Hedgehog Pathway Activation Disorders (Hedgehog-Driven Neoplasms)

name: Hedgehog Pathway Activation Disorders
display_name: Hedgehog Pathway Activation Disorders (Hedgehog-Driven Neoplasms)
creation_date: "2026-08-02T01:01:07Z"
description: >-
  The Hedgehog pathway activation disorders are neoplastic diseases driven by
  ligand-independent, constitutive activation of Hedgehog signaling. A genetic
  lesion removes the pathway's tonic restraint — either loss of function of a
  negative regulator (the tumor suppressors PTCH1, PTCH2, or SUFU) or gain of
  function of the positive transducer SMO — and both directions converge on the
  same net state: constitutive Smoothened activity and constitutive GLI
  transcriptional output driving Hedgehog-dependent proliferation. The class spans
  germline tumor-predisposition syndromes and their sporadic somatic counterparts,
  and is the mechanistic basis for Smoothened-inhibitor therapy.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
- SHARED_TREATMENT_RESPONSE
grouping_rationale: >-
  Grouped on a shared developmental signaling pathway, in the same spirit as the
  MONDO RASopathy class. The practical payoff is therapeutic and is the reason
  the grouping earns its place rather than being a restatement of tumor histology:
  the Smoothened inhibitors vismodegib and sonidegib are effective on the basis of
  pathway membership, but only for lesions upstream of the drug target —
  SUFU-mutant tumours are intrinsically resistant because the lesion sits
  downstream of SMO. That distinction is a pure mechanism-graph fact, invisible
  to any histology- or organ-based classification, and it is why per-member
  differentiating mechanisms record the position of each lesion in the cascade.
  Members are kept as separate Disease entries because they differ in the mutated
  node, in germline versus somatic origin, and in tumour type (basal cell
  carcinoma versus medulloblastoma).

  Criteria are NECESSARY_AND_SUFFICIENT: constitutive, ligand-independent
  activation of the SMO-GLI axis both characterizes every member and identifies
  candidate members not yet listed. This is appropriate here — unlike the
  aspirational groupings in this set — because the defining lesion is a discrete
  molecular state rather than a partially-curated clinical family. Deliberately
  out of scope: Hedgehog LOSS-of-signaling disorders (holoprosencephaly and the
  related midline defects), which perturb the same pathway in the opposite
  direction and belong in a sibling class, not this one.
membership_criteria:
- description: >-
    A disorder is a Hedgehog pathway activation disorder if and only if its
    pathophysiology conforms to the hedgehog pathway activation module —
    ligand-independent constitutive Smoothened activity and GLI transcriptional
    output arising from loss of a pathway negative regulator or gain of function
    of SMO.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: hedgehog_pathway_activation
    description: >-
      Conforms to the hedgehog_pathway_activation module at one or more nodes.
members:
- member: Gorlin Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The germline umbrella member (nevoid basal cell carcinoma syndrome):
      heterozygous PTCH1 loss with somatic second-hit inactivation releases
      Smoothened across many tissues, giving multiple early-onset basal cell
      carcinomas, odontogenic keratocysts, palmar/plantar pits, and
      medulloblastoma risk — the syndrome in which the pathway's role in human
      cancer was first established.
    gene:
      preferred_term: PTCH1
      term:
        id: hgnc:9585
        label: PTCH1
  notes: >-
    Umbrella entry. The two gene-scoped entries below (PTCH1-related and
    SUFU-related nevoid basal cell carcinoma syndrome) are its molecular
    subdivisions and are listed as separate members because dismech curates them
    as separate Disease entries; they are not independent diseases from this one.
- member: PTCH1-related nevoid basal cell carcinoma syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The receptor-level, drug-sensitive branch: PTCH1 loss sits directly
      upstream of Smoothened, so the constitutive signal is blockable by SMO
      inhibitors — this is the genotype in which vismodegib and sonidegib work.
      Carries the higher odontogenic keratocyst burden and lower medulloblastoma
      risk relative to the SUFU branch.
    gene:
      preferred_term: PTCH1
      term:
        id: hgnc:9585
        label: PTCH1
    module: hedgehog_pathway_activation#Loss of Hedgehog Pathway Negative Regulation
- member: SUFU-related nevoid basal cell carcinoma syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The downstream, drug-resistant branch and the clinically decisive
      distinction in this class: SUFU acts below Smoothened on GLI directly, so
      SMO inhibitors cannot suppress the signal. Confers a markedly higher
      medulloblastoma risk and fewer jaw keratocysts than the PTCH1 branch,
      which is why genotype rather than syndrome name should drive surveillance
      and therapy.
    gene:
      preferred_term: SUFU
      term:
        id: hgnc:16466
        label: SUFU
    module: hedgehog_pathway_activation#Loss of Hedgehog Pathway Negative Regulation
- member: Basal Cell Carcinoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The sporadic somatic counterpart of Gorlin syndrome, and the member that
      shows the mechanism is not confined to germline disease: the great majority
      of sporadic basal cell carcinomas carry somatic PTCH1 loss or activating
      SMO mutation, typically UV-signature. Acquired SMO resistance mutations
      emerging on vismodegib are the therapeutic mirror image of the SUFU branch.
    gene:
      preferred_term: SMO
      term:
        id: hgnc:11119
        label: SMO
    module: hedgehog_pathway_activation#Constitutive Smoothened Activity
- member: Medulloblastoma, SHH-Activated
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The non-cutaneous member, and the one where the pathway defines a formal
      WHO molecular subgroup rather than merely explaining a tumour: SHH
      activation in cerebellar granule neuron precursors, arising from PTCH1,
      SMO, or SUFU lesions or GLI2/MYCN amplification, with TP53 status further
      stratifying outcome.
    module: hedgehog_pathway_activation#Constitutive GLI Transcriptional Output
notes: >-
  Curated as the dismech-side counterpart of proposed MONDO node #7 in
  docs/reports/mondo-mechanism-classification-proposal-2026-08-01.md. No
  `mappings:` block is given because MONDO has no term for this class: searches
  of MONDO labels, synonyms, and definition text for "hedgehog", "smoothened",
  and "sonic hedgehog" return only two veterinary hits about the animal
  (`ataxia, middle-African hedgehog`; `cardiomyopathy, hedgehogs`). A mapping
  should be added if and when the proposed term is minted.

  Because the criteria are NECESSARY_AND_SUFFICIENT, `just check-groupings` will
  report candidate members — any dismech disorder conforming to the module but
  not listed here. Strong uncurated candidates to expect as coverage grows:
  Curry-Jones syndrome (mosaic SMO), Hedgehog-driven rhabdomyosarcoma subsets,
  and ameloblastoma with SMO mutation.