Vitamin D-Dependent Rickets (VDDR)

name: Vitamin D-Dependent Rickets
display_name: Vitamin D-Dependent Rickets (VDDR)
creation_date: "2026-08-19T00:00:00Z"
description: >-
  The vitamin D-dependent rickets (VDDR) are a small named series in which
  rickets arises because vitamin D activation, signaling, or metabolite handling
  fails while dietary intake and sunlight exposure are adequate. Types 1A, 1B,
  2A, and 3 have established causal genes. Type 2B is an unresolved
  receptor-positive/postreceptor umbrella: HNRNPC C1/C2 response-element
  competition was demonstrated only in one alopecic index lineage and has not
  been connected to the large Cauca cluster or other historical receptor-positive
  cases. The members converge on defective skeletal mineralization but diverge
  sharply in biochemistry, causal certainty, and treatment response, which is why
  they are grouped rather than merged.
grouping_basis:
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on a shared pathway rather than a shared gene family: the members are
  united by lesions at different points of one signalling axis, not by homology.
  They are deliberately kept as separate Disease entries because the differences
  are diagnostically and therapeutically decisive rather than cosmetic.
  Calcitriol is low or inappropriately normal in type 1A, variable and often
  normal or high despite very low 25-hydroxyvitamin D in type 1B, low in type 3,
  and elevated in type 2A; both principal reported type 2B strata also had
  elevated calcitriol, without establishing a universal umbrella pattern.
  25-hydroxyvitamin D is normal or high in type 1A but low in types 1B and 3.
  Type 1A typically responds to calcitriol or alfacalcidol replacement. Type 1B
  treatment is variable, often using sustained supraphysiologic parent vitamin D;
  some patients need calcitriol or can respond to calcifediol. Treatment response
  in type 2A is heterogeneous: calcium bypass is often required, but some patients
  respond to very high-dose calciferols or active analogs. The single type 2B
  index patient was hypocalcemic, and rachitic bone
  disease was corrected during a high-dose calcitriol regimen that also included
  calcium; that n=1 observation cannot define treatment for the whole umbrella.
  Alopecia is not unique to type 2A: it was present in the HNRNPC-linked
  type 2B index child but absent from the Cauca cluster. Merging the members into
  one entry would force a single causal chain across synthetic, receptor,
  unresolved postreceptor, and catabolic mechanisms that are not equivalent.

  The name is a double misnomer that the grouping preserves rather than corrects,
  because it is the term the literature and the ontologies use: "dependent"
  denotes dependence on the active hormone rather than on dietary vitamin D, and
  types 2A and 2B are vitamin D-RESISTANT, the mechanistic inverse of types 1A and
  1B. Curators should read the type number, not the series name.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0024299
      label: vitamin D-dependent rickets
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO vitamin D-dependent rickets
      class. Note that MONDO:0010810 (type 1B) is asserted under
      MONDO:0009924 (type 1) and so falls within this class, even though its label
      stem is "vitamin D hydroxylation-deficient rickets" rather than "vitamin
      D-dependent rickets".
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        All five listed members are is-a descendants of MONDO:0024299. The
        intermediate MONDO grouping terms MONDO:0009924 (type 1) and
        MONDO:0019642 (type 2) are not separately curated as DisMech entries;
        they are ontology-internal groupings over the gene-level members listed
        here.
membership_criteria:
- description: >-
    A disorder belongs to the vitamin D-dependent rickets if it produces rickets
    through disrupted vitamin D activation, signaling, or metabolite handling in
    the presence of adequate vitamin D supply: it has a pathophysiology node
    conforming to the impaired-mineralization endpoint of the defective skeletal
    mineralization module AND it presents with rickets. This is a necessary
    endpoint criterion; the vitamin D-axis scope in this description distinguishes
    the named series from other mechanistic routes to the same endpoint.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front
      description: >-
        Has a pathophysiology node conforming to the shared impaired-mineralization
        endpoint of the defective skeletal mineralization module.
    - criterion_predicate: HAS_PHENOTYPE
      phenotype_term:
        preferred_term: Rickets
        term:
          id: HP:0002748
          label: Rickets
      description: Presents with rickets.
- description: >-
    A disorder is NOT a vitamin D-dependent rickets if its rickets arises from
    renal phosphate wasting with normal parathyroid hormone (the hypophosphatemic
    rickets, which enter the defective skeletal mineralization module through its
    phosphopenic trigger arm), or from failure to clear a mineralization inhibitor
    (hypophosphatasia, which enters through the inhibitor-excess arm). Established
    VDDR entities generally reach the endpoint through calciopenic physiology, but
    the Cauca type 2B stratum had low-normal calcium and normal phosphate; its
    intermediate route is not established and is not assigned to that arm here.
  criteria_semantics: NECESSARY
  notes: >-
    Deliberately left as prose with no structured `logic` block. The exclusion is
    arm-level, and `CONFORMS_TO_MODULE` is evaluated on the module STEM only -
    `_eval_leaf` in `src/dismech/groupings.py` splits the reference at "#" and
    discards the node anchor - so a leaf naming
    `defective_skeletal_mineralization#Phosphopenic Substrate Deficiency` is
    indistinguishable from one naming any other node of the same module. Written
    as a `NOT` over that leaf, this criterion evaluated to NOT_SATISFIED for all
    five members, reporting five false contradictions, because every member does
    conform to the module (through a different arm). Restore the structured form
    if and when the evaluator honours the node anchor.
members:
- member: Vitamin D-Dependent Rickets Type 1A
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Loss of renal 1-alpha-hydroxylase (CYP27B1): the last activation step fails,
      so 25-hydroxyvitamin D is normal or high while calcitriol is low or
      inappropriately normal. It typically responds to replacement with
      calcitriol or alfacalcidol.
    gene:
      preferred_term: CYP27B1
      term:
        id: hgnc:2606
        label: CYP27B1
    module: defective_skeletal_mineralization#Calciopenic Substrate Deficiency
- member: Vitamin D-Dependent Rickets Type 1B
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Impaired activity of CYP2R1, a principal hepatic 25-hydroxylase, reduces
      25-hydroxyvitamin D; calcitriol is variable and can remain normal or high
      despite very low substrate, so the biochemistry can mimic nutritional
      deficiency. Full rickets is usually biallelic and recessive, while
      dosage-dependent heterozygous effects occur in some alleles and families.
      Treatment is variable: sustained supraphysiologic parent vitamin D is often
      used, some patients need calcitriol or can respond to calcifediol, and
      relapse after dose reduction has been reported among responders.
    gene:
      preferred_term: CYP2R1
      term:
        id: hgnc:20580
        label: CYP2R1
    module: defective_skeletal_mineralization#Calciopenic Substrate Deficiency
- member: Vitamin D-Dependent Rickets Type 2A
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Vitamin D receptor resistance (VDR): hormone synthesis is intact and
      calcitriol is ELEVATED, but target-tissue response is impaired and
      allele-dependent. Zinc-finger variants typically preserve ligand binding
      while impairing or abolishing VDRE binding. Alopecia in a subset reflects a
      hormone-independent role of the receptor in the hair follicle and is not
      corrected by normalizing calcium. Calcium bypass is often required, while
      response to pharmacologic doses of vitamin D analogs varies by allele and
      clinical severity.
    gene:
      preferred_term: VDR
      term:
        id: hgnc:12679
        label: VDR
    phenotype_term:
      preferred_term: Alopecia
      term:
        id: HP:0001596
        label: Alopecia
    module: defective_skeletal_mineralization#Calciopenic Substrate Deficiency
- member: Vitamin D-Dependent Rickets Type 2B
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An unresolved receptor-positive/postreceptor umbrella with no established
      causal gene or inheritance. A single alopecic index lineage showed normal
      VDR coding sequence, cell-contextual receptor dysfunction, and overexpressed
      HNRNPC C1/C2 competition with VDR-RXR at response elements. The more-than-200
      child Cauca cluster had normal VDR cDNA, no alopecia, and no HNRNPC study;
      other historical receptor-positive cases also show distinct cellular
      readouts. It satisfies the grouping boundary by vitamin D-resistant rickets,
      not by one demonstrated genotype or universal HNRNPC mechanism.
    module: defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front
- member: Vitamin D-Dependent Rickets Type 3
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Gain of catabolic function (heterozygous CYP3A4 p.Ile301Thr): synthesis and
      reception are intact, but vitamin D metabolites are cleared too rapidly.
      This dominantly acting mechanism makes conventional dosing inadequate;
      sufficiently high calcitriol or vitamin D dosing can nevertheless maintain
      normal mineral biochemistry in reported patients.
    gene:
      preferred_term: CYP3A4
      term:
        id: hgnc:2637
        label: CYP3A4
    module: defective_skeletal_mineralization#Calciopenic Substrate Deficiency
notes: >-
  Scope boundary. The hereditary HYPOPHOSPHATEMIC rickets (X-linked
  hypophosphatemia, autosomal dominant and recessive forms, hereditary
  hypophosphatemic rickets with hypercalciuria) are NOT members: they reach the
  same mineralization failure through renal phosphate wasting with normal
  parathyroid hormone, and they are vitamin D-resistant in the trivial sense that
  vitamin D was never the problem. Nutritional rickets is likewise not a member -
  it is the common acquired disorder these entities are defined against. All of
  them conform to `defective_skeletal_mineralization`, which is the level at which
  they are genuinely alike. Type 2B membership preserves the conventional MONDO
  and literature grouping while its lump-versus-split boundary remains open; the
  grouping must not be read as evidence that all receptor-positive cases share
  HNRNPC dysregulation.