| Domain | Core finding | Quantitative/current evidence | Suggested ontology terms |
|---|---|---|---|
| Disease definition/classification | Mastocytosis is a clonal mast-cell neoplasm with skin-limited and systemic forms; contemporary frameworks recognize CM, SM subtypes, and mast cell sarcoma. WHO 5th edition/ICC differ slightly in subclassification, but both retain indolent vs advanced disease concepts. (pqac-00000006, pqac-00000008) | WHO/ICC-recognized entities include CM, BMM, ISM, SSM, ASM, SM-AHN, MCL, mast cell sarcoma; ICC 2023 emphasizes refined morphology/molecular criteria (Wang 2023, DOI:10.1002/ajh.26966). (pqac-00000008) | MONDO:0007950 mastocytosis; MONDO:0019023 cutaneous mastocytosis; MONDO:0016586 systemic mastocytosis; NCIT: Systemic Mastocytosis; HPO: HP:0002444 Mast cell proliferation |
| Core driver genetics | KIT is the dominant disease gene; KIT p.D816V is the major activating mutation in adult SM and causes ligand-independent signaling and mast-cell accumulation/survival. (pqac-00000005, pqac-00000006, pqac-00000010) | >90% of patients with mastocytosis harbor a somatic KIT mutation by sensitive testing; KIT p.D816V is present in >90–95% of adult SM in recent reviews. Adult hotspot: exon 17/codon 816. (pqac-00000005, pqac-00000010) | HGNC:6342 KIT; SO:0001583 missense_variant; GO:0004714 transmembrane receptor protein tyrosine kinase activity; GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway |
| Additional somatic genetics | Advanced SM commonly carries additional myeloid-neoplasm mutations that modify phenotype and prognosis, especially SRSF2/ASXL1/RUNX1 (“S/A/R”) and also TET2, RUNX1, CBL, JAK2, RAS. (pqac-00000003, pqac-00000010) | S/A/R high-risk profile is enriched in advanced disease and worse outcomes; male patients had S/A/R-type aberrations in 63% vs 40% of females in ECNM registry analysis. (pqac-00000009) | HGNC:11824 TET2; HGNC:10770 SRSF2; HGNC:18357 ASXL1; HGNC:10471 RUNX1; NCIT: Somatic Mutation; GO:0000398 mRNA splicing |
| Germline/modifier genetics | Inherited modifiers exist but are not established primary causes for most cases; hereditary alpha-tryptasemia (TPSAB1 copy gain) is enriched in SM and may amplify mediator-related severity/anaphylaxis risk. (pqac-00000010) | HαT occurs in ~3–6% of general Western populations vs up to 17% of SM patients. Reported germline associations also include IL13, IL6, IL6R, IL31, IL4R, TLR loci. (pqac-00000010) | HGNC:12019 TPSAB1; HP:0040283 Elevated circulating tryptase concentration; NCIT: Germline Mutation |
| Diagnostic criteria | SM diagnosis requires tissue morphology plus minor criteria; current ICC major criterion is dense multifocal mast-cell infiltrates in extracutaneous tissue, with minor criteria spanning atypical morphology, aberrant immunophenotype, KIT activation, and serum tryptase elevation. (pqac-00000008) | Major: multifocal dense infiltrates of ≥15 mast cells in marrow/other extracutaneous organ. Minor: >25% atypical/spindle mast cells; CD25/CD2 and/or CD30 aberrant expression; KIT D816V or other activating KIT mutation; persistent serum tryptase >20 ng/mL. Diagnosis: major + 1 minor, or 3 minor. (pqac-00000008) | NCIT: Bone Marrow Biopsy; LOINC/biomarker: serum tryptase; CL:0000097 mast cell; HP:0033365 Abnormal mast cell morphology |
| B- and C-findings / staging | Disease burden and organ damage stratify SM into indolent/smoldering vs advanced forms. B-findings reflect high burden without overt dysfunction; C-findings define organ damage and need for cytoreduction. (pqac-00000004, pqac-00000005) | SSM: ≥2 B-findings; ASM/MCL: C-findings present. Examples include marrow mast-cell burden ≥30% or tryptase ≥200 ng/mL (B); cytopenias, malabsorption, hepatic dysfunction/ascites, hypersplenism, osteolysis/pathologic fractures (C). (pqac-00000004) | NCIT: Organ Dysfunction; HPO: HP:0002242 Hepatomegaly; HP:0001744 Splenomegaly; HP:0003277 Osteolysis |
| Phenotypes: mediator-related | Symptoms arise from mast-cell degranulation and mediator release, often fluctuating/episodic and disproportionate to mast-cell burden. (pqac-00000005, pqac-00000012) | Common manifestations across reviews include pruritus, flushing, abdominal cramping/diarrhea, anaphylaxis, hypotension; pediatric CM review identifies pruritus as most common and anaphylaxis rare but increased with extensive lesions/high tryptase. (pqac-00000012) | HPO: HP:0000989 Pruritus; HP:0031284 Flushing; HP:0002014 Diarrhea; HP:0100845 Anaphylaxis; GO:0043303 mast cell degranulation |
| Phenotypes: infiltration-related | Tissue infiltration causes organomegaly, marrow dysfunction, skeletal disease, GI malabsorption, and aggressive-organ-damage features. (pqac-00000005, pqac-00000004) | Hepatomegaly/splenomegaly occur in ~40% of AdvSM patients in 2024 review; osteoporosis/fragility fractures were present in 35% of an adult regional cohort, including young patients. (pqac-00000005, pqac-00000009) | HPO: HP:0002240 Hepatic insufficiency; HP:0001744 Splenomegaly; HP:0000939 Osteoporosis; HP:0002757 Pathologic fracture |
| Epidemiology | Mastocytosis is rare but likely underdiagnosed; recent registry work suggests higher incidence/prevalence than older estimates. (pqac-00000005, pqac-00000009) | Sweden 2024: annual incidence 1.56/100,000 (95% CI 1.29–1.87), prevalence 23.9/100,000 (95% CI 22.8–25.0). Verona/Veneto cohort: adult SM prevalence 10.2/100,000 in Veneto and 17.2/100,000 in Verona province; mean incidence 1.09/100,000/year. (pqac-00000009) | NCIT: Incidence; NCIT: Prevalence; MONDO:0007950 |
| Demographics/sex effects | Overall sex distribution is near-balanced, but advanced forms—especially SM-AHN—show male predominance and worse outcomes in males. (pqac-00000009) | In ECNM registry analysis of 3403 patients, 55.3% were female overall, but SM-AHN was 70% male; organomegaly was 23% in males vs 13% females, skin involvement 71% vs 86%, respectively. (pqac-00000009) | PATO: male/female biological sex; HPO: HP:0001744 Splenomegaly; HP:0000951 Skin lesion |
| Pediatric disease | Pediatric mastocytosis is usually cutaneous, often begins in infancy/early childhood, and frequently regresses around puberty; systemic disease is uncommon but follow-up is required. (pqac-00000012) | Reviews state CM is the commonest childhood form; most children regress spontaneously around puberty, whereas diffuse CM is rarer and more severe. Advanced SM in children is described as sporadic. (pqac-00000012) | MONDO:0019023 cutaneous mastocytosis; HPO: HP:0011462 Childhood onset; HP:0031284 Flushing; HP:0001009 Macule |
| Pediatric mutation spectrum | Children show a broader KIT spectrum than adults, with lesional KIT mutations that often involve non-D816V sites, including extracellular-domain variants; peripheral blood D816V may be negative despite skin disease. (pqac-00000002, pqac-00000012) | Reported pediatric variants include KIT Del419, ITD501-502, ITD502-503, K509I; lesional D816V can occur, but peripheral blood ASqPCR may be negative in CM. (pqac-00000002, pqac-00000012) | HGNC:6342 KIT; SO:0000667 insertion; SO:1000032 deletion; NCIT: Skin Biopsy |
| Molecular pathophysiology | Upstream driver: constitutive KIT activation. Downstream pathways include STAT5, PI3K/AKT, mTOR, and other kinase networks, promoting survival, proliferation, trafficking, and mediator release. (pqac-00000003, pqac-00000006) | Reviews synthesize KIT-dependent and KIT-independent signaling in advanced disease; in vitro KIT D816V mast-cell lines support pharmacologic suppression of proliferation and signaling. (pqac-00000003, pqac-00000004) | GO:0007169 receptor tyrosine kinase signaling; GO:0038128 ERBB/RTK downstream signaling analog; GO:0042127 regulation of cell population proliferation; CL:0000097 mast cell |
| Prognosis | Prognosis spans near-normal survival in indolent disease to very poor survival in leukemic disease; molecular burden and subtype matter. (pqac-00000001, pqac-00000005) | Median OS by subtype in 2024 review: ISM 198 months, SSM 52 months, ASM 41 months, SM-AHN 24 months, MCL 2 months. KIT D816V allele burden reduction ≥25% has been associated with improved OS. (pqac-00000001) | NCIT: Overall Survival; NCIT: Prognostic Factor; NCIT: Mutation Burden |
| Prognostic scoring | Modern risk tools integrate clinical and molecular features rather than morphology alone. (pqac-00000009) | IPSM and mutation-adjusted systems such as MARS are referenced as contemporary tools for risk stratification in SM, especially advanced disease. (pqac-00000009) | NCIT: Risk Assessment; NCIT: Prognostic Score |
| Symptom-directed treatment | Indolent disease management is largely supportive and anti-mediator focused; trigger avoidance and anaphylaxis preparedness are central. (pqac-00000012) | Common measures: H1/H2 antihistamines, cromolyn, leukotriene-directed approaches, epinephrine autoinjector for severe reactions; pediatric reviews emphasize avoidance of triggers and ready access to adrenaline. (pqac-00000012) | NCIT: Histamine H1 Receptor Antagonist; NCIT: Histamine H2 Receptor Antagonist; CHEBI: histamine; NCIT: Epinephrine |
| Midostaurin | Midostaurin is a multikinase inhibitor active against KIT D816V and established for AdvSM. (pqac-00000004, pqac-00000009) | Preclinical IC50 against mast-cell lines ~0.05–0.3 µM; pivotal clinical study showed meaningful responses in AdvSM, with median OS reported around 20.7 months in one summarized study context. (pqac-00000004, pqac-00000009) | NCIT: Midostaurin; NCIT: Protein Kinase Inhibitor Therapy |
| Avapritinib | Avapritinib is a selective KIT D816V inhibitor and major recent advance for AdvSM, with molecular and pathologic responses. (pqac-00000001, pqac-00000007) | 2024 review notes improved quality and quantity of life with avapritinib; adverse events summarized as hair color changes 34%, thrombocytopenia 22%, transaminase increases 22%, neutropenia 19%, taste disorder 19%, without reported cognitive or bleeding events in the cited dataset. (pqac-00000007) | NCIT: Avapritinib; NCIT: Tyrosine Kinase Inhibitor Therapy |
| Emerging targeted therapy | Next-generation selective KIT inhibitors are in active development to improve tolerability and sequencing after/around avapritinib. (pqac-00000001, pqac-00000007) | Bezuclastinib/CGT9486 is in phase 2 SUMMIT for indolent/smoldering SM (NCT05186753; 237 planned participants in retrieved trial record). Elenestinib is highlighted in 2024 therapeutic reviews as an emerging agent. (pqac-00000001) | NCIT: Investigational Agent; NCIT: Clinical Trial; NCIT: KIT Inhibitor |
| Transplant / advanced interventions | Allogeneic hematopoietic stem-cell transplantation remains the only potentially curative option for selected very high-risk AdvSM/MCL, but is restricted to fit patients and specialized centers. (pqac-00000001, pqac-00000005) | Persistently poor outcomes in high-risk groups, especially MCL, sustain transplant consideration despite targeted-therapy advances. (pqac-00000001) | NCIT: Allogeneic Hematopoietic Stem Cell Transplantation |
| Diagnostics in practice | Bone marrow evaluation, serum tryptase, flow/IHC immunophenotyping, and highly sensitive KIT testing are the current diagnostic backbone; sensitive assays outperform routine NGS for low-VAF KIT variants. (pqac-00000008, pqac-00000012) | 2024 KIT-detection review states KIT variants may be “well below the sensitivity of common NGS methods used in routine diagnostic panels,” supporting allele-specific/qPCR-type approaches for diagnosis/follow-up. (pqac-00000012) | NCIT: Polymerase Chain Reaction; NCIT: Next Generation Sequencing; NCIT: Flow Cytometry; LOINC: serum tryptase |
| Animal/natural disease | Comparative mast-cell neoplasia occurs in dogs, cats, and other mammals; KIT mutations are common across species, but prognostic correlates differ from human mastocytosis. (pqac-00000002) | Review notes KIT mutations are common in dog, cat, and human mast-cell neoplasia; in dogs certain KIT mutations correlate with more malignant/lethal disease, whereas in feline and human disease KIT is more useful diagnostically/therapeutically than prognostically. (pqac-00000002) | NCBITaxon:9606 human; NCBITaxon:9615 dog; NCBITaxon:9685 cat; OMIA/VBO terms as applicable |
| Experimental models | Human mast-cell lines and xenografts are the principal research models; ROSA KIT D816V and HMC-1 are especially useful for pathway and drug studies. (pqac-00000002, pqac-00000006) | Available human lines include HMC-1, LAD1/2, LUVA, ROSA, MCPV-1; ROSA KIT D816V can engraft NSG mice and generate an ASM/MCL-like disease, enabling in vivo drug validation. (pqac-00000002, pqac-00000006) | Cellosaurus: HMC-1; CL:0000097 mast cell; NCBITaxon:10090 mouse; NCIT: Xenograft Model |


*Table: This compact table summarizes the core disease-knowledge domains for mastocytosis, emphasizing current classification, genetics, diagnosis, prognosis, treatment, and model systems. It is designed as a quick-reference scaffold for populating a structured knowledge-base entry.*