Mastocytosis (cutaneous and systemic)

name: Mastocytosis
display_name: Mastocytosis (cutaneous and systemic)
creation_date: "2026-08-27T00:00:00Z"
description: >-
  Mastocytosis is a clonal myeloid neoplasm in which abnormal mast cells
  accumulate in one or more organ systems, most often driven by a somatic
  activating KIT mutation (usually D816V in adults, and D816V or an exon 8/9
  extracellular-domain variant in children). Two mechanisms recur across the
  whole spectrum and account for its clinical shape: KIT-driven clonal mast
  cell proliferation and accumulation, which produces the infiltrative
  manifestations (skin lesions, marrow involvement, organomegaly, cytopenias),
  and mast cell mediator release, which produces the episodic manifestations
  (flushing, pruritus, gastrointestinal symptoms, anaphylaxis). The WHO divides
  the disease into cutaneous mastocytosis, several forms of systemic
  mastocytosis, and mast cell sarcoma; the cutaneous/systemic boundary is drawn
  by extracutaneous involvement, and the systemic forms range from indolent
  disease with near-normal life expectancy to mast cell leukemia.
grouping_basis:
- SHARED_MECHANISM
- SHARED_GENE_FAMILY
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on a shared driver and a shared final common pathway: every member is
  a clonal mast cell disease in which an activating KIT mutation drives mast
  cell proliferation and accumulation, and in which mast cell mediator release
  produces the episodic symptoms. That shared mechanism is real and is why the
  concept is coherent, but it is not a reason to merge the members into one
  Disease entry. The members are deliberately kept separate because they differ
  in the compartment involved (skin only versus extracutaneous organs), in
  natural history (childhood maculopapular cutaneous mastocytosis frequently
  regresses, whereas adult systemic disease does not), in prognosis (near-normal
  life expectancy in cutaneous and indolent systemic disease versus limited life
  expectancy in aggressive systemic mastocytosis and mast cell leukemia), and in
  management (symptomatic mediator blockade versus KIT-inhibitor or
  cytoreductive therapy). A single blended pathograph spanning skin-limited
  paediatric disease and mast cell leukemia would assert a course and a
  treatment logic that is false at both ends, which is why this concept is
  modelled as a union over distinct entries rather than as a root Disease with
  has_subtypes. It is also why the WHO subtypes of systemic mastocytosis
  (indolent, smouldering, aggressive, SM with an associated haematological
  neoplasm, mast cell leukemia) stay where they already are, as has_subtypes of
  the Systemic Mastocytosis entry, rather than being re-declared here.

  "Frequently regresses" is the right contrast to draw against the systemic
  arm, but it should not be read as "benign and self-limiting". The paediatric
  systematic review that supplies the regression rate opens by rejecting
  exactly that framing — the evolution of an individual case is impossible to
  predict — and records a fatal outcome in 2.9% of patients. The split argument
  does not need the cutaneous arm to be benign; it needs its natural history to
  differ from the systemic arm's, which it does.

  CLINICAL_CONVENTION is recorded alongside the mechanistic bases because the
  cutaneous/systemic line and the sub-division of systemic disease are drawn by
  consensus diagnostic criteria (bone marrow mast cell clusters, tryptase,
  CD25, B- and C-findings), not by a difference in driver mutation.

  Two membership gaps are curation gaps rather than boundary decisions: the
  other cutaneous forms (diffuse cutaneous mastocytosis, mastocytoma of skin)
  and mast cell sarcoma have no DisMech entries yet and should be added as
  members when they are curated.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007950
      label: mastocytosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds to the MONDO mastocytosis class. Both
      listed members are is-a descendants of MONDO:0007950 (systemic
      mastocytosis MONDO:0016586 and maculopapular cutaneous mastocytosis
      MONDO:0019316). exactMatch records the intended conceptual alignment;
      MONDO mastocytosis descendants without DisMech entries are curation gaps,
      not evidence that the grouping concept is only a close match. MONDO's own
      metadata for the class corroborates modelling it here as a Grouping rather
      than as a root Disease: MONDO:0007950 carries subset disease_grouping and
      subset ordo_group_of_disorders, records no causal gene (RO:0004003) and no
      OMIM xref, and its NCIT-sourced definition describes a range rather than
      an entity ("ranging from cutaneous proliferations which may regress
      spontaneously, to aggressive neoplasms associated with organ failure and
      short survival").
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Both listed members are is-a descendants of MONDO:0007950. Additional
        MONDO mastocytosis descendants without DisMech entries (diffuse
        cutaneous mastocytosis, mastocytoma of skin, mast cell sarcoma) should
        be surfaced as curation gaps from this exact mapping.
membership_criteria:
- description: >-
    A disorder belongs to the mastocytosis grouping if it is a clonal mast cell
    disease: it is associated with an activating somatic KIT mutation AND shows
    increased mast cell proliferation AND presents with mastocytosis as a
    clinical finding. The gene criterion names KIT rather than the specific
    D816V allele on purpose. D816V is the usual adult driver but it is not
    universal across the spectrum: in paediatric cutaneous mastocytosis roughly
    as many cases carry a KIT variant outside exon 17 (largely in the exon 8/9
    extracellular domain) as carry a codon 816 mutation, so a D816V-specific
    criterion would contradict the curated membership of the cutaneous arm.

    The criteria are declared NECESSARY_AND_SUFFICIENT rather than merely
    NECESSARY because the conjunction restates the WHO definition of the
    disease: a clonal KIT-driven mast cell expansion that has accumulated in
    tissue to the point of being a pathological finding is a mastocytosis,
    whatever compartment it sits in. Declaring it in both directions is what
    makes the known membership gaps self-reporting — diffuse cutaneous
    mastocytosis, mastocytoma of skin and mast cell sarcoma will surface as
    candidate members the moment they are curated, instead of depending on
    someone remembering to revisit this file. The conjunction is deliberately
    tight enough not to over-collect: monoclonal mast cell activation syndrome
    carries a clonal KIT D816V mast cell population but does not meet the mast
    cell burden that the proliferation and mastocytosis-finding operands
    require, and KIT-mutant neoplasms of other lineages (GIST, KIT-mutant
    melanoma) fail both of those operands. Evaluated against the current
    knowledge base the criteria return no candidate non-members, so the
    sufficiency claim is not silently pulling in unrelated entries.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    operator: AND
    operands:
    - criterion_predicate: HAS_GENE
      description: >-
        Caused by an activating somatic mutation in KIT (the mast cell growth
        factor receptor), at codon 816 or elsewhere in the gene.
      gene:
        preferred_term: KIT
        term:
          id: hgnc:6342
          label: KIT
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: >-
        Increased mast cell proliferation, the process underlying mast cell
        accumulation in skin or extracutaneous organs.
      biological_processes:
      - preferred_term: mast cell proliferation
        term:
          id: GO:0070662
          label: mast cell proliferation
        modifier: INCREASED
    - criterion_predicate: HAS_PHENOTYPE
      description: >-
        Mastocytosis is present as a clinical finding, i.e. a pathological
        accumulation of mast cells in tissue.
      phenotype_term:
        preferred_term: Mastocytosis
        term:
          id: HP:0100495
          label: Mastocytosis
  evidence:
  - reference: PMID:39216803
    reference_title: "Harmonization of Diagnostic Criteria in Mastocytosis for Use in Clinical Practice: WHO vs ICC vs AIM/ECNM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mastocytosis is a clonal myeloid disorder defined by an increase and accumulation of mast cells (MCs) in one or multiple organ systems."
    explanation: >-
      The consensus harmonization paper defines mastocytosis by clonal mast cell
      increase and accumulation, which is what the proliferation and phenotype
      operands of this criterion encode.
  - reference: PMID:39216803
    reference_title: "Harmonization of Diagnostic Criteria in Mastocytosis for Use in Clinical Practice: WHO vs ICC vs AIM/ECNM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The World Health Organization (WHO) divides the disease into cutaneous mastocytosis (CM), several forms of systemic mastocytosis (SM), and MC sarcoma."
    explanation: >-
      Establishes the cutaneous/systemic division this grouping is drawn over,
      and names mast cell sarcoma as the third arm currently uncurated.
  - reference: PMID:19865100
    reference_title: "Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mutation of codon 816 (exon 17) was found in 42% of cases, and mutations outside exon 17 were observed in 44%."
    explanation: >-
      Quantifies why the gene operand names KIT rather than D816V: in 50
      children with cutaneous mastocytosis, non-exon-17 KIT variants were as
      common as codon 816 mutations. Marked PARTIAL because it supports the
      breadth of the KIT criterion while showing that no single allele is
      necessary.
members:
- member: Maculopapular Cutaneous Mastocytosis
  member_type: DISEASE
  display_name: Maculopapular cutaneous mastocytosis (urticaria pigmentosa)
  disease_term:
    preferred_term: maculopapular cutaneous mastocytosis
    term:
      id: MONDO:0019316
      label: maculopapular cutaneous mastocytosis
  differentiating_mechanisms:
  - description: >-
      The cutaneous arm: KIT-driven clonal mast cell accumulation confined to
      the dermis, with no extracutaneous organ involvement meeting systemic
      diagnostic criteria. It is the commonest presentation of childhood
      mastocytosis, and unlike the systemic arm it frequently regresses — the
      polymorphic large-lesion variant typical of children may resolve around
      puberty, whereas the monomorphic small-lesion variant typical of adults
      tends to persist. Regression is a population-level tendency, not a
      prognosis for an individual child: the course is not predictable at
      presentation and a small minority of paediatric cases are fatal. That difference in natural history, not a different
      driver gene, is what separates this member from Systemic Mastocytosis.
    gene:
      preferred_term: KIT
      term:
        id: hgnc:6342
        label: KIT
    phenotype_term:
      preferred_term: Maculopapular skin eruption
      term:
        id: HP:0040186
        label: Maculopapular exanthema
    evidence:
    - reference: PMID:26476479
      reference_title: "Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients"
      explanation: >-
        The ECNM/AAAAI/EAACI consensus report defines the monomorphic and
        polymorphic variants of maculopapular cutaneous mastocytosis that this
        member entry curates as its subtypes.
    - reference: PMID:25662299
      reference_title: "Paediatric mastocytosis: a systematic review of 1747 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lesions occurred before the age of 2 years in 90% of cases, and presented as urticaria pigmentosa (75% of cases), mastocytoma (20%) or diffuse cutaneous mastocytosis (5%)."
      explanation: >-
        Systematic review of 1747 paediatric cases showing that maculopapular
        cutaneous mastocytosis (urticaria pigmentosa) is the dominant childhood
        presentation, and naming the two cutaneous forms not yet curated as
        members of this grouping.
    - reference: PMID:25662299
      reference_title: "Paediatric mastocytosis: a systematic review of 1747 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%."
      explanation: >-
        Carries the regression claim for this member: in the 1747-case
        paediatric systematic review, two thirds of cases regressed completely
        or partially and a further quarter stabilized. Paediatric mastocytosis
        is overwhelmingly cutaneous and predominantly maculopapular (urticaria
        pigmentosa in 75% of the same series), so this is the quantitative
        support for the natural-history difference that keeps the cutaneous arm
        a separate entry.
    - reference: PMID:25662299
      reference_title: "Paediatric mastocytosis: a systematic review of 1747 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Paediatric mastocytosis was previously considered to be a benign and spontaneously regressing disease. However, this evolution is impossible to predict."
      explanation: >-
        Bounds the regression claim above. The same review that reports 67%
        regression opens by rejecting "benign and spontaneously regressing" as
        a description of the individual case, which is why this member's
        description states regression as a population-level tendency rather
        than as a prognosis.
    - reference: PMID:25662299
      reference_title: "Paediatric mastocytosis: a systematic review of 1747 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, the outcome was fatal in 2·9% of patients."
      explanation: >-
        The concrete reason the cutaneous arm is not modelled as benign: a
        small minority of paediatric cases in this series died. Supports the
        qualification carried in this member's description and in the grouping
        rationale.
    - reference: PMID:28770635
      reference_title: "Natural history and treatment of cutaneous and systemic mastocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diffuse cutaneous mastocytosis and systemic mastocytosis subtypes did not show evidence of complete resolution in the studies reviewed."
      explanation: >-
        The other half of the contrast: the same meta-analysis found no
        evidence of complete resolution in any systemic subtype. Regression is
        a cutaneous-arm property, which is why a blended pathograph over both
        arms would assert a false course at the cutaneous end.
    - reference: PMID:28770635
      reference_title: "Natural history and treatment of cutaneous and systemic mastocytosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In cutaneous mastocytosis, the complete resolution rate for mastocytoma was 10% per year (95% CI: 4.8%, 15.1%) while the rate for urticaria pigmentosa was 1.9% per year (95% CI: -0.5%, 4.3%)."
      explanation: >-
        Graded PARTIAL because of what these two intervals do and do not
        establish. Urticaria pigmentosa is this member, and its pooled complete
        resolution rate of 1.9% per year has a confidence interval crossing
        zero, so this meta-analysis does not by itself establish a nonzero
        resolution rate for maculopapular cutaneous mastocytosis; the only
        statistically distinguishable figure, 10% per year, is for mastocytoma
        of skin, which is not yet a curated member of this grouping. It is kept
        because it is the one pooled per-year estimate available for the
        cutaneous forms and because it bounds the rate, but the regression
        claim rests on PMID:25662299 rather than on this item.
- member: Systemic Mastocytosis
  member_type: DISEASE
  display_name: Systemic mastocytosis
  disease_term:
    preferred_term: systemic mastocytosis
    term:
      id: MONDO:0016586
      label: systemic mastocytosis
  differentiating_mechanisms:
  - description: >-
      The systemic arm: KIT D816V-driven clonal mast cell proliferation in
      extracutaneous organs, principally bone marrow, diagnosed on multifocal
      spindled mast cell clusters plus minor criteria (elevated tryptase,
      aberrant CD25, KIT D816V). This member carries the whole WHO systemic
      spectrum as its own has_subtypes — indolent, smouldering, aggressive, SM
      with an associated haematological neoplasm, and mast cell leukemia — which
      is why those subtypes are not re-declared as members here. It is
      distinguished from the cutaneous arm by extracutaneous involvement, by the
      absence of spontaneous regression, and by the availability of
      KIT-inhibitor and cytoreductive therapy (midostaurin, avapritinib,
      cladribine, interferon-alpha) for the advanced forms.
    gene:
      preferred_term: KIT
      term:
        id: hgnc:6342
        label: KIT
    biological_processes:
    - preferred_term: mast cell proliferation
      term:
        id: GO:0070662
        label: mast cell proliferation
      modifier: INCREASED
    evidence:
    - reference: PMID:33524167
      reference_title: "Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs."
      explanation: >-
        States the extracutaneous localization that is the defining difference
        between this member and the cutaneous arm.
    - reference: PMID:33524167
      reference_title: "Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL)."
      explanation: >-
        Enumerates the WHO systemic subtypes that the Systemic Mastocytosis
        entry already carries as has_subtypes, supporting the decision not to
        re-declare them as grouping members.
    - reference: PMID:39216803
      reference_title: "Harmonization of Diagnostic Criteria in Mastocytosis for Use in Clinical Practice: WHO vs ICC vs AIM/ECNM."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients diagnosed with CM or nonadvanced SM, including indolent SM, have a near-normal life expectancy, whereas those with advanced SM, including aggressive SM and MC leukemia, have limited life expectancy."
      explanation: >-
        The prognostic split across the grouping's span — the concrete reason a
        single blended pathograph over cutaneous and advanced systemic disease
        would be misleading.
references:
- reference: PMID:39216803
  title: "Harmonization of Diagnostic Criteria in Mastocytosis for Use in Clinical Practice: WHO vs ICC vs AIM/ECNM."
- reference: PMID:33524167
  title: "Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management."
- reference: PMID:26476479
  title: "Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology."
- reference: PMID:25662299
  title: "Paediatric mastocytosis: a systematic review of 1747 cases."
- reference: PMID:28770635
  title: "Natural history and treatment of cutaneous and systemic mastocytosis."
- reference: PMID:19865100
  title: "Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations."
notes: >-
  Concept decision for MONDO:0007950 (issue #9035). The priority queue flagged
  mastocytosis as CURATE_ROOT_WITH_SUBTYPES, which issue #8727 records as a
  priority hint rather than a lump-versus-split ruling. It is modelled here as a
  Grouping because both arms already exist as distinct curated Disease entries
  with their own MONDO terms and their own pathographs, and because the five WHO
  systemic subtypes named in issue #9035 are already has_subtypes of the
  Systemic Mastocytosis entry — a root Disease would have had to duplicate that
  curated block or nest subtypes inside subtypes.

  Follow-up worth doing separately: the KIT-driven chain (activating KIT
  mutation -> constitutive KIT signalling -> clonal mast cell proliferation and
  accumulation -> mast cell mediator release) is duplicated node for node in
  both member entries, and the KIT-inhibitor target_mechanisms links from
  avapritinib and midostaurin back to the KIT node were added to the Systemic
  Mastocytosis entry alongside this grouping. That duplication is exactly the
  shape a kb/modules/ mechanism module captures: both members could then
  declare conforms_to against it and this grouping could carry a
  CONFORMS_TO_MODULE criterion in addition to the gene/process/phenotype
  criterion it uses now. No module was created here, because factoring the
  chain out means rewriting the pathophysiology of two already-curated entries
  and that is a separate reviewable change, not a side effect of settling the
  root concept.

  Deep research: research/Mastocytosis-deep-research-falcon.md (falcon, 9/9
  references resolved, confabulation rate 0). just preflight-dr returned SKIP
  because MONDO records no causal gene for a grouping-subset class, so the
  manual NEC check was run instead: the report's gene profile is dominated by
  KIT (76 mentions, against SRSF2/ASXL1/RUNX1/TET2 at 6 each, which are the
  expected advanced-SM co-mutations rather than a rival entity), the MONDO
  definition and synonyms match the queried concept, and MONDO carries no OMIM
  xref to disagree with. No named-entity confusion. The report's citations are
  DOI-only, and DOIs are snippet-skipped by the reference validator, so nothing
  from it was cited here: every snippet in this file is a PMID quote verified
  against the local reference cache.

  Known content gap surfaced by that report and left for a separate change: the
  WHO 5th edition recognises bone marrow mastocytosis (BMM) as a systemic
  subtype, which the Systemic Mastocytosis entry's has_subtypes does not yet
  carry.