Rosai-Dorfman Disease

1. Disease Information

Overview. Rosai-Dorfman disease (RDD), now preferentially called Rosai-Dorfman-Destombes disease (RDD) to credit Destombes' 1965 description, is a rare non-Langerhans-cell histiocytosis. The defining lesion is an accumulation of large, activated histiocytes (tissue macrophages) with a characteristic morphology — voluminous pale cytoplasm, a round nucleus with a prominent nucleolus, and emperipolesis (intact lymphocytes, plasma cells, or red cells trafficking through the histiocyte cytoplasm). Originally described in 1969 by Juan Rosai and Ronald Dorfman as "sinus histiocytosis with massive lymphadenopathy" (SHML), it was long regarded as a benign reactive/inflammatory process, but the discovery of recurrent clonal MAPK-pathway mutations has reframed a substantial subset as a clonal histiocytic neoplasm.

Think of the RDD histiocyte as an overstuffed cellular vacuum cleaner that has swallowed its neighbors whole and refuses to digest them — that swallowing-but-not-killing (emperipolesis) is the morphologic signature.

Key identifiers (verify against the local MONDO/OAK adapter before use): - MONDO: MONDO:0006412 (Rosai-Dorfman disease) — verify with runoak -i sqlite:obo:mondo info MONDO:0006412 - MeSH: D006666 — "Histiocytosis, Sinus" - ICD-10: D76.3 (other histiocytosis syndromes) - ICD-11: EK92 (or 4B21 region for histiocytic/dendritic cell neoplasms — verify) - ICD-O / WHO: classified within histiocytic/dendritic neoplasms; placed in the "R group" of the 2016 revised histiocytosis classification - GARD: 7588; SNOMED CT: 34287003 ("Sinus histiocytosis with massive lymphadenopathy") - OMIM: No OMIM number for sporadic RDD; the familial/syndromic form maps to OMIM 602782 (Histiocytosis-lymphadenopathy plus syndrome / SLC29A3 spectrum)

Synonyms / alternative names: Sinus histiocytosis with massive lymphadenopathy (SHML); Rosai-Dorfman-Destombes disease (RDD); Destombes-Rosai-Dorfman disease; (familial form:) Faisalabad histiocytosis.

Data provenance: This entry is built from aggregated disease-level resources (consensus guidelines, case series, mutation surveys, ontologies) rather than individual EHR records. The largest data sources are the 2018 international consensus (Abla et al., PMID 29720485) and pooled molecular case series.

2. Etiology

RDD is etiologically heterogeneous — the consensus framework recognizes that it spans a reactive-to-neoplastic continuum, and different subtypes likely have different drivers.

Primary causal factors: - Clonal somatic MAPK/ERK-pathway activation (a major, recently recognized driver). Activating mutations in KRAS, NRAS, MAP2K1 (MEK1), ARAF, and occasionally CSF1R/CBL are found in roughly one-third to one-half of cases tested, indicating a clonal neoplastic process in those patients (Garces et al., PMID 28664935; molecular surveys below). "Mutually exclusive recurrent KRAS and MAP2K1 mutations… were detected in one-third of cases of Rosai–Dorfman disease, suggesting this subgroup are clonal and involve activation of the MAPK/ERK pathway" (paraphrase of PMID 28664935 — verify exact wording). - Reactive / immune-dysregulatory mechanism. In mutation-negative cases, a polyclonal, cytokine-driven macrophage activation (an exaggerated immune response, possibly post-infectious) remains the leading model. Associations with autoimmune disease (~10% of cases) support an immune-dysregulation arm. - Germline genetic causes (familial RDD). Biallelic germline SLC29A3 mutations cause familial RDD / Faisalabad histiocytosis / the H-syndrome spectrum (PMID 20140240). Germline FAS (TNFRSF6) mutations link RDD to autoimmune lymphoproliferative syndrome (ALPS). - Proposed infectious triggers (historically): Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), parvovirus B19 — repeatedly investigated but never confirmed as causal; current evidence does not support an infectious etiology for most cases.

Risk factors. - Genetic: germline SLC29A3 (familial), germline FAS (ALPS-associated); somatic MAPK mutations are acquired drivers rather than inherited risk. - Demographic/environmental: young age (classic nodal form peaks in the first two decades), African ancestry (classic nodal form more frequent), and a possible male predominance in nodal disease. No robust occupational, dietary, or toxic exposure has been established.

Protective factors: None established. No protective alleles or lifestyle factors are documented.

Gene-environment interactions: Not well characterized. The most plausible interaction is a clonal histiocyte bearing a MAPK mutation operating within an immune/cytokine milieu that determines disease extent and the autoimmune-associated subset; this remains hypothesis-level.

3. Phenotypes

RDD is protean. The hallmark presentation is massive, painless, bilateral cervical lymphadenopathy, but extranodal involvement occurs in ~43% of patients and can affect virtually any site.

Phenotype characteristics: - Onset: Classic nodal RDD favors children/young adults (historical mean ~20.6 years), whereas extranodal and cutaneous forms and the treated/molecularly-profiled cohorts skew older (median ~50 years; cobimetinib cohort median 57). → onset spans childhood to late adulthood, broadly bimodal/variable. - Severity: Highly variable — from asymptomatic, self-limited lymphadenopathy to life-threatening organ infiltration. - Progression: Often episodic/relapsing-remitting with spontaneous remissions; a minority is progressive. - QoL impact: Driven by site — disfiguring lymphadenopathy/cutaneous lesions, visual compromise (orbital), neurologic deficits (CNS/spinal), airway obstruction, or organ failure (renal/pulmonary). No RDD-specific validated QoL instrument exists.

4. Genetic / Molecular Information

Somatic driver genes (the neoplastic arm). RDD harbors recurrent activating mutations in the MAPK/ERK (RAS-RAF-MEK-ERK) pathway:

• MAP2K1 (MEK1; HGNC:6840; OMIM 176872) — the single most frequent gene, ~14% of all RDD; in microdissected specimens the incidence is higher. Typical variants: p.Q56P, p.F53_Q58 in-frame deletions, p.P124 substitutions (kinase-activating).
• KRAS (HGNC:6407; OMIM 190070) — ~12.5%; e.g., p.G12D, p.G12V, p.A146T.
• NRAS (HGNC:7989) — e.g., p.G13D.
• ARAF (HGNC:646) — recurrent in a subset.
• CSF1R, CBL — less common.
• BRAF p.V600E is characteristically ABSENT in RDD (a key contrast with Erdheim-Chester disease and Langerhans cell histiocytosis), though rare BRAF-V600E "RDD-like" histiocytoses are reported as diagnostic pitfalls (PMC11871196).

Frequency summary (paraphrased from molecular surveys, e.g., Cangelosi/MDPI review PMC9654168 and Garces PMID 28664935): "From 30% to 50% of patients with RDD harbor somatic mutations… frequently involving ARAF, NRAS, KRAS, MAP2K1, CSF1, and CBL genes, of which MAP2K1 and KRAS were most frequent (~14% and ~12.5%)." Verify exact numbers before citing. A 2025 whole-exome study of Saudi patients (Frontiers Oncol, PMC12094912) revisited and expanded this landscape.

• KRAS and MAP2K1 mutations are mutually exclusive, consistent with single-pathway (MAPK) activation as the unifying mechanism (PMID 28664935).
• Clonality: Mutation-bearing cases are clonal; this underlies the 2016 WHO reframing of RDD as (in part) a neoplasm.

Germline / inherited: - SLC29A3 (HGNC:23096; OMIM 612373) — biallelic loss-of-function germline mutations cause familial RDD / Faisalabad histiocytosis / H syndrome (autosomal recessive; OMIM 602782). "Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease" (PMID 20140240). Compound germline SLC29A3 + somatic MAP2K1 has been reported in pediatric recurrent RDD (PMID 32944792). - FAS / TNFRSF6 — germline mutations link RDD to ALPS type Ia; these patients show more aggressive ALPS, male predominance, and early onset.

Variant classification / type: drivers are activating missense substitutions and small in-frame indels (gain-of-function); germline SLC29A3 variants are loss-of-function (missense/nonsense/frameshift). Somatic drivers are absent or rare in population databases (gnomAD); germline SLC29A3 pathogenic alleles are rare with founder clustering in consanguineous populations.

Functional consequence: MAPK driver mutations cause constitutive ERK signaling (gain of function) → histiocyte proliferation/survival. SLC29A3 mutations cause loss of ENT3 nucleoside-transport function in lysosomal/mitochondrial membranes, leading to nucleoside accumulation and aberrant macrophage activation.

Epigenetics / chromosomal abnormalities: No recurrent, established epigenetic signature or characteristic karyotypic aberration is described; RDD is genomically quiet apart from the single-pathway MAPK drivers.

Suggested gene/term annotations: MAP2K1 (hgnc:6840), KRAS (hgnc:6407), NRAS (hgnc:7989), ARAF (hgnc:646), SLC29A3 (hgnc:23096), FAS (hgnc:11920); GO:0070371 (ERK1 and ERK2 cascade); GO:0000165 (MAPK cascade).

5. Environmental Information

• Environmental factors: No confirmed toxic, radiation, or occupational exposure.
• Lifestyle factors: None established.
• Infectious agents: EBV, HHV-6, parvovirus B19, Klebsiella, Brucella have all been proposed as triggers historically; none is confirmed causal. Current consensus does not classify RDD as an infectious disease. (NCBITaxon references would be speculative and should not be added as causal.)

This section is largely not applicable / negative — worth recording explicitly so the KB doesn't imply an environmental etiology.

6. Mechanism / Pathophysiology

Causal chain (neoplastic/clonal arm — best supported):

1. Somatic MAPK-activating lesion (e.g., MAP2K1 p.Q56P, KRAS p.G12D) arises in a histiocyte/macrophage progenitor →
2. Constitutive RAS-RAF-MEK-ERK signaling (GO:0070371 ERK1/ERK2 cascade) drives histiocyte proliferation and survival →
3. Clonal expansion of large, activated S100+ histiocytes in nodal sinuses and extranodal tissue →
4. Emperipolesis — engulfment (without destruction) of lymphocytes/plasma cells/erythrocytes by these histiocytes (a non-specific but characteristic morphologic readout) →
5. Mass effect and tissue infiltration → organ-specific manifestations (lymphadenopathy, CNS mass, renal/pulmonary infiltration) and an accompanying plasma-cell-rich, polyclonal inflammatory infiltrate (→ hypergammaglobulinemia, elevated ESR).

Reactive/immune arm (mutation-negative cases): dysregulated, cytokine-driven macrophage activation (a "phagocytic storm" of activated M2-like macrophages) with prominent plasmacytosis, possibly downstream of immune dysregulation or autoimmunity, producing the same histiocyte morphology without demonstrable clonal driver.

Cellular identity of the RDD histiocyte. The cell is a late-activated, monocyte-derived macrophage / "RDD histiocyte" with an immunophenotype intermediate between macrophage and dendritic cell: - Positive: S100 (nuclear + cytoplasmic), CD68, CD163 (macrophage), fascin, CD14, OCT2, cyclin D1 (the latter two increasingly used diagnostically and consistent with cell-cycle/ERK activation). - Negative: CD1a−, CD207/langerin− (excludes Langerhans cell histiocytosis); ALK−.

Suggested CL terms: CL:0000235 (macrophage); CL:0000576 (monocyte); CL:0000842 (mononuclear cell). Suggested GO: GO:0070371 (ERK1/ERK2 cascade), GO:0000165 (MAPK cascade), GO:0006909 (phagocytosis), GO:0002281 (macrophage activation involved in immune response), GO:0008283 (cell population proliferation).

Protein dysfunction: MEK1 (MAP2K1) and KRAS gain-of-function → unregulated downstream kinase activity. ENT3 (SLC29A3) loss → impaired lysosomal nucleoside efflux.

Immune involvement: central — RDD is a disorder of the mononuclear phagocyte system with a heavy reactive plasma-cell/lymphocyte component; ~10% co-occur with autoimmune disease; IgG4+ plasma cells are increased in a subset (overlap with IgG4-related disease).

Upstream vs downstream: Upstream = MAPK driver mutation (or immune-dysregulatory trigger); midstream = clonal histiocyte proliferation + emperipolesis + plasmacytosis; downstream = mass effect, organ infiltration, systemic inflammatory phenotype.

Molecular profiling: Targeted/whole-exome sequencing is the main modality (above). No established transcriptomic/proteomic/metabolomic disease signature is in routine use; single-cell and spatial data are emerging but not yet definitive.

7. Anatomical Structures Affected

• Primary: lymph nodes (UBERON:0000029), especially cervical (UBERON:0000029 / cervical lymph node UBERON:0002429). Classic disease = lymphatic system (UBERON:0006558 lymphoid system / UBERON:0001744 lymphoid tissue).
• Extranodal (any organ; most frequent):
• Skin (UBERON:0002097) and subcutaneous soft tissue
• Orbit/eye and adnexa (UBERON:0001697 orbit; UBERON:0000970 eye)
• Nasal cavity / paranasal sinuses (UBERON:0001707 nasal cavity)
• Central nervous system — dura/meninges (UBERON:0002361 meninges), brain (UBERON:0000955), spinal cord (UBERON:0002240)
• Bone (UBERON:0001474) — metaphysis/diaphysis of long bones
• Kidney (UBERON:0002113); lung (UBERON:0002048); upper respiratory/airway
• Salivary glands, breast (UBERON:0000310), GI tract, soft tissue
• Body systems: lymphatic/hematopoietic, integumentary, nervous, respiratory, urinary, skeletal, ocular.
• Tissue/cell level: expanded nodal sinuses lined/filled by histiocytes; connective/soft tissue at extranodal sites (more fibrotic, fewer histiocytes). Target cell = activated macrophage (CL:0000235).
• Subcellular: RAS/MEK signaling at the plasma membrane/cytosol; ENT3 localizes to lysosomal/mitochondrial membranes (GO:0005764 lysosome) in the familial form; nuclear S100/OCT2/cyclin D1 staining.
• Lateralization: classic cervical lymphadenopathy is bilateral; extranodal lesions are often focal/asymmetric.

8. Temporal Development

• Onset: classic nodal form — childhood/young adulthood (historical mean ~20.6 y); extranodal and molecularly-profiled cohorts — adult/older adult (median ~50–57 y). Onset pattern usually subacute to chronic/insidious; lymphadenopathy may enlarge over weeks–months.
• Progression / course: highly variable — self-limited in many nodal/cutaneous cases (spontaneous remission in ~20–50% of nodal/cutaneous disease per consensus) vs. relapsing-remitting over years vs. progressive organ-infiltrative disease in a minority. "Outcomes are usually favorable, particularly for cases of nodal and cutaneous disease, which are often self-limited. Other patients experience an unpredictable clinical course, with alternating periods of remission and reactivation lasting years" (paraphrase of Abla et al., PMID 29720485 — verify).
• Staging: no formal AJCC-style staging; prognosis correlates with the number of nodal groups and extranodal systems involved.
• Remission: both spontaneous and treatment-induced.
• Critical intervention windows: organ-threatening sites (CNS/spinal compression, airway, orbit with visual compromise) require timely debulking/therapy.

9. Inheritance and Population

Epidemiology. - Prevalence: ~1 in 200,000 (consensus estimate, PMID 29720485). - Incidence: ~100 new cases per year in the US (consensus estimate). - Age: historically mean ~20.6 y for classic nodal disease; median ~50 y in mixed/extranodal contemporary series. - Sex: slight male predominance in classic nodal disease (~1.4:1); some extranodal/cutaneous series show female predominance — overall roughly balanced and series-dependent. - Ethnicity/geography: classic nodal form more frequent in individuals of African descent; cutaneous RDD more common in Asian patients (especially women); sinonasal disease more common in Asian patients.

Genetic-etiology parameters: - Inheritance: sporadic RDD is not inherited (somatic/acquired). The familial form (SLC29A3) is autosomal recessive (OMIM 602782); FAS-associated RDD follows ALPS (autosomal dominant with variable penetrance). - Penetrance/expressivity: SLC29A3-related disease shows wide intrafamilial variability — the same c.1088G>A allele can produce H syndrome in one relative and RDD in another (PMC8522101). - Consanguinity / founder effects: familial SLC29A3 disease clusters in consanguineous Middle Eastern/South Asian families (Faisalabad histiocytosis). - Anticipation / mosaicism: not described.

Demographics: affects all populations; no single endemic region; sex and ethnic skews are subtype-dependent as above.

10. Diagnostics

Diagnosis is histopathologic, integrated with clinical and radiologic context (and exclusion of mimics).

• Biopsy / histopathology (gold standard): large histiocytes with abundant pale/"watery-clear" cytoplasm, vesicular nuclei with prominent nucleoli, and emperipolesis; admixed plasma cells and lymphocytes; sinus expansion in nodal disease; more fibrosis/fewer histiocytes extranodally. "The presence of RDD histology is required, but not sufficient, for diagnosis" (paraphrase, PMID 29720485 — verify).
• Immunohistochemistry panel (recommended: CD68, CD163, S100, OCT2, cyclin D1, CD1a, langerin, ALK):
• Positive: S100 (nuclear+cytoplasmic), CD68, CD163, fascin, OCT2, cyclin D1.
• Negative: CD1a, CD207/langerin (→ excludes LCH), ALK.
• Molecular testing: targeted NGS for MAPK-pathway mutations (MAP2K1, KRAS, NRAS, ARAF; confirm BRAF-V600E status) — increasingly standard because it identifies clonal disease and guides MEK-inhibitor therapy.
• Laboratory: elevated ESR, polyclonal hypergammaglobulinemia, anemia (sometimes autoimmune hemolytic), variable leukocytosis. None is specific.
• Imaging: CT/MRI to map nodal/extranodal extent; PET-CT for whole-body assessment and treatment response (FDG-avid lesions); MRI essential for CNS/spinal disease (dural-based, contrast-enhancing, meningioma-mimicking).
• Genetic testing (familial): germline SLC29A3 sequencing when familial RDD / H-syndrome features are present; FAS testing if ALPS features.
• Differential diagnosis (key mimics to exclude): Langerhans cell histiocytosis (CD1a+/langerin+), Erdheim-Chester disease (BRAF-V600E+, "foamy" histiocytes, CD163+/S100±), lymphoma (esp. Hodgkin and ALCL), reactive sinus histiocytosis, IgG4-related disease, metastatic carcinoma/melanoma (S100+ — emperipolesis and CD68/CD163 help), tuberculosis/other granulomatous disease, juvenile xanthogranuloma.

Screening: No population screening. For SLC29A3 families, cascade genetic testing/counseling is appropriate.

11. Outcome / Prognosis

• Overall: generally favorable, especially nodal and cutaneous disease (frequently self-limited). Course is unpredictable with remission-reactivation cycles.
• Mortality: historical disease-related mortality ~7% (Foucar et al., 17/238) to ~12% (Pulsoni et al., 10/80).
• High-risk / poor-prognosis features:
• Multifocal / multisystem disease (prognosis worsens with number of nodal groups and extranodal systems involved)
• Renal involvement (~40% mortality)
• Lower respiratory / pulmonary involvement (~45% mortality)
• GI involvement (~20% mortality in one series)
• CNS disease (morbidity from mass effect/compression)
• Immune dysregulation / associated autoimmune disease
• Morbidity: disfigurement, visual loss (orbital), neurologic deficits (CNS/spinal), airway compromise, organ dysfunction.
• Prognostic/predictive biomarkers: KRAS/MEK (MAP2K1) mutation status predicts response to MEK inhibition (see §12) — a genuinely actionable prognostic/predictive marker.

12. Treatment

There is no single standard; therapy is site- and severity-driven, codified in the 2018 consensus (PMID 29720485) and NCCN histiocytosis guidelines.

• Observation — for asymptomatic/uncomplicated nodal or cutaneous disease; 20–50% of nodal/cutaneous cases remit spontaneously. → MAXO:0000950 (supportive care) / watchful waiting.
• Surgery — curative for unifocal disease; debulking for airway obstruction, spinal cord compression, orbital/organ compromise; excision is the most effective treatment for localized cutaneous RDD. → MAXO:0000004 (surgical procedure).
• Corticosteroids — first-line systemic agent for symptomatic disease (prednisone ~40–70 mg/day or 1 mg/kg/day with taper; dexamethasone 8–20 mg/day); variable, often non-durable. → NCIT:C15986 (Pharmacotherapy) + therapeutic_agent CHEBI prednisone/dexamethasone; NCIT corticosteroid class.
• Chemotherapy — for refractory/systemic disease: cladribine (2-CdA, 5 mg/m²×5 q28d) and clofarabine (notably effective in children/refractory disease); low-dose methotrexate + 6-mercaptopurine; vinca alkaloids (variable). → MAXO:0000647 (chemotherapy) + CHEBI cladribine/clofarabine/methotrexate.
• Immunomodulatory — thalidomide/lenalidomide (cutaneous and refractory nodal/bone disease); rituximab (autoimmune-associated RDD); sirolimus (mTOR inhibitor; resistant RDD with autoimmune cytopenias).
• Targeted therapy — MEK inhibition (the major recent advance):
• Cobimetinib received FDA approval (Nov 2022) for adults with histiocytic neoplasms, including RDD — the first agent approved across all forms of histiocytosis.
• Retrospective cohort (Abeykoon et al., JAMA Oncol 2022, PMID 36201194, n=16): overall response 63% (5 CR + 5 PR); median PFS 21.4 months. Outcomes were markedly better in KRAS/MEK-altered patients: response 88% vs 38% (P=.03), CR among responders 71% vs 0% (P=.002), and at 1 year 100% vs 29% free from progression/death. Grade ≥2 toxicity in 75%; 56% needed dose reduction/discontinuation. → MAXO/NCIT pharmacotherapy; therapeutic_agent cobimetinib (CHEBI:90851 — verify); therapeutic_modality: SMALL_MOLECULE.
• Other reports: trametinib (incl. topical), and BRAF inhibitors are not indicated (RDD is BRAF-V600E−).
• Radiotherapy — modest, mainly for refractory soft-tissue/orbital disease with visual compromise or palliation (30–50 Gy). → MAXO:0000014 (radiation therapy).
• Treatment strategy / personalized medicine: test for MAPK mutations → MEK inhibitor (cobimetinib) for KRAS/MAP2K1-mutated or multisystem/refractory disease; reserve cytotoxics/immunomodulators for mutation-negative or MEK-refractory cases; observe indolent localized disease.

Active trials: Central China RDD Registry (NCT05284942); Lenalidomide + dexamethasone for RDD (NCT04924647); cobimetinib basket trial (NCT02649972). Verify status before citing as clinical_trials entries.

13. Prevention

• Primary prevention: None — sporadic RDD is not preventable (no modifiable cause).
• Secondary prevention: no population screening; early biopsy of persistent massive lymphadenopathy/organ masses enables timely diagnosis.
• Genetic counseling: relevant only for familial SLC29A3 (autosomal recessive) and FAS/ALPS kindreds — carrier testing, cascade screening, reproductive counseling; prenatal/preimplantation testing is theoretically possible for known familial variants. → MAXO:0000079 (genetic counseling).
• Tertiary prevention: treat organ-threatening disease early to prevent permanent deficits (vision, neurologic, renal, respiratory); monitor for relapse.
• Immunization / public health / behavioral / environmental measures: not applicable (no infectious or environmental cause established).

14. Other Species / Natural Disease

• Taxonomy: RDD is essentially a human disease (NCBITaxon:9606).
• Veterinary / natural disease: Rare RDD-like / emperipolesis-positive histiocytic proliferations have been described anecdotally in animals, but RDD is not an established naturally-occurring veterinary entity, and there is no OMIA entry analogous to sporadic human RDD. → Largely not applicable.
• Comparative biology / orthologs: human driver genes have clear orthologs (Map2k1, Kras, Nras, Slc29a3 in mouse), enabling mechanistic modeling, but spontaneous cross-species RDD disease is not documented.
• Zoonotic potential: none (non-infectious).

This section is best recorded as not applicable / no established natural animal disease.

15. Model Organisms

There is no widely-used, faithful animal model that recapitulates RDD specifically — a genuine knowledge gap (candidate for a KNOWLEDGE_GAP discussion in the entry).

• Mouse (Mus musculus, MGI): conditional MAPK-activation alleles (e.g., Kras^G12D, Map2k1-activating, Braf models) in the myeloid/histiocyte lineage produce histiocytic/macrophage proliferations and model the broader histiocytosis MAPK paradigm, but none reproduces RDD's full clinicopathologic picture (emperipolesis, S100+ phenotype, sinus expansion). Slc29a3-knockout mice model the familial/lysosomal arm (macrophage lysosomal nucleoside accumulation, histiocytic infiltration) and are the most disease-relevant genetic model.
• In vitro / cellular: primary patient histiocytes and macrophage cultures bearing MAPK mutations are used to study ERK signaling and MEK-inhibitor response; iPSC/organoid RDD models are not established.
• Applications: MAPK-driver mouse models and patient-derived cells are most useful for mechanism (ERK signaling) and MEK-inhibitor pharmacology; Slc29a3 mice for the lysosomal/familial mechanism.
• Limitations: emperipolesis and the characteristic S100+ RDD histiocyte morphology are poorly recapitulated; the reactive/immune arm has no good model. → Recommend tagging model evidence evidence_source: MODEL_ORGANISM and noting human-model mismatch.
• Resources: MGI/IMPC for Slc29a3, Map2k1, Kras, Nras alleles.

Priority Evidence Citations (verify each with just fetch-reference before committing)

Suggested MONDO mapping: MONDO:0006412. Module-conformance candidates for the dismech entry: tumor_promoting_inflammation (reactive/inflammatory arm) and sustaining_proliferative_signaling (the constitutive MAPK/ERK driver arm) — RDD is a clean example of a histiocytosis sitting on the inflammation↔clonal-neoplasia boundary, so a mechanistic_hypotheses block contrasting the clonal-MAPK vs reactive-immune models would capture the genuine scientific uncertainty.

Sources: - Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease (Blood 2018, PMC6024636) - Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai–Dorfman disease (Mod Pathol 2017, PMID 28664935) - Outcomes After Treatment With Cobimetinib in RDD by KRAS/MEK Status (JAMA Oncol 2022, PMC9539729) - Rosai–Dorfman Disease between Proliferation and Neoplasia (Cancers 2022, PMC9654168) - Revisiting the molecular landscape of RDD: WES of Saudi patients (Front Oncol 2025, PMC12094912) - Mutations in SLC29A3 cause familial histiocytosis / familial RDD (PLoS Genet 2010, PMID 20140240) - Pediatric recurrent RDD: germline SLC29A3 + somatic MAP2K1 (PMID 32944792) - How I Diagnose Rosai-Dorfman Disease (Am J Clin Pathol 2023) - Clinicopathological features, treatment approaches, and outcomes in RDD (PMC7012468) - FDA Approves Oral MEK Inhibitor Cobimetinib for Histiocytic Neoplasms (ASCO Post 2022) - Phenotypic intrafamilial variability with the same SLC29A3 mutation (PMC8522101) - Sinus histiocytosis with massive lymphadenopathy — GARD - OMIM 602782 — Histiocytosis-lymphadenopathy plus syndrome - Rosai-Dorfman disease pathology — DermNet NZ

Curator reminder: the 2018 consensus quotes reproduced above came through the search tool as paraphrases of PMID 29720485. Before any of these become evidence snippet: values, fetch the real abstract (just fetch-reference PMID:29720485) and confirm exact substring matches, then run just validate-references and just validate-terms-file.