Rachitic and Osteomalacic Disorders

name: Rachitic and Osteomalacic Disorders
creation_date: "2026-08-27T00:00:00Z"
description: >-
  The broad union of curated disorders that reach a single rate-limiting
  failure — hydroxyapatite is not deposited at the mineralization front —
  regardless of the route by which they get there. In growing bone that failure
  presents as rickets, because the hypertrophic zone of the growth plate expands
  when terminal chondrocyte apoptosis is impaired; in the mature skeleton the
  same lesion presents as osteomalacia alone. The members span all three
  mechanistically incompatible entry arms of the
  `defective_skeletal_mineralization` module: calciopenic (low calcitriol
  signalling or low dietary calcium, with secondary hyperparathyroidism),
  phosphopenic (renal phosphate wasting with normal parathyroid hormone,
  FGF23-driven or a direct tubular transport defect), and inhibitor excess
  (failure to clear inorganic pyrophosphate). They are grouped, not merged,
  precisely because those arms are diagnostically and therapeutically opposite
  at the bedside while converging on one histological endpoint.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on a shared terminal mechanism and its shared skeletal expression, NOT
  on a shared pathway, gene family, or treatment. The distinction matters here
  more than in most groupings: the calciopenic arm is treated by supplying
  calcium or active vitamin D, the phosphopenic arm by supplying phosphate or
  blocking FGF23 (burosumab), and the inhibitor-excess arm by enzyme replacement
  (asfotase alfa) — giving a member of one arm the therapy for another is
  ineffective or harmful. Parathyroid hormone separates the first two arms at the
  bedside (elevated in the calciopenic arm, normal in the phosphopenic arm), and
  serum calcium may be high rather than low in the inhibitor-excess arm. Merging
  the members into one Disease entry would therefore assert a single causal chain
  across three mutually exclusive pathophysiologies.

  This grouping exists because "rickets" is a dual-coded disease-like phenotype
  (HP:0002748 and MONDO:0005520), not a mechanism. The KB's answer to that
  concept is deliberately three artifacts rather than one: the
  `defective_skeletal_mineralization` module carries the mechanism, the narrower
  `Vitamin D-Dependent Rickets` grouping carries the named calciopenic Mendelian
  series, and this grouping carries the union across arms. No `Rickets` Disease
  entry is created, and none should be.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005520
      label: rickets
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0005520 is the general rickets disease class; this grouping is a
      specific curated union of the etiologies that produce it, so the MONDO term
      is the broader concept. `skos:exactMatch` would be wrong in both
      directions. MONDO flags its own `rickets` EXACT synonym with the
      `MONDO:ambiguous` source tag and axiomatizes the class around decreased
      circulating vitamin D (`relationship: RO:0004029 HP:0100512`) while
      subsuming the hypophosphatemic branch, which is explicitly vitamin
      D-resistant with normal 25-hydroxyvitamin D — so an exact mapping would
      import an axiom that this grouping's own members contradict. Conversely
      this grouping is not strictly narrower either: it admits hypophosphatasia,
      which MONDO places under inborn errors of metabolism rather than under
      rickets, and Cadmium Poisoning, whose skeletal disease is osteomalacia in
      the mature skeleton. `broadMatch` records the cross-reference without
      asserting either subsumption, and deliberately does not retire
      MONDO:0005520 from the curation queue while monarch-initiative/dismech#8970
      (the prioritizer's ranking of dual-coded phenotype umbrellas) is open.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Recorded CONSISTENT for the `broadMatch` predicate specifically, which
        asserts only a cross-reference and not subsumption in either direction;
        the enum has no value for the partial correspondence described here.
        Most members are is-a descendants of MONDO:0005520 through its
        hypophosphatemic and vitamin D-dependent branches, and renal
        osteodystrophy (MONDO:0006946, the CKD-Mineral Bone Disorder anchor) is
        also placed beneath it. Hypophosphatasia (MONDO:0018570) is NOT placed
        under rickets in MONDO despite rickets being its cardinal skeletal
        finding, which is itself the clearest ontology-level evidence that the
        rachitic phenotype crosscuts the disease hierarchy. Nutritional rickets —
        the form MONDO's own definition of the class describes — has no DisMech
        Disease entry yet and is therefore not a listed member; that is a
        curation gap, not a boundary decision.
membership_criteria:
- description: >-
    A disorder is a rachitic or osteomalacic disorder if and only if it conforms
    to the defective skeletal mineralization module — that is, some
    pathophysiology node of the entry declares conformance to the module's shared
    endpoint, impaired hydroxyapatite deposition at the mineralization front,
    reached through any of the three entry arms. The route is deliberately not
    constrained: route-specific membership is what the narrower groupings are
    for.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front
    description: >-
      Conforms to the defective skeletal mineralization module (failure to
      deposit hydroxyapatite at the mineralization front).
  evidence:
  - reference: PMID:37427438
    reference_title: 'Approach to Rickets: Is It Calciopenic or Phosphopenic?'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rickets is a childhood disorder of decreased mineralization of bone tissue.
      It is either calciopenic or phosphopenic, according to the deficient
      mineral.
    explanation: >-
      States the shared endpoint (decreased mineralization of bone tissue) and
      the mineral-deficiency axis along which two of the grouping's three entry
      arms are separated. Evidence source is OTHER because this is a review
      article rather than a primary study.
  - reference: PMID:26893260
    reference_title: Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In hypophosphatasia, extracellular accumulation of TNSALP natural
      substrates includes inorganic pyrophosphate, an inhibitor of
      mineralization, which explains the dento-osseous and arthritic
      complications featuring tooth loss, rickets or osteomalacia, and calcific
      arthopathies.
    explanation: >-
      Places the third entry arm inside the boundary: a mineralization-inhibitor
      defect with adequate mineral substrate still produces rickets or
      osteomalacia, so the criterion cannot be written in terms of mineral
      deficiency alone. Evidence source is OTHER because this is a review
      article.
  notes: >-
    `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 the anchor above documents the intended endpoint but does not
    narrow evaluation. That is harmless for this grouping, which deliberately
    accepts conformance at any node of the module, but it is the same limitation
    that forced the arm-level exclusion in `Vitamin_D-Dependent_Rickets` to be
    written as prose.
- description: >-
    Every member's defective mineralization is expressed clinically as rickets in
    the growing skeleton, osteomalacia in the mature skeleton, or both, depending
    on the age at which the mineralization defect is active. This is a necessary
    consequence of membership and is what makes the grouping clinically
    recognizable rather than purely mechanistic.
  criteria_semantics: NECESSARY
  notes: >-
    Deliberately left as prose with no structured `logic` block. Written as an OR
    over `HAS_PHENOTYPE` HP:0002748 (Rickets) and HP:0002749 (Osteomalacia), this
    criterion would report a false contradiction for CKD-Mineral Bone Disorder,
    which curates neither HP term today even though renal osteodystrophy is the
    textbook osteomalacic disorder. That is a missing annotation on the member
    entry, not a boundary violation, and encoding it as structured logic would
    convert a curation gap into a reported contradiction. Restore the structured
    form once the annotation is added.
members:
- member: Vitamin D-Dependent Rickets
  member_type: GROUPING
  differentiating_mechanisms:
  - description: >-
      The nested vitamin D-axis Mendelian series (types 1A, 1B, 2A, 2B, 3), in
      which rickets arises because vitamin D activation, signaling, or metabolite
      handling fails while dietary intake and sunlight exposure are adequate. It
      is included as a single GROUPING member rather than by re-listing its five
      gene-level entries, which are the members of that grouping. It is the only
      arm of this union whose members are defined by a shared signalling axis
      rather than by a shared physiological deficit. Types 1A, 1B, 2A and 3 reach
      the endpoint through calciopenic physiology; the nested grouping
      deliberately does NOT assign type 2B to that arm, because the Cauca stratum
      had low-normal calcium with normal phosphate and its intermediate route is
      not established.
    module: defective_skeletal_mineralization#Calciopenic Substrate Deficiency
    evidence:
    - reference: PMID:37427438
      reference_title: 'Approach to Rickets: Is It Calciopenic or Phosphopenic?'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Vitamin D-dependent rickets classification is made according to genetic
        abnormalities of enzymes that are involved in vitamin D metabolism.
      explanation: >-
        Confirms that the nested series is delimited by lesions in vitamin D
        metabolism, which is what distinguishes it from the other members of this
        union. Evidence source is OTHER because this is a review article.
  notes: >-
    Nutritional vitamin D-deficiency rickets is NOT covered by this nested
    grouping and has no Disease entry; it shares the calciopenic arm but is the
    common acquired disorder the hereditary series is defined against.
- member: X-Linked Hypophosphatemia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The prototype of the phosphopenic arm and its commonest hereditary cause:
      loss of PHEX function raises circulating FGF23, which both wastes phosphate
      in the proximal tubule and suppresses calcitriol synthesis. Parathyroid
      hormone is characteristically normal and 25-hydroxyvitamin D is normal, so
      the disease is vitamin D-resistant in the trivial sense that vitamin D was
      never the problem — the feature that most sharply separates this member
      from the vitamin D-dependent series.
    gene:
      preferred_term: PHEX
      term:
        id: hgnc:8918
        label: PHEX
    module: defective_skeletal_mineralization#Phosphopenic Substrate Deficiency
    evidence:
    - reference: PMID:38066669
      reference_title: Impaired Growth Plate Maturation in XLH Is due to Both Excess FGF23 and Decreased 1,25-Dihydroxyvitamin D Signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This increase in FGF23 impairs activation of vitamin D and attenuates
        renal phosphate reabsorption, leading to rickets.
      explanation: >-
        States the FGF23-driven route from renal phosphate wasting to rickets
        that defines this member's arm.
- member: Hypophosphatasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The sole member entering through the inhibitor-excess arm, and
      biochemically the mirror image of the other two: mineral substrate supply
      is adequate and serum calcium may be HIGH rather than low, but deficient
      tissue-nonspecific alkaline phosphatase fails to hydrolyse extracellular
      inorganic pyrophosphate, which blocks hydroxyapatite crystal growth. It is
      also the member MONDO does not place under rickets at all.
    gene:
      preferred_term: ALPL
      term:
        id: hgnc:438
        label: ALPL
    module: defective_skeletal_mineralization#Mineralization Inhibitor Excess
    evidence:
    - reference: PMID:28238808
      reference_title: 'Hypophosphatasia: An overview For 2017.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Among them is inorganic pyrophosphate (PPi), a potent inhibitor of
        mineralization.
      explanation: >-
        Identifies the accumulating inhibitor that defines this member's entry
        arm. Evidence source is OTHER because this is a review article.
- member: CKD-Mineral Bone Disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The only member whose mineral disturbance is acquired, systemic and
      multi-axis rather than a single lesion: falling renal function retains
      phosphate, lowers calcitriol synthesis and drives secondary
      hyperparathyroidism together. It therefore does not sit cleanly in either
      single-lesion arm: the calcitriol deficit places it on the calciopenic
      arm, while its phosphate disturbance is retention with elevated PTH, not
      the renal phosphate wasting with normal PTH that defines the phosphopenic
      arm in this grouping's rationale. It is also the
      only member in which mineralization failure competes with high-turnover
      bone disease and extraskeletal calcification for the clinical picture.
    module: defective_skeletal_mineralization#Calciopenic Substrate Deficiency
    evidence:
    - reference: PMID:32961953
      reference_title: 'Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or
        vitamin D; abnormalities in bone turnover, mineralization, volume, linear
        growth, or strength; and/or vascular or other soft tissue calcification.
      explanation: >-
        Documents that the defining abnormality set spans mineralization together
        with the calcium, phosphate, PTH and vitamin D axes at once, which is
        what makes this member multi-axis rather than assignable to one arm.
  notes: >-
    This entry curates neither HP:0002748 (Rickets) nor HP:0002749 (Osteomalacia)
    today, despite osteomalacia being a recognized histological subtype of renal
    osteodystrophy. That missing annotation is why the second membership-criteria
    block is prose rather than structured logic; adding it is a discrete follow-up.
- member: Cystinosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Reaches the phosphopenic arm through generalized proximal tubular
      dysfunction (renal Fanconi syndrome) caused by lysosomal cystine
      accumulation, rather than through an FGF23 signal. Because the tubular
      lesion wastes bicarbonate and calcium alongside phosphate, the rachitic
      biochemistry is mixed rather than purely phosphopenic — the reason this
      member is not simply an XLH analogue.
    gene:
      preferred_term: CTNS
      term:
        id: hgnc:2518
        label: CTNS
    module: defective_skeletal_mineralization#Phosphopenic Substrate Deficiency
    evidence:
    - reference: PMID:20301574
      reference_title: Cystinosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Characterized in untreated infants/children by renal Fanconi syndrome, poor
        growth, hypophosphatemic/calcipenic rickets, impaired glomerular function
      explanation: >-
        Names the mixed hypophosphatemic/calciopenic character of the rickets in
        this member, distinguishing it from the pure FGF23-driven phosphopenic
        members.
- member: Tyrosinemia Type I
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Reaches the phosphopenic arm through a Fanconi-type tubulopathy that is
      itself secondary to an intermediary-metabolism block: succinylacetone
      accumulating from FAH deficiency is toxic to the proximal tubule. It is
      therefore the member in which rickets is furthest downstream of the primary
      lesion, and the one in which treating the metabolic block (nitisinone)
      rather than the mineral deficit is the definitive therapy.
    gene:
      preferred_term: FAH
      term:
        id: hgnc:3579
        label: FAH
    module: defective_skeletal_mineralization#Phosphopenic Substrate Deficiency
    evidence:
    - reference: PMID:20301688
      reference_title: Tyrosinemia Type I.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        liver dysfunction and renal tubular dysfunction associated with growth
        failure and rickets.
      explanation: >-
        Links the renal tubular dysfunction of this member to rickets, the route
        by which it enters the phosphopenic arm.
- member: Fanconi-Bickel Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Reaches the phosphopenic arm through a Fanconi-type tubulopathy caused by
      loss of the GLUT2 facilitative glucose transporter, so the tubular defect is
      a transport lesion rather than a toxic one, and it is accompanied by
      hepatorenal glycogen accumulation and dysregulated glucose homeostasis that
      the other Fanconi-route members do not share.
    gene:
      preferred_term: SLC2A2
      term:
        id: hgnc:11006
        label: SLC2A2
    module: defective_skeletal_mineralization#Phosphopenic Substrate Deficiency
    evidence:
    - reference: PMID:39548873
      reference_title: Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        70% exhibited both developmental delay and hypophosphatemic rickets, and
        68.4% experienced growth retardation.
      explanation: >-
        Quantifies hypophosphatemic rickets in a large cohort of this member,
        establishing it as a core rather than incidental feature.
- member: Fibrous Dysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The mosaic, acquired-in-somatic-tissue route into the phosphopenic arm:
      post-zygotic activating GNAS variants produce fibro-osseous lesions whose
      abnormal osteoprogenitors secrete FGF23, so phosphate wasting is
      proportional to skeletal disease burden rather than constitutive. This is
      the member in which the phosphopenic lesion is dose-dependent and can be
      subclinical, and in which the rachitic disease is superimposed on a
      structurally abnormal skeleton.
    gene:
      preferred_term: GNAS
      term:
        id: hgnc:4392
        label: GNAS
    module: defective_skeletal_mineralization#Phosphopenic Substrate Deficiency
    evidence:
    - reference: PMID:31037426
      reference_title: 'Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nearly 50% of patients with FD/MAS exhibit some degree of renal phosphate
        wasting
      explanation: >-
        Establishes renal phosphate wasting as a common but not universal feature
        of this member, which is the burden-dependence that differentiates it
        from the constitutive hereditary FGF23 disorders.
- member: Cadmium Poisoning
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The only environmentally acquired member, and the one whose skeletal
      disease is characteristically osteomalacia in the mature skeleton rather
      than rickets: chronic cadmium exposure damages the proximal tubule and
      causes phosphate wasting, producing the itai-itai disease described in
      Japan. It is the clearest demonstration that the grouping's endpoint is
      age-dependent in presentation, and that the entry arm can be an exposure
      rather than a genotype.
    module: defective_skeletal_mineralization#Phosphopenic Substrate Deficiency
    evidence:
    - reference: PMID:19341754
      reference_title: Historical perspectives on cadmium toxicology.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a bone disease with fractures and severe pain, the itai-itai disease, a
        form of Cd-induced renal osteomalacia, was identified in Japan.
      explanation: >-
        Identifies this member's skeletal disease as renal osteomalacia of
        environmental origin, the mature-skeleton expression of the grouping's
        shared endpoint.
notes: >-
  Naming. This is the broad artifact requested as `Rickets_and_Osteomalacia` /
  `Rachitic_Disorders` in monarch-initiative/dismech#8995. It is named for
  disorders rather than for the phenotype pair so that it cannot be mistaken for
  a Disease entry, and it names both expressions because members such as Cadmium
  Poisoning present with osteomalacia and no rickets.

  Relationship to the other rickets artifacts. The mechanism lives in
  `kb/modules/defective_skeletal_mineralization.yaml`; this grouping is a union
  over that module's conformers and adds no mechanism of its own. The narrower
  `Vitamin_D-Dependent_Rickets` grouping is nested here as a single GROUPING
  member, so its five gene-level entries are deliberately NOT re-listed as direct
  members — the same nesting convention `Lysosomal_Storage_Disorders` uses. A
  disorder may be a member here and a member of a narrower rachitic grouping at
  the same time; that is the point of the nesting.

  Deliberate non-members. Nutritional (vitamin D-deficiency) and dietary
  calcium-deficiency rickets — the commonest forms worldwide and the ones
  MONDO:0005520's own definition describes — are absent because no Disease entry
  exists for them yet (monarch-initiative/dismech#8995 item 3). Tumour-induced
  osteomalacia, and iron-carbohydrate (ferric carboxymaltose) induced
  hypophosphatemia, are likewise absent for want of entries; all three are
  expected members once curated, and none is excluded on boundary grounds.
  Separately, `FGFR2-Related_Bent_Bone_Dysplasia`, `Craniometaphyseal_Dysplasia`,
  `Gnathodiaphyseal_Dysplasia` and
  `Short_Stature_Amelogenesis_Imperfecta_And_Skeletal_Dysplasia_With_Scoliosis`
  each considered conformance to the mineralization module and each recorded a
  reasoned decision to decline it; they are correctly outside this union and
  should not be added without revisiting those decisions.

  VDDR1C is not a member of any rachitic grouping here. The reported
  `CYP4A22`-associated "vitamin D-dependent rickets type 1C" (PMID:38847469) was
  retracted (retraction notice PMID:39873438, preceded by an expression of
  concern PMID:39569444). No entry should be created for it, and a deep-research
  report that surfaces VDDR1C as an established entity is itself a reason to
  distrust the rest of that report.

  Because the membership criterion is NECESSARY_AND_SUFFICIENT over module
  conformance, any future disorder that declares `conforms_to` against
  `defective_skeletal_mineralization` will be reported by `just check-groupings`
  as a candidate member. That is intended: it makes the union self-maintaining
  rather than a snapshot.