred_term: calcium(2+)
      term:
        id: CHEBI:29108
        label: calcium(2+)
  target_phenotypes:
  - preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  target_mechanisms:
  - target: Defective Skeletal Mineralization
    treatment_effect: RESTORES
    description: >-
      The rachitic bone disease was reported corrected during the combined
      regimen. RESTORES describes that observed skeletal outcome and does not
      isolate the contribution of high-dose calcitriol from calcium or imply a
      treatment response in the Cauca stratum.
  notes: >-
    The exact regimen and outcomes are stated in the full text of PMID:12716975
    (PMCID:PMC156334). The sanctioned `just fetch-reference PMID:12716975` cache
    is abstract-only, so no purportedly verbatim evidence snippet is attached.
    Baseline hypocalcemia is recorded elsewhere, but no post-treatment calcium
    value is asserted here. Persistent alopecia is a nonresponse outcome, not a
    target of the successful skeletal regimen.
diagnosis:
- name: Clinical and biochemical assessment of receptor-positive vitamin D resistance
  diagnosis_term:
    preferred_term: Clinical Evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >-
    Rickets or lower-limb deformity together with relatively low calcium, high
    alkaline phosphatase, normal 25-hydroxyvitamin D, and elevated calcitriol can
    support suspicion of target-organ vitamin D resistance. The documented
    pattern comes from the Cauca cohort and does not by itself establish that an
    individual has the index-case HNRNPC mechanism.
  results: >-
    A vitamin-D-resistant rachitic biochemical pattern supports further
    evaluation but is not specific for VDDR2B or either evidence stratum.
  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.
    explanation: >-
      Defines the directly observed cluster biochemical pattern.
- name: VDR coding-sequence analysis as an exclusionary test
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Demonstrating a normal VDR coding sequence helps distinguish these reports
    from VDR-related vitamin D-dependent rickets type 2A. A negative VDR result
    does not confirm VDDR2B, identify HNRNPC dysregulation, or prove that the two
    evidence strata share a disorder.
  results: >-
    A normal VDR coding sequence is exclusionary for a coding lesion in VDR; it is
    not a positive molecular test for VDDR2B.
  evidence:
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing revealed that the VDR coding region was normal. Expression
      studies of the patient's VDR showed functionally normal VDR as evidenced by
      normal transactivation in the presence of 1,25(OH)2D3.
    explanation: >-
      Directly supports normal VDR coding and transferred function in the index
      case.
  - 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: >-
      The cDNA analysis showed normal nucleotide sequence.
    explanation: >-
      Directly supports a normal VDR cDNA sequence in the Cauca cohort.
- name: HNRNPC-VDRE functional assays (research only)
  description: >-
    VDRE mobility-shift, chromatin-occupancy, transactivation, HNRNPC
    overexpression, and siRNA assays characterized the index-case mechanism.
    These are research assays with no validated clinical threshold or evidence
    of diagnostic sensitivity or specificity.
  results: >-
    Excess HNRNPC C1/C2 occupancy with impaired VDR transactivation can reproduce
    the index-case cellular phenotype but is not a validated confirmatory test.
  evidence:
  - reference: PMID:17071612
    reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      By contrast, transient expression of an hnRNP C1/C2 small interfering RNA
      increased VDR transactivation by 39% (p < 0.005).
    explanation: >-
      Documents one of the reciprocal functional perturbations; it supports
      mechanism research, not clinical validation.
differential_diagnoses:
- 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: >-
    Type 2A can share rickets, elevated calcitriol, hypocalcemia, and alopecia,
    but it is caused by biallelic loss-of-function variants in VDR.
  distinguishing_features:
  - A pathogenic biallelic VDR genotype supports type 2A rather than this receptor-positive umbrella.
  - A normal VDR coding sequence only excludes a coding lesion; it does not confirm type 2B.
  evidence:
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR2a (OMIM 277440) is due to biallelic loss-of-function mutations in the
      gene encoding the vitamin D receptor (VDR; 601769) on chromosome 12q13.11,
      and therefore represents a bona fide form of tissue resistance to vitamin D.
    explanation: >-
      Establishes the causal VDR genotype that distinguishes type 2A.
- 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: >-
    Modern VDDR3 is a distinct, dominantly acting CYP3A4 p.Ile301Thr
    gain-of-function disorder with accelerated inactivation and low
    25-hydroxyvitamin D and calcitriol. Conventional dosing can be inadequate,
    although the original subjects maintained normal mineral biochemistry with
    sufficiently high calcitriol or vitamin D dosing. It must not be inferred
    from the historical phrase "HVDRR type III" used for the receptor-positive
    index case before modern VDDR3 was defined.
  distinguishing_features:
  - Modern VDDR3 has a heterozygous CYP3A4 p.Ile301Thr gain-of-function variant; de novo occurrence in the original subjects is not asserted as universal.
  - Both major circulating vitamin D metabolites are reduced rather than the elevated calcitriol reported in the Cauca receptor-positive cluster.
  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 modern type 3 clinical and biochemical pattern.
  - 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: >-
      Establishes the molecular identity of modern VDDR3 and scopes de novo
      occurrence to the two original subjects rather than the whole disorder.
animal_models: []
experimental_models:
- name: Index-case skin fibroblast culture
  description: >-
    Skin fibroblast cultures from the alopecic index child and controls were used
    to measure calcitriol binding, endogenous VDR nuclear association,
    24-hydroxylase response, VDR coding sequence, and suppression of wild-type
    VDR transactivation in the patient-cell context.
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  conditions:
  - Alopecic index-case fibroblasts
  - Control fibroblasts
  - 1,25-dihydroxyvitamin D3 exposure
  cell_source: Skin fibroblasts from the single index child and controls
  culture_system: Patient and control fibroblast monolayers
  publication: PMID:8287584
  modeled_mechanisms:
  - target: Index-Case Endogenous VDR Nuclear-Localization Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Patient-derived cells directly reproduce ligand binding with absent normal
      nuclear localization in the index case's own cellular context.
    limitations: >-
      This is a culture from one patient and is not the intestinal target tissue;
      it cannot establish that the finding is shared by the Cauca cohort or other
      receptor-positive cases.
    evidence:
    - reference: PMID:8287584
      reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear
        localization resulting in an absence of functional response to
        1,25(OH)2D3.
      explanation: >-
        Directly supports the localization phenotype in the patient-derived
        culture.
  - target: Index-Case Loss of Vitamin D-Responsive Transcription
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      Calcitriol-responsive 24-hydroxylase activity and cotransfection in patient
      cells provide functional readouts of the suppressive patient-cell context.
    limitations: >-
      The assays measure selected vitamin D responses in fibroblasts and do not
      reproduce whole-body mineral physiology.
    evidence:
    - reference: PMID:12716975
      reference_title: 'Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Initial cotransfection studies showed that the cells of the patient
        suppressed basal and hormone-induced transactivation by wild-type VDR.
      explanation: >-
        Directly supports a suppressive transcriptional phenotype in patient
        cells without conflating it with heterologous CV-1 transfer.
  evidence:
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient and control cell lines prepared from skin fibroblasts and peripheral
      blood lymphocytes were used to measure binding of 1,25(OH)2D3 and to isolate
      vitamin D receptor mRNA.
    explanation: >-
      Defines the patient-derived and control cellular systems.
- name: Heterologous CV-1 transfer of index-case VDR cDNA
  description: >-
    The index patient's VDR cDNA was transferred into VDR-deficient CV-1 cells
    and tested with a cotransfected reporter. Normal calcitriol-dependent
    transactivation in this heterologous context demonstrates that the VDR coding
    product itself was functional; it does not reproduce the patient-cell defect.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: African green monkey
    term:
      id: NCBITaxon:9534
      label: Chlorocebus aethiops
  conditions:
  - Index-patient VDR cDNA transfer
  - VDR-deficient CV-1 recipient cells
  - 1,25-dihydroxyvitamin D3 exposure
  cell_source: VDR-deficient CV-1 cells receiving index-patient VDR cDNA
  culture_system: Heterologous cotransfection reporter system
  publication: PMID:8287584
  modeled_mechanisms:
  - target: Index-Case Loss of Vitamin D-Responsive Transcription
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Normal reporter transactivation after transfer fails to reproduce the
      transcriptional loss and demonstrates intrinsic function of the patient's
      VDR coding product outside the suppressive patient context.
    limitations: >-
      The heterologous recipient lacks the patient's cellular environment, so the
      assay cannot reproduce the localization or HNRNPC/VDRE phenotype and should
      not be treated as a rescue of the patient state.
    evidence:
    - reference: PMID:8287584
      reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Expression studies of the patient's VDR showed functionally normal VDR as
        evidenced by normal transactivation in the presence of 1,25(OH)2D3.
      explanation: >-
        Directly supports normal function of the transferred VDR cDNA in CV-1.
  evidence:
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VDR cDNA was also transfected into VDR-deficient CV-1 cells and functional
      response to 1,25(OH)2D3 assessed by co-transfection with a chloramphenicol
      acetyltransferase (CAT) reporter plasmid.
    explanation: >-
      Defines the heterologous recipient and reporter assay.
- name: Index-case EBV-transformed B-cell line
  description: >-
    EBV-transformed B-cell lines from the index patient and a matched control were
    used for VDRE-binding-protein studies and the GSE22523 calcitriol-response
    microarray. This is the direct patient-cell transcriptomic resource for the
    HNRNPC/VDRE mechanism.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  conditions:
  - Index-patient EBV-transformed B cells
  - Matched-control EBV-transformed B cells
  - Vehicle and 1,25-dihydroxyvitamin D3 exposure
  cell_source: Index-patient and matched-control peripheral B cells
  culture_system: Epstein-Barr-virus-transformed B-cell lines
  publication: PMID:21123297
  modeled_mechanisms:
  - target: Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The patient line carries the elevated VDRE-binding-protein state used to
      characterize competitive occupancy.
    limitations: >-
      It is one transformed B-cell line from one patient; viral transformation,
      cell lineage, and long-term culture limit transfer to intestine or bone and
      provide no evidence for the Cauca cohort.
    evidence:
    - reference: PMID:17071612
      reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The temporal and reciprocal pattern of VDR and hnRNPC1/C2 interaction with
        the VDRE was lost in HVDRR cells overexpressing the hnRNP C1/C2 REBiP.
      explanation: >-
        Directly supports disrupted reciprocal occupancy in the patient-cell
        system.
  - target: Index-Case Loss of Vitamin D-Responsive Transcription
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      The microarray measures the breadth of calcitriol-responsive transcription
      lost in the patient line relative to control.
    limitations: >-
      Expression response in transformed B cells is a cellular readout, not a
      direct skeletal or intestinal phenotype.
    evidence:
    - reference: PMID:21123297
      reference_title: Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        DNA array analysis showed that of 114 genes regulated by
        1,25(OH)(2)D(3) in control cells, almost all (113) were rendered
        insensitive to the hormone in VDRE-BP-overexpressing HVDRR cells.
      explanation: >-
        Provides the direct transcriptomic readout for this model.
  notes: >-
    EBV transformation, the matched-control design, and the four duplicate
    conditions were verified against the official GSE22523 record.
- name: HKC-8 HNRNPC C1/C2 overexpression system
  description: >-
    Human HKC-8 cells were engineered to overexpress HNRNPC C1 or C2. Each
    isoform suppressed VDR-VDRE transactivation, testing an actor-level
    perturbation without reproducing the complete patient state.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  conditions:
  - HNRNPC C1 overexpression
  - HNRNPC C2 overexpression
  - Control transfection
  - Transient CYP24-VDRE luciferase reporter
  - 10 nM calcitriol stimulation
  cell_source: HKC-8 human renal epithelial cell line
  culture_system: Transient cDNA overexpression and CYP24-VDRE luciferase reporter assay
  publication: PMID:17071612
  modeled_mechanisms:
  - target: Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Isoform overexpression suppresses VDR-VDRE transactivation, testing
      sufficiency of increased HNRNPC activity in this engineered context.
    limitations: >-
      Engineered expression magnitude and a renal epithelial line may not match
      the patient B-cell or fibroblast state. The model does not establish a
      germline cause or applicability to the Cauca cohort.
    evidence:
    - reference: PMID:17071612
      reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1
        and hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%,
        respectively; both p < 0.005).
      explanation: >-
        Directly reports the overexpression perturbation.
- name: ROS 17/2.8 HNRNPC C1/C2 siRNA system
  description: >-
    Rat ROS 17/2.8 cells were transfected with HNRNPC C1/C2 siRNA. Increased VDR
    transactivation after knockdown shows that endogenous HNRNPC restrains the
    response in this rat cell context; it was not a rescue of patient-derived
    cells.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  conditions:
  - HNRNPC C1/C2 siRNA
  - Control transfection
  - Stable CYP24-VDRE luciferase reporter
  - 10 nM calcitriol stimulation
  cell_source: ROS 17/2.8 rat osteosarcoma-derived cell line
  culture_system: Transient siRNA knockdown with stable CYP24-VDRE luciferase reporter
  publication: PMID:17071612
  modeled_mechanisms:
  - target: Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Knockdown relieves endogenous repression of VDR transactivation in a
      responsive rat cell line.
    limitations: >-
      This is a cross-species wild-type cell system, not patient material. It
      tests normal endogenous regulation rather than reversal of the index-case
      HNRNPC-overexpression state.
    evidence:
    - reference: PMID:17071612
      reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        By contrast, transient expression of an hnRNP C1/C2 small interfering RNA
        increased VDR transactivation by 39% (p < 0.005).
      explanation: >-
        Directly reports the siRNA perturbation without treating it as a patient
        rescue.
- name: MG63 osteoblast-like HNRNPC perturbation model
  description: >-
    Human MG63 osteoblast-like cells were used to test HNRNPC isoform
    overexpression and later knockdown effects on vitamin-D-directed transcription
    and RNA processing. This is a mechanistic osteoblast-line model, not a
    patient-derived VDDR2B model or disease dataset.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  conditions:
  - HNRNPC C1 overexpression
  - HNRNPC C2 overexpression
  - Combined HNRNPC C1 and C2 overexpression
  - HNRNPC C1/C2 knockdown
  - 1,25-dihydroxyvitamin D exposure
  cell_source: MG63 human osteosarcoma-derived osteoblast-like cell line
  culture_system: Adherent transformed cell-line culture
  publication: PMID:25506471
  modeled_mechanisms:
  - target: Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Isoform overexpression and knockdown separately probe HNRNPC control of
      vitamin D-directed transcription and RNA processing in a human
      bone-lineage context.
    limitations: >-
      MG63 is a transformed osteosarcoma line with endogenous HNRNPC and no
      patient background. Species-specific HNRNPC heterodimerization means the
      paired human/mouse experiments cannot be transferred without qualification.
    evidence:
    - reference: PMID:25506471
      reference_title: The heterodimeric structure of heterogeneous nuclear ribonucleoprotein C1/C2 dictates 1,25-dihydroxyvitamin D-directed transcriptional events in osteoblasts.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        By contrast, overexpression of either huC1 or huC2 was sufficient to
        suppress 1,25(OH)2D-induced gene expression in human MG-63 osteoblast-like
        cells, with combined over-expression of huC1 and huC2 having an additive
        suppressive effect (Figure 1b).
      explanation: >-
        Directly supports isoform perturbation in the human MG63 system.
    - reference: PMID:27672039
      reference_title: Concerted effects of heterogeneous nuclear ribonucleoprotein C1/C2 to control vitamin D-directed gene transcription and RNA splicing in human bone cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Knockdown of hnRNPC1/C2 suppressed expression of CYP24A1, but also
        increased expression of an exon 10-skipped CYP24A1 splice variant; in a
        minigene model the latter was attenuated by a functional VDRE in the
        CYP24A1 promoter.
      explanation: >-
        Directly supports the knockdown condition and its parallel expression
        and splicing readouts in MG63 cells.
  evidence:
  - reference: PMID:27672039
    reference_title: Concerted effects of heterogeneous nuclear ribonucleoprotein C1/C2 to control vitamin D-directed gene transcription and RNA splicing in human bone cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In MG63 osteoblastic cells, increased expression of the 1,25(OH)2D target
      gene CYP24A1 involved immunoprecipitation of hnRNPC1/C2 with CYP24A1
      chromatin and RNA.
    explanation: >-
      Confirms parallel chromatin- and RNA-association readouts in the cell
      system; it does not establish that the two actions are coupled through
      vitamin-D-induced transcription.
datasets:
- accession: geo:GSE22523
  title: Analysis of vitamin D response element binding protein target genes reveals a role for vitamin D in osteoblast mTOR signaling
  description: >-
    Human expression microarray comparing EBV-transformed B-cell lines from the
    single VDDR2B index patient and a matched control, each with vehicle or
    1,25-dihydroxyvitamin D exposure in biological duplicate. The resource tests
    the index-case cellular transcriptional response; it is not a cohort of the
    Cauca cluster.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: EBV-transformed B-cell line
    term:
      id: CL:0000236
      label: B cell
    cell_type_term:
      preferred_term: B cell
      term:
        id: CL:0000236
        label: B cell
  sample_count: 8
  conditions:
  - Index-patient EBV B cells with vehicle
  - Index-patient EBV B cells with 1,25-dihydroxyvitamin D
  - Matched-control EBV B cells with vehicle
  - Matched-control EBV B cells with 1,25-dihydroxyvitamin D
  platform: GPL6244
  publication: PMID:21123297
  notes: >-
    Official NCBI GEO metadata verified on 2026-08-20: eight human samples,
    platform GPL6244, two biological replicates per four condition groups, and
    PMID:21123297. GSE63086 is deliberately omitted because it is an MG63
    mechanistic perturbation dataset rather than a patient VDDR2B resource.
imaging_findings: []
clinical_trials: []
discussions:
- discussion_id: controversy_vddr2b_entity_boundary
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Cauca-Cohort Receptor-Positive Vitamin D Resistance
  - pathophysiology#Index-Case Endogenous VDR Nuclear-Localization Failure
  - pathophysiology#Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
  prompt: >-
    Do the Cauca cluster, the alopecic HNRNPC/VDRE index case, and other historical
    receptor-positive postreceptor cases represent one disease entity or several
    mechanistically distinct forms of vitamin D resistance?
  rationale: >-
    The evidence strata are not connected by pedigree, genotype, or a shared
    molecular assay. The 1983 postreceptor case had normal cytosolic and nuclear
    ligand binding but impaired 24-hydroxylase induction. The 1993 alopecic index
    case instead lacked normal endogenous VDR nuclear localization, and only its
    later cell lineage was tied to HNRNPC C1/C2 competition. The Cauca cohort had
    no alopecia, low-normal calcium, normal phosphate, and no HNRNPC study. MONDO
    currently combines a postreceptor/HNRNPC description, no-alopecia synonyms,
    and "Sporadic" metadata that do not jointly fit the primary strata; those
    ontology assertions are treated as an unresolved source mismatch, not as
    proof of one entity or a demonstrated inheritance mode. Modern classification
    has not resolved the mismatch: the 2023 skeletal-disorder nosology table
    labels the entity HNRNPC-related and "AD?" while qualifying the proposed
    HNRNPC dominant-negative basis as coming from a single patient, and the 2024
    review recounts the index case and Cauca cluster separately, calls VDDR2B
    less well defined, and notes that the cluster phosphorus pattern lacks
    replication. These later summaries are treated as classification context,
    not as new causal-gene or inheritance evidence.
  evidence:
  - reference: PMID:6313754
    reference_title: Impaired stimulation of 25-hydroxyvitamin D-24-hydroxylase in fibroblasts from a patient with vitamin D-dependent rickets, type II. A form of receptor-positive resistance to 1,25-dihydroxyvitamin D3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient, therefore, appeared to have a receptor-positive form of
      resistance to 1,25-(OH)2D3.
    explanation: >-
      Establishes a historical receptor-positive case that predates the later
      alopecic HNRNPC index lineage.
  - reference: PMID:6313754
    reference_title: Impaired stimulation of 25-hydroxyvitamin D-24-hydroxylase in fibroblasts from a patient with vitamin D-dependent rickets, type II. A form of receptor-positive resistance to 1,25-dihydroxyvitamin D3.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We conclude that impaired induction of 24-hydroxylase in the presence of
      normal receptor binding is evidence for postreceptor resistance to the
      action of 1,25-(OH)2D3.
    explanation: >-
      Defines that case's distinct measured postreceptor phenotype without
      assigning the HNRNPC mechanism.
  - reference: PMID:8287584
    reference_title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VDR from the patient were able to bind 1,25(OH)2D3 but showed no nuclear
      localization resulting in an absence of functional response to
      1,25(OH)2D3.
    explanation: >-
      Shows the contrasting localization phenotype in the alopecic index lineage.
  - 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: >-
      None of them presented alopecia, myopathy, seizures or aminoaciduria.
    explanation: >-
      Documents a major phenotype difference between the cluster and the
      alopecic index case.
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VDDR2b appears to be a very uncommon condition, if indeed it is a distinct
      disorder at all.
    explanation: >-
      The clinical review explicitly leaves the entity boundary unresolved.
  - reference: PMID:38365463
    reference_title: Vitamin D deficiency or resistance and hypophosphatemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Defective 1α hydroxylation of vitamin D, 25 hydroxylation of vitamin D, and
      vitamin D receptor result in VDDR1A, VDDR1B and VDDR2A, respectively
      whereas defective binding of vitamin D to vitamin D response element due
      to overexpression of heterogeneous nuclear ribonucleoprotein and accelerated
      vitamin D metabolism cause VDDR2B and VDDR3, respectively.
    explanation: >-
      Shows that a current review still summarizes VDDR2B as one
      hnRNP-overexpression entity. PARTIAL marks that the cached abstract does not
      resolve the distinct primary strata or establish a causal HNRNPC lesion.
  proposed_experiments:
  - experiment_id: exp_vddr2b_stratum_resolution
    name: Prospective resolution of receptor-positive vitamin D-resistance strata
    description: >-
      Ascertain VDR-coding-negative patients prospectively and record alopecia,
      mineral biochemistry, endogenous VDR localization, calcitriol-responsive
      transcription, HNRNPC abundance, and VDRE occupancy under a common protocol,
      followed by genome and transcriptome sequencing.
    decision_criterion: >-
      Recurrent shared molecular and genetic findings across phenotypic strata
      would support lumping; reproducible stratum-specific mechanisms would
      support splitting the umbrella concept.
- discussion_id: knowledge_gap_vddr2b_hnrnpc_cause
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Index-Case Endogenous VDR Nuclear-Localization Failure
  - pathophysiology#Index-Case HNRNPC C1/C2 Competition at Vitamin D Response Elements
  prompt: >-
    What caused HNRNPC C1/C2 overexpression in the single index case, and how is
    VDRE competition related to the earlier endogenous VDR localization failure?
  rationale: >-
    Reciprocal overexpression and siRNA experiments support HNRNPC C1/C2 as a
    transcriptional actor, but no causal germline lesion or upstream regulatory
    event was identified. The earlier localization result and the later occupancy
    result were not placed in one experimentally tested causal sequence. Germline
    HNRNPC haploinsufficiency has since been associated with a distinct
    neurodevelopmental disorder, not with this rachitic phenotype, so it cannot be
    imported as evidence for VDDR2B inheritance.
  evidence:
  - reference: PMID:17071612
    reference_title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1 and
      hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%,
      respectively; both p < 0.005).
    explanation: >-
      Supports the actor-level mechanism without establishing its upstream cause.
  - reference: PMID:32596195
    reference_title: Diagnosis and Management of Vitamin D Dependent Rickets.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      No gene has yet been identified as the cause of VDDR2b so it is impossible
      to state with precision the number of affected subjects.
    explanation: >-
      Explicitly documents the absent causal-gene assignment.
  - reference: PMID:37541189
    reference_title: HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe 13 individuals with global developmental delay,
      intellectual disability, behavioral abnormalities, and subtle facial
      dysmorphology with heterozygous HNRNPC germline variants.
    explanation: >-
      Demonstrates that established germline HNRNPC disease has a distinct
      neurodevelopmental phenotype and does not validate HNRNPC inheritance for
      this rickets umbrella.
  proposed_experiments:
  - experiment_id: exp_vddr2b_genome_sequencing_hnrnpc_regulation
    name: Causal analysis of HNRNPC regulation in the index lineage
    description: >-
      Perform genome, transcriptome, copy-number, chromatin, and allele-specific
      expression analysis on archived index-lineage material; perturb candidate
      regulatory events and normalize HNRNPC expression to test rescue of VDRE
      occupancy, VDR localization, and calcitriol-responsive transcription.
notes: >-
  This entry intentionally has empty `genetic` and `inheritance` sections: no
  causal gene or mode of inheritance has been demonstrated. HNRNPC is a molecular
  actor only. MONDO:0010931 remains the ontology anchor, but its combined
  HNRNPC/no-alopecia/sporadic framing does not map cleanly onto the unlinked
  primary strata and is not propagated as fact. No prevalence or global
  phenotype frequencies are calculated. The historical index-case phrase
  "HVDRR type III" is not modern CYP3A4-related VDDR3. No disease-specific
  imaging finding or clinical-trial enrollment was verified; both sections are
  explicitly empty.
references:
- reference: PMID:6313754
  title: Impaired stimulation of 25-hydroxyvitamin D-24-hydroxylase in fibroblasts from a patient with vitamin D-dependent rickets, type II. A form of receptor-positive resistance to 1,25-dihydroxyvitamin D3.
- reference: PMID:7586652
  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.
- reference: PMID:8287584
  title: Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
- reference: PMID:12716975
  title: 'Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance.'
- reference: PMID:17071612
  title: 'Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.'
- reference: PMID:21123297
  title: Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling.
- reference: PMID:25506471
  title: The heterodimeric structure of heterogeneous nuclear ribonucleoprotein C1/C2 dictates 1,25-dihydroxyvitamin D-directed transcriptional events in osteoblasts.
- reference: PMID:27672039
  title: Concerted effects of heterogeneous nuclear ribonucleoprotein C1/C2 to control vitamin D-directed gene transcription and RNA splicing in human bone cells.
- reference: PMID:29461981
  title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
- reference: PMID:32596195
  title: Diagnosis and Management of Vitamin D Dependent Rickets.
- reference: PMID:37541189
  title: HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder.
- reference: PMID:36779427
  title: 'Nosology of genetic skeletal disorders: 2023 revision.'
- reference: PMID:38365463
  title: Vitamin D deficiency or resistance and hypophosphatemia.
review_notes: >-
  The 2026 deep review separates the Cauca cluster, the alopecic HNRNPC/VDRE
  index lineage, and other historical receptor-positive cases; it does not infer
  one shared disease mechanism. Primary evidence is used for clinical and cell
  claims, with the 2020 review limited to general mineral physiology and explicit
  uncertainty. The exact index treatment and laboratory values were inspected in
  the full text of PMID:12716975 but are recorded without snippet blocks because
  the sanctioned cache is abstract-only. All reference-cache additions were
  generated with `just fetch-reference`; no cache was hand-edited.

  For current-classification context, the relevant PMID:36779427 nosology table
  was inspected, but the sanctioned cache omits that table; its "HNRNPC-related"
  and "AD?" classification and its single-patient qualification are therefore
  recorded without an invented snippet and are not propagated into `genetic` or
  `inheritance`. The sanctioned PMID:38365463 cache is abstract-only; its full
  VDDR2B discussion was inspected for the separate index/Cauca account,
  less-well-defined status, and lack-of-replication observation, again without a
  purportedly cache-verifiable quotation. PMID:38706696 was excluded because its
  summary table appears to assign VDR to VDDR2B; PMID:39893280 has no
  VDDR2B-specific abstract content; PMID:33438017 is VDR/type-2A focused; and
  PMID:36475338/Endotext are broad, redundant summaries.

  The shared Vitamin D-Dependent Rickets grouping is corrected in this review.
  The reciprocal note in `Vitamin_D-Dependent_Rickets_Type_2A.yaml` still says
  type 2B has the same clinical phenotype with a structurally normal receptor;
  parent scope reserves that file for the immediate next campaign target, so the
  stale statement is documented here rather than changed in this review.
📚

References & Deep Research

References

13
PMID:6313754
Impaired stimulation of 25-hydroxyvitamin D-24-hydroxylase in fibroblasts from a patient with vitamin D-dependent rickets, type II. A form of receptor-positive resistance to 1,25-dihydroxyvitamin D3.
No top-level findings curated for this source.
PMID:7586652
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.
No top-level findings curated for this source.
PMID:8287584
Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene.
No top-level findings curated for this source.
PMID:12716975
Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: a cause of vitamin D resistance.
No top-level findings curated for this source.
PMID:17071612
Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein.
No top-level findings curated for this source.
PMID:21123297
Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling.
No top-level findings curated for this source.
PMID:25506471
The heterodimeric structure of heterogeneous nuclear ribonucleoprotein C1/C2 dictates 1,25-dihydroxyvitamin D-directed transcriptional events in osteoblasts.
No top-level findings curated for this source.
PMID:27672039
Concerted effects of heterogeneous nuclear ribonucleoprotein C1/C2 to control vitamin D-directed gene transcription and RNA splicing in human bone cells.
No top-level findings curated for this source.
PMID:29461981
CYP3A4 mutation causes vitamin D-dependent rickets type 3.
No top-level findings curated for this source.
PMID:32596195
Diagnosis and Management of Vitamin D Dependent Rickets.
No top-level findings curated for this source.
PMID:37541189
HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder.
No top-level findings curated for this source.
PMID:36779427
Nosology of genetic skeletal disorders: 2023 revision.
No top-level findings curated for this source.
PMID:38365463
Vitamin D deficiency or resistance and hypophosphatemia.
No top-level findings curated for this source.