Primary Cutaneous Amyloidosis — Comprehensive Disease Research Report

Prepared: 2026-08-01 · Target entity: Primary (localized) cutaneous amyloidosis (PLCA/PCA) · MONDO:0015301

Evidence provenance note. Citations marked [cached] have been verified against abstracts already fetched into references_cache/ in this worktree — the quoted snippets below are exact substrings of those cached abstracts and are safe to use directly in evidence items. Citations marked [lead] were surfaced by literature/database search in this session but have not yet been fetched via just fetch-reference; per the dismech DR SOP, treat them as leads and verify PMID + snippet + ontology terms before committing them to YAML.

1. Disease Information

Overview

Primary localized cutaneous amyloidosis (PLCA, also PCA) is a group of chronic, skin-limited disorders defined by extracellular deposition of amyloid in the papillary dermis without visceral organ involvement. In the two dominant keratinocyte-derived forms (lichen and macular amyloidosis) the fibril precursor is degenerate epidermal keratin, not a plasma-cell or hepatic-precursor protein — which mechanistically separates PLCA from AL/ATTR/AA systemic amyloidosis. A third clinical form, nodular amyloidosis, is mechanistically distinct: it is a localized cutaneous plasma-cell dyscrasia depositing AL (immunoglobulin light chain) amyloid, and it carries a real (if modest) risk of representing or evolving into systemic disease.

The canonical mechanistic quote for the keratinocyte-origin claim:

"Amyloids in lichenoid and macular amyloidoses, and in basal cell epithelioma had an identical antigenicity with epidermal keratin, whereas amyloids in nodular amyloidosis and systemic amyloidosis did not have this identity." — Kobayashi & Hashimoto, J Invest Dermatol 1983, PMID:6184423 [cached]

"It was concluded that at least some of the amyloid substance in organ-limited cutaneous amyloidosis is derived from degenerated epidermal keratinocytes through filamentous degeneration or apoptosis." — PMID:6184423 [cached]

Modern proteomic subtyping has refined the precursor identity to specific basal keratins:

Title: "LC-MS/MS and immuno-electron subtyping combined with genetics show that OSMR mutations cause amyloid deposition of keratins 5/14 in familial primary localized cutaneous amyloidosis" — Bourguiba et al., JEADV 2022, PMID:34459039 [cached] (title-level evidence only; this is a correspondence piece with no structured abstract in the cache — quote the title, not a fabricated body sentence)

Key identifiers

Synonyms (from the MONDO record, OAK-verified)

primary localised cutaneous amyloidosis; PLCA (narrow); familial primary localized cutaneous amyloidosis (narrow); amyloidosis IX; amyloidosis familial cutaneous lichen; lichen amyloidosis familial. Clinically also: lichen amyloidosus, papular amyloidosis, lichenoid amyloidosis, macular amyloidosis, biphasic amyloidosis, frictional amyloidosis, amyloidosis cutis dyschromica (ACD).

Information provenance

Predominantly disease-level aggregated (OMIM/Orphanet/GeneReviews-style, review syntheses) plus individual-patient case series and pedigree studies (Taiwanese, Chinese, Brazilian, Pakistani, Central European cohorts). No large EHR-derived phenotype work identified; there is no registry. This is a good candidate for a definitions[] block with derivation_basis: ESTABLISHED_CRITERIA but validation_status: PROPOSED — no validated computable phenotype exists.

2. Etiology

Causal factors — a genuinely multifactorial disease

PLCA is best modeled as a complex/multifactorial disorder with a well-characterized Mendelian subset. Three converging causal streams:

1. Germline cytokine-receptor lesions (Mendelian arm). Autosomal-dominant missense variants in OSMR and IL31RA; autosomal-recessive loss-of-function in GPNMB (ACD).
2. Chronic mechanical/frictional epidermal injury (environmental arm). Long-term rubbing with nylon towels/brushes, and chronic scratching, are established triggers, especially for macular amyloidosis in Asian and Middle Eastern populations [lead: PMID:19207438, PMID:9330050, PMID:3391726].
3. Chronic pruritus of any cause feeding a scratch–damage–deposition loop. Atopic dermatitis is the most frequent comorbid itch driver.

The full-text of the Taiwanese genetics paper states the multifactorial framing explicitly:

"The precise pathogenesis of PCA is unclear, but it is considered to be multifactorial, involving both genetic and environmental contributions. Earlier reports have implicated frictional epidermal damage, apoptosis, viral infection, and other triggers in the disease etiology." — Lin et al., Eur J Hum Genet 2010, PMID:19690585 [cached, full text]

Genetic risk factors

Causal / high-effect: - OSMR (HGNC:8507, hgnc:8507 — verify with OAK before curating), 5p13.1 — heterozygous missense in the extracellular fibronectin type III-like (FNIII) domains. AD. - IL31RA (5q11.2) — heterozygous missense, also FNIII-domain. AD. - GPNMB (7p15) — biallelic truncating (and some missense) alleles → amyloidosis cutis dyschromica. AR.

Susceptibility / modifier: - RET codon 634 (and rarely other codons) — cutaneous lichen amyloidosis is a recognized MEN2A variant phenotype. ~⅓ of C634 carriers develop CLA (range 9–50%) [lead: PMID:12864791; PMC11587112]. - Haplotype background: the Taiwanese p.P694L allele sits on a shared ancestral haplotype (25-GAAAA) in 5/6 families plus 2 sporadic cases — a founder effect; the same amino-acid change in a Chilean family arose on a different haplotype, i.e. p.P694L is both ancestral and recurrent, favored by a CpG mutational hotspot (CCG>CTG) [cached, PMID:19690585 full text]. - Locus heterogeneity: 8/29 Taiwanese pedigrees mapped to chr5 without an OSMR coding lesion; two pedigrees gave negative LOD scores at chr5 entirely — so additional PLCA loci remain undiscovered.

Ancestry: Southern Chinese/Taiwanese, Southeast Asian, South American, Middle Eastern, and South Asian populations are over-represented.

Environmental risk factors

Protective factors

No validated genetic protective variants and no established dietary/lifestyle protective factors are reported. The only actionable "protective" intervention is cessation of frictional trauma (abandoning nylon towel/brush use) and effective itch control to break the scratch–deposition cycle. This should be recorded as expert-consensus-level, not evidence-graded.

Gene–environment interaction

The most defensible G×E model: a hypomorphic OSMR/IL31RA allele lowers the threshold at which ordinary frictional/pruritic epidermal stress produces amyloidogenic keratinocyte degeneration. Supporting observations: - OSMR missense variants appear in 34.38% of sporadic PLCA as well as 63.89% of familial PLCA, i.e. the same alleles behave as susceptibility factors outside pedigrees [cached, PMID:30734345]. - Allele dosage shifts onset: "Age of onset of PLCA with OSMR homozygous mutation (median age 20 years) was earlier than that of PLCA with OSMR heterozygous mutation (median age 32 years; P < 0.01) or PLCA with wildtype genotype (median age 32 years; P < 0.01)." [cached, PMID:30734345] - Genotype tracks severity: in a Taiwanese four-affected-member family, "those who have p.P694L mutation showed greater severity of PCA… larger areas of skin lesion… and a higher density of amyloid papules, as compared with those without the mutation." [cached, PMID:19690585 full text]

3. Phenotypes

Core phenotype set with HPO terms (all OAK-verified against sqlite:obo:hp)

Cellular/laboratory-level phenotypes (suitable for category: Cellular): - Reduced intraepidermal nerve fiber (IENF) density — small-fiber neuropathy - Elevated warm detection threshold on quantitative sensory testing - Increased epidermal OSMRβ and IL-31RA immunostaining - Increased basal keratinocyte Ki67 positivity; increased FLG/LOR expression

Phenotype characteristics

Age of onset. Adult-onset is the rule. Median 32 years in OSMR-heterozygous and wild-type Chinese patients, 20 years in OSMR-homozygotes [cached, PMID:30734345]. Central European mean age at diagnosis 54.6 ± 15.2 years (range 27–87); mean onset MA 53 ± 16.1, LA 46.7 ± 18.2 [lead, PMID:38137741]. Chinese HRQoL cohort: mean age 43.7 (18–91), mean onset 36.5 years [lead, PLOS One 2015, doi:10.1371/journal.pone.0120623]. ACD is earlier — childhood to adolescence.

Severity. Highly variable; genotype-dependent (see above). Pruritus is the severity driver, not lesion extent.

Progression. Chronic and slowly progressive; essentially never spontaneously remitting. Lesions persist for decades (reported disease durations 3–30 years in the dupilumab series [cached, PMID:39975679]).

Frequency among affected individuals. Pruritus dominates: in the dupilumab series both index patients reported Pruritus NRS 10/10 [cached, PMID:39975679]. Caution: most published frequency statements are qualitative — per docs/frequency-evidence-guidelines.md, omit frequency: rather than manufacture a band for most of these.

Quality-of-life impact

The best single QoL source is a Chinese cross-sectional study of 104 PCA patients vs 101 controls [lead, PLOS One 2015]: - Mean DLQI 9.05 ± 3.88 — moderate impairment - Highest subdomain: symptoms/feelings (2.29 ± 1.05); lowest: work/school (0.98 ± 0.73) - "Younger age, female gender, more pruritus and distribution pattern were independent predictor correlates of the high DLQI scores." - Itch severity showed the strongest association with DLQI

Corroborating per-patient data [cached, PMID:39975679]: baseline DLQI 16 and 24 in the two index cases, falling to 1 and 0 on dupilumab. Suggested instruments for a dismech definitions/outcome block: DLQI, Peak Pruritus NRS (PP-NRS), IGA, and the modified EASI (m-EASI) used in that series.

4. Genetic / Molecular Information

Causal genes

† HGNC IDs are from memory of standard mappings — verify each with uv run runoak -i sqlite:obo:hgnc info hgnc:XXXX before curating, and use the repo's lowercase hgnc: prefix.

Pathogenic variants — OSMR

All reported PLCA1 alleles are missense substitutions in the extracellular fibronectin type III-like (FNIII) repeats:

"The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function." — PMID:18179886 [cached]

"we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (one family), p.P694L (six families), and p.K697T (three families)." — PMID:19690585 [cached]

Population frequency. "None of the 142 control subjects from Taiwan (or over 250 control chromosomes from other populations) showed presence of p.P694L or the other missense mutations." [cached, PMID:19690585 full text]. p.P694L = rs387906822, ClinVar VCV000030221 / RCV000023144, classified in association with "Amyloidosis, primary localized cutaneous, 1" [lead — pull the current ClinVar review status and gnomAD AF directly before asserting a classification].

Somatic vs germline. All PLCA1/2/3 variants are germline. No somatic driver is described. The nodular form involves a clonal somatic plasma-cell population producing light chain — a different molecular category entirely.

Functional consequence — partial loss of function, not dominant negative. This is a nuance worth curating precisely:

"p.P694L mutant failed to activate STAT5 and STAT3, and… p.G513D mutant failed to activate STAT5… No dominant negative effect was observed, as OSM can activate either STAT5 or STAT3 phosphorylation in both WT/p.G513D and WT/p.P694L co-infected HaCaT cells." — PMID:33502684 [cached, full text]

Neither variant mislocalizes the receptor; the defect is signaling-competence, and the paper labels them explicitly "partial loss-of-function mutants."

Pathogenic variants — IL31RA

• p.S521F (c.1562C>T, NM_139017), exon 12 — one Taiwanese FPCA family; absent from 142 controls; codon conserved across mammals; "also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations." [cached, PMID:19690585]

Pathogenic variants — GPNMB (amyloidosis cutis dyschromica)

"the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD." — Yang et al., AJHG 2018, PMID:29336782 [cached]

Missense alleles in consanguineous Pakistani families extend the spectrum:

"We found a novel homozygous mutation, p.Gly363Val (c.1088 G>T), in GPNMB in all affected cases. In a replication study, another homozygous missense mutation in GPNMB, pIle174Met (c.522 C>G), was carried by the affected son. The two mutations were not observed in our in-house data set comprising 217 healthy Pakistani individuals or in The Genome Aggregation Database." — PMID:33687658 [cached]

Structural modeling (COMPUTATIONAL evidence): "p.Gly363Val enhanced its stability, whereas p.Ile174Met caused instability." Additional GPNMB alleles reported in Chinese pedigrees [lead: PMID:31260093]; a semidominant inheritance mode has been proposed [lead].

Modifier genes

RET C634 is the best-established syndromic modifier. Within-family locus heterogeneity is documented (one Taiwanese family had two independent genetic causes segregating simultaneously — mother/son with p.P694L, father/other son without any OSMR lesion) [cached, PMID:19690585].

Epigenetics and chromosomal abnormalities

No disease-specific DNA methylation, histone-modification, or chromosomal abnormality data identified. Do not curate speculative epigenetic content. Chromosomal microarray and karyotyping have no role in PLCA.

5. Environmental Information

• Mechanical/frictional: nylon towel, nylon brush, loofah, backscratcher; occupational/cultural bathing practices. Named entities: "nylon brush macular amyloidosis," "frictional amyloidosis" [lead: PMID:9330050, PMID:3391726, PMID:19207438]. Prolonged friction produces hyperkeratosis, keratinocyte damage (filamentous degeneration), and melanocyte stimulation.
• Iatrogenic: long-term subcutaneous injection sites (e.g. insulin) have been implicated in localized amyloid deposition [lead, PMC11587112].
• Lifestyle: no smoking/alcohol/diet association established.
• Infectious agents: EBV was historically proposed as a trigger [cached, PMID:19690585 citing "viral infection"]. Not substantiated — do not curate as a mechanism node without a primary source.
• Comorbid/associated conditions (mostly case-report level, low confidence — curate as association_signals or comorbidities, not as pathophysiology):
• Sjögren syndrome ↔ nodular cutaneous amyloidosis — the strongest of these. Eight patients across three amyloidosis centers; "All of the patients were women in whom SS had been diagnosed at a median age of 47 years… The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients. In 3 of these 4 patients as well as 2 other patients, a light chain-restricted plasma cell population was observed near the amyloid deposits." PMID:18576343 [cached]
• Systemic sclerosis / limited cutaneous SSc, CREST, SLE, RA, primary biliary cholangitis, autoimmune thyroiditis, IgA nephropathy, sarcoidosis, ankylosing spondylitis — all case-report-level [lead].
• Central European cohort comorbidity profile [lead, PMID:38137741]: endocrine/metabolic 41.5% (dyslipidemia 22%, thyroid disease 12.2%, diabetes 7.3%), cardiovascular 34.1% (hypertension 29.3%), atopy 12.2%, malignancy 12.2%. These are plausibly age-confounded background rates — flag as uncontrolled.

6. Mechanism / Pathophysiology

Proposed causal chain (curation-ready pathograph)

[TRIGGER, MOLECULAR]
  OSMR / IL31RA FNIII-domain missense  ──┐
  (impaired receptor dimerization)       │
  GPNMB loss of function ────────────────┤   +  Chronic frictional / scratch-induced
                          │      epidermal injury (environmental)
                          ▼
[MOLECULAR] Loss of OSM/OSMRβ–gp130 signal transduction
    → failure to phosphorylate STAT5 (and STAT3), ERK1/2, AKT
                          ▼
[MOLECULAR] Inactivation of the STAT5 → KLF7 axis
    (KLF7 is a direct STAT5 target gene)
                          ▼
[CELLULAR]  De-repressed basal keratinocyte differentiation (↑KRT1, KRT10, FLG, LOR)
    + AHNAK upregulation → keratinocyte hyperproliferation (↑Ki67, ↑EdU)
    + Bcl-xL suppression → increased keratinocyte apoptosis
                          ▼
[CELLULAR]  Filamentous degeneration / apoptosis of basal keratinocytes;
    keratin 5/14 tonofilament release into papillary dermis
                          ▼
[MOLECULAR] Keratin misfolding, β-sheet conversion, fibrillogenesis
    (± galectin-7, actin, apolipoprotein E, serum amyloid P as co-deposits)
                          ▼
[TISSUE]    Amyloid deposition in dermal papillae
    + impaired macrophage clearance (IL31RA→MCP-1 axis defect)
                          ▼
[TISSUE]    Small-fibre neuropathy: ↓intraepidermal nerve fibres,
    ↑epidermal OSMRβ/IL-31RA expression → nerve-fibre hypersensitivity
                          ▼
[ORGANISM]  Chronic intractable pruritus → scratching → further keratinocyte
    damage  ──────► FEEDS BACK to the injury node (vicious cycle)

Molecular pathways

IL-6-family cytokine receptor signaling is the core pathway. OSMRβ is a shared subunit of two receptors: the type II OSM receptor (OSMRβ + gp130) and the IL-31 receptor (OSMRβ + IL-31RA). This explains why lesions in both genes produce the same phenotype.

"OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation." — PMID:18179886 [cached]

Suggested GO terms (OAK-verified): - GO:0038165 oncostatin-M-mediated signaling pathway - GO:0140370 type II oncostatin-M receptor complex (cellular component) - GO:0004924 oncostatin-M receptor activity (molecular function) - GO:0007259 cell surface receptor signaling pathway via JAK-STAT - GO:1990000 amyloid fibril formation - GO:1905908 positive regulation of amyloid fibril formation - GO:0030216 keratinocyte differentiation; GO:0045618 positive regulation of keratinocyte differentiation - GO:0010838 positive regulation of keratinocyte proliferation - GO:0006915 apoptotic process - GO:0008544 epidermis development - GO:0072635 interleukin-31 production

The STAT5/KLF7 axis (the strongest mechanistic result available)

Liu et al. established the directionality: OSM is a negative regulator of keratinocyte differentiation, acting through STAT5 → KLF7. Losing OSMRβ signaling therefore de-represses differentiation.

"In summary, we identified OSM as a negative regulator of epidermal keratinocyte differentiation that acts via STAT5/KLF7 signaling in vivo and in vitro. Dysregulation of the OSM/OSMRβ/STAT5/KLF7 axis by OSMR mutation could lead to PLCA." — PMID:33502684 [cached, full text]

Supporting chain of experiments in that paper (all IN_VITRO / MODEL_ORGANISM): - GO analysis of PLCA-vs-control RNA profiles: dysregulated genes were dominated by keratinocyte differentiation processes - PLCA lesional epidermis: ↑FLG, ↑LOR, ↑Ki67 in basal keratinocytes - OSM stimulation of HaCaT/primary keratinocytes and 3D skin models decreases KRT1/KRT10/FLG/LOR; OSMR knockout rescues this - STAT5 inhibitor "almost completely" rescues; STAT3 inhibitor partial; ERK1/2 and AKT inhibitors no effect → STAT5 is the operative arm - ChIP-qPCR + luciferase reporter: STAT5 binds the KLF7 locus on OSM stimulation; three STAT5 sites in the KLF7 promoter all contribute - KLF7 overexpression ↓ differentiation markers; KLF7 knockout blocks OSM-induced differentiation change - RNA-seq accessions: GEO: GSE150884, GSE150994, GSE151174 — directly usable as a dismech datasets[] entry

AHNAK — the proliferation arm

"we found that AHNAK peptide fragments were enriched in the lesions of PLCA patients, as detected by laser capture microdissection and mass spectrometry analysis… pre-treatment with OSM can inhibit AHNAK expression in HaCaT cells, NHEKs, and 3D human skin models, but OSMR knockout or OSMR mutations abolished this down-regulation trend… the knockdown of AHNAK could induce G1 phase cell cycle arrest and inhibit keratinocyte proliferation." — Liu et al., J Dermatol Sci 2023, PMID:37100691 [cached]

"these data indicated that the elevated expression of AHNAK by OSMR mutations led to hyperproliferation and overdifferentiation of keratinocytes" — PMID:37100691 [cached]

Integrated 2026 synthesis

The most current mechanistic review ties the arms together and adds the clearance-failure arm:

"Oncostatin M (OSM) mediates keratinocyte proliferation through the STAT5-KLF7 axis upon OSMRβ engagement. Pathogenic variants in OSMR disrupt receptor dimerization, thereby suppressing signal transduction. These alterations together with cytokine dysregulation concomitantly elevate the expression of AHNAK and suppress that of Bcl-xL, which accelerate keratinocyte differentiation and apoptosis respectively, leading to the thickening of the stratum corneum and amyloid fibril deposition. Furthermore, dysregulated expression of chemokine monocyte chemoattractant protein-1 (MCP-1) by pathogenic variant in IL-31RA reduces monocyte-mediated clearance of amyloid fibrils, thereby promoting their pathological retention." — Teng et al., Int J Dermatol 2026, PMID:42029085 [cached]

This gives a clean two-arm model: overproduction (keratinocyte apoptosis/differentiation) + underclearance (monocyte/macrophage failure).

Pruritus mechanism — small-fibre neuropathy

"WDT was significantly higher in patients at all sites and correlated with itch scores (r = 0·59; P < 0·01). Patient biopsies revealed lower IENF counts (P < 0·01 using protein gene product 9.5, β3-tubulin and Neurofilament 200 stains) and increased epidermal expression of OSMRβ (P < 0·01) and IL-31RA (P < 0·01)." — Tey et al., Br J Dermatol 2016, PMID:26748444 [cached]

"SFN is present in PLCA. Pruritus in PLCA is likely associated with hypersensitivity of cutaneous nerve fibres, which may be related to an increased expression of epidermal IL-31 receptors. Targeting IL-31 receptors is therefore a potential therapeutic approach." — PMID:26748444 [cached]

Notably, cutaneous IL-31, NGF, and TrkA were not significantly increased, and serum IL-31 was not elevated — the abnormality is receptor-side, not ligand-side. This is an important negative result to curate faithfully.

⚠️ Open controversy worth a discussions: KNOWLEDGE_GAP entry. The 2026 review flags a direct conflict in the literature:

"The mechanisms of IL-31-mediated pruritus remain to be elucidated, given the conflicting observations that while some studies report wider cutaneous innervation in FPLCA patients, others demonstrate opposing results in general lichen amyloidosis patients." — PMID:42029085 [cached]

Protein dysfunction and amyloid composition

• Precursor: basal keratins K5/K14 (immuno-EM + LC-MS/MS) [cached, PMID:34459039 title-level]
• Antigenic identity with epidermal keratin, with disulfide bonds preserved (lichen form) [cached, PMID:6184423]
• Co-deposited components: galectin-7, actin, apolipoprotein E, serum amyloid P component, ubiquitin [lead: PMID:23278892, PMID:25172508]
• ⚠️ Contested: a proteomic study concluded that "the main constituent of subepidermal localized cutaneous amyloidosis is not galectin-7" [lead: PMID:32867548 / PMC7962860]. Curate galectin-7 with an explicit supports: PARTIAL or a paired REFUTE evidence item — do not present it as settled.
• ACD: deposits are DNA/keratin-positive, with intracytoplasmic fibrillary aggregates in scattered lesional keratinocytes [cached, PMID:29336782]
• Nodular: AL — monoclonal immunoglobulin light chain from local clonal plasma cells [cached, PMID:18576343; lead: Medscape/JAMA Dermatol series]

Cellular processes and cell types (CL terms, OAK-verified)

Immune involvement

PLCA is not classically an inflammatory dermatosis, and the older literature says so explicitly [cached, PMID:19690585 full text: "Although PCA itself is not considered as an inflammatory skin disease…"]. But the therapeutic response to dupilumab and nemolizumab, plus this observation, argues for a type-2 inflammatory contribution in at least a subset:

"Studies have shown that serum and cutaneous levels of type 2 cytokines (IL-4, IL-13, IL-31) and their receptors were elevated in patients with PCA, and their expression were decreased when symptoms were alleviated, indicating that type 2 inflammation may involve in LA pathogenesis" — PMID:39975679 [cached, full text]

GPNMB itself is a negative regulator of inflammation and a lysosomal-dysfunction/autophagy marker in macrophages, so ACD plausibly involves an inflammatory/clearance dimension [cached, PMID:29336782].

Metabolic changes / biochemical abnormalities

None identified. No enzyme deficiency, no ion channel defect, no metabolomic or lipidomic signature reported. Explicitly record as "not applicable / not reported" rather than leaving the reader to infer.

Molecular profiling summary

7. Anatomical Structures Affected

Organ level

• Primary: skin (UBERON:0002097 skin of body — verify), exclusively
• Secondary organ involvement: none by definition. Systemic/visceral deposition excludes the diagnosis. The one caveat: nodular PLCA may be the presenting lesion of, or progress to, systemic AL amyloidosis (heart, kidney, liver, GI, nerve).
• Body system: integumentary; peripheral nervous system secondarily (small-fibre)
• Syndromic extension: in MEN2A-associated CLA, thyroid (medullary carcinoma), adrenal (pheochromocytoma), parathyroid

Tissue and cell level

• Papillary dermis — UBERON:0001992 papillary layer of dermis (OAK-verified) — the amyloid deposition site
• Epidermis — hyperkeratosis, acanthosis, basal-layer degeneration
• Dermoepidermal junction — pigment incontinence
• Cell populations: see CL table in §6

Subcellular level (GO Cellular Component)

• Keratin filament / intermediate filament cytoskeleton — the source structure; "filamentous degeneration" of tonofilaments
• Extracellular space / extracellular matrix — deposition compartment
• Type II oncostatin-M receptor complex GO:0140370; plasma membrane — the receptor lesion site
• Lysosome / autophagosome — relevant in the GPNMB/ACD arm
• Melanosome — GPNMB's canonical role; relevant to ACD dyschromia

Localization and laterality

Bilateral and typically symmetric. - Lichen amyloidosis: shins/pretibial (classic), calves, ankles, thighs, extensor forearms, back - Macular amyloidosis: interscapular upper back (classic, rippled/reticulate), also arms, chest - MEN2A-associated CLA: characteristically interscapular, overlapping the notalgia paresthetica dermatome (T2–T6) - Nodular: acral, face, trunk, genitalia — often solitary or few - ACD: generalized trunk and limbs - Per the Chinese cohort: "PLCA lesions are typically localized to the shins, forearm and back." PMID:30734345 [cached] - Atypical variants (geographic and morphologic) are extensively catalogued — auricular concha, poikiloderma-like, vitiliginous, bullous, dyschromic [lead: PMID:34286474 Hamie 2021]

8. Temporal Development

Onset. Adult; insidious. Median 32 years (Chinese, wild-type/heterozygous), 20 years (OSMR homozygous) [cached, PMID:30734345]; mean 54.6 years at diagnosis in Central Europe [lead, PMID:38137741] — the diagnosis–onset gap suggests substantial diagnostic delay. ACD onset is childhood/adolescence. MEN2A-associated CLA: mean age at skin-lesion diagnosis 20 ± 13 years, preceding the endocrine components (mean 31 ± 17 years) [lead, PMC11587112] — clinically important, since CLA can be the earliest sign of MEN2A.

Progression. Slow, chronic, and essentially unremitting without treatment. No recognized staging system. Lichen and macular forms are "one often overlapping process" [cached, PMID:41528921], and biphasic amyloidosis represents patients manifesting both — so "progression" between subtypes is better modeled as phenotypic overlap than as staging.

Course pattern. Chronic-progressive with fluctuating pruritus intensity. Reported disease durations at presentation: 3–30 years [cached, PMID:39975679].

Duration. Lifelong.

Remission. Spontaneous remission is not described. Treatment-induced remission is achievable — complete lesion clearance occurred in 4/14 dupilumab-treated patients, with most others achieving significant improvement [cached, PMID:39975679]. Pruritus responds much faster than lesions (1–12 weeks vs 4–28 weeks).

Critical periods / windows of intervention. Two actionable ones: 1. Early interruption of the itch–scratch–friction loop before dense amyloid accumulates — the only plausibly disease-modifying non-drug intervention. 2. CLA as a sentinel for MEN2A — recognizing interscapular CLA in childhood/young adulthood can trigger RET testing years before MTC becomes clinically apparent, which is a genuine mortality-relevant window [cached, PMID:42194535].

9. Inheritance and Population

Epidemiology

• Asian population estimated prevalence ≈ 0.98 per 10,000 [lead — Pigment International 2023 review; corresponds to prevalence_class: BAND_1_5_PER_10000, rate_per_100000: 9.8]. Verify this figure against a citable primary source before curating.
• Singapore (Middle Road Hospital) annual incidence stable at 0.4% of dermatology attendances, 1984–1986 [lead: PMID:2224732 — this is a clinic proportion, not a population rate; do NOT convert it to rate_per_100000]
• Rare in Central/Northern Europe — a single Swiss/Central European tertiary center accumulated only 41 cases [lead, PMID:38137741]
• ~10% of cases are familial [lead, review-level]; in South America, Ollague et al. reported ~⅓ of PCA cases have a positive family history [cached, PMID:19690585 full text]
• No GBD, SEER, or national registry data exist for PLCA

Inheritance (genetic subset)

• PLCA1 (OSMR), PLCA2 (IL31RA): autosomal dominant — HPO HP:0000006
• PLCA3 / ACD (GPNMB): autosomal recessive — HPO HP:0000007
• Consanguinity is a clear contributor to the ACD arm: both Pakistani ACD families were consanguineous [cached, PMID:33687658]
• Homozygous OSMR genotypes exist and produce earlier, more severe disease with a striking sex skew: "The male/female ratio of patients carrying a homozygous OSMR mutation (0.29) was significantly lower than that of patients carrying a heterozygous OSMR mutation (1.08; P < 0.05) and of patients with wildtype OSMR (1.75; P < 0.01)." [cached, PMID:30734345]
• Multi-locus: within-family locus heterogeneity documented, but this is not digenic inheritance — do not use HP:0010984. It is two independent monogenic causes co-segregating in one pedigree.

Penetrance. Incomplete and age-dependent; not formally quantified. Expressivity is markedly variable — even within a single family (severity tracked with p.P694L carriage) [cached, PMID:19690585].

Anticipation. Not described. Germline mosaicism. Not reported. Carrier frequency. Not established for any of the three genes.

Founder effect. Yes — Taiwanese p.P694L on the shared 25-GAAAA haplotype in 5/6 families plus 2 sporadic cases; the Chilean p.P694L carriers had a different haplotype background, establishing p.P694L as both ancestral and recurrent (CpG hotspot) [cached, PMID:19690585].

Population demographics

• Ethnic/geographic: highest in Southern Chinese, Taiwanese, Southeast Asian, and South American (Brazil, Chile) populations; also over-represented in Middle Eastern and South Asian populations. Explicitly reported prevalence gradient within Southeast Asia: more common in Chinese than in Malays or Indians [cached, PMID:19690585 full text].
• Sex ratio: female predominance overall. Central Europe M:F = 0.64:1 [lead, PMID:38137741]; Chinese HRQoL cohort 43M:61F (59% female) [lead]; the Sjögren-associated nodular cohort was 8/8 female [cached, PMID:18576343]. But the genotyped Chinese cohort shows the direction depends on OSMR genotype (see above) — worth curating that nuance rather than a flat ratio.
• Age distribution: peaks 3rd–6th decade; ACD is pediatric-onset.

10. Diagnostics

Clinical tests

Biopsy + histochemistry is the diagnostic cornerstone. Diagnosis is clinicopathologic; there is no blood test.

• Histopathology: hyperkeratosis, irregular acanthosis, expansion of the dermal papillae by eosinophilic globular amyloid deposits, pigment incontinence with dermal melanophages, sparse perivascular infiltrate [lead: PMC11947714 case series]
• Congo red + polarized light microscopy (CR-PLM) — the reference standard, showing apple-green birefringence. In PCA, "most of the apple-green birefringence patterns were a short, curved line or dot-like; a lump-like pattern was rare" [lead: PMID:39663859]. Because deposits are small and subepidermal, birefringence can be subtle and false negatives are common.
• Congo red UV-emitted fluorescence microscopy (CR-UFM) — a 2025 advance reported as superior to CR-PLM, CR staining, crystal violet, and H&E in diagnosing PCA [lead: PMID:39663859]. Worth curating as an emerging diagnostic.
• Other stains: crystal violet, thioflavin T, pagoda red, Dylon
• Immunohistochemistry: anti-cytokeratin (CK5/6, K5/K14 positivity supports keratinocyte origin — used in both dupilumab index cases [cached, PMID:39975679]); anti-κ/λ light chain to identify AL in nodular lesions; serum amyloid P
• LC-MS/MS proteomic amyloid subtyping — definitive typing, distinguishing keratin-derived from AL [cached, PMID:34459039]
• Electron microscopy / immuno-EM — non-branching 6–10 nm fibrils; identifies intracytoplasmic fibrillary aggregates in ACD keratinocytes [cached, PMID:29336782]
• Dermoscopy (non-invasive adjunct): the characteristic macular-amyloidosis pattern is "a central hub of either white or brown surrounded by various configurations of brownish pigmentation, including fine radiating streaks, dots, leaf-like projections, and bulbous projections" [lead: Pudasaini 2024, Skin Health Dis]
• Quantitative sensory testing + IENF density on PGP9.5 — research-grade, demonstrates the small-fibre neuropathy [cached, PMID:26748444]. Not routine clinical practice.

Laboratory work-up to exclude systemic disease (mandatory in nodular form)

Serum and urine protein electrophoresis with immunofixation, serum free light chain ratio, CBC, creatinine/eGFR, LFTs, NT-proBNP and troponin, ECG/echocardiography, and consideration of bone marrow biopsy and fat pad aspirate. For nodular PLCA, long-term follow-up is recommended even when the initial systemic screen is negative.

Genetic testing

• Recommended approach: targeted single-gene or small-panel sequencing of OSMR first in familial/early-onset/severe cases (highest yield: 63.89% in familial and 34.38% in sporadic Chinese PLCA [cached, PMID:30734345]), then IL31RA, then GPNMB if the phenotype is dyschromic/recessive.
• DNA mass spectrometry genotyping of recurrent OSMR alleles has been used as a rapid screen in sporadic disease [cached, PMID:24237668 — title/metadata only; the cached record has no abstract body, so no snippet is quotable. Cite by title or find an alternative source.]
• WES — the discovery route for GPNMB/ACD [cached, PMID:33687658]; appropriate for atypical/unsolved cases. WGS offers no established incremental value.
• RET testing should be considered in any patient with interscapular or generalized CLA, particularly with any endocrine sign or family history — CLA can precede MTC by a decade [cached, PMID:42194535].
• Not indicated: chromosomal microarray, karyotype, FISH, mtDNA testing, repeat-expansion testing.

Omics-based diagnostics

Only tissue proteomics (LC-MS/MS amyloid typing) has real diagnostic utility. RNA-seq, metabolomics, epigenomics, and liquid biopsy have no established diagnostic role in PLCA.

Clinical criteria and differential diagnosis

No formal consensus diagnostic criteria (ACR/EULAR/society-level) exist for PLCA — worth noting explicitly.

"Historically, cutaneous amyloidosis has been misdiagnosed" — Janodia & Schwartz, Dermatology 2026, PMID:41528921 [cached]

Differential diagnosis by subtype: - Lichen amyloidosis vs. lichen simplex chronicus, prurigo nodularis, hypertrophic lichen planus, lichen planus, pretibial myxedema, papular mucinosis, colloid milium, nodular scabies. (Discriminator: Congo red-positive papillary dermal deposits; keratin-derived on IHC.) - Macular amyloidosis vs. post-inflammatory hyperpigmentation, notalgia paresthetica (which may coexist and be causal), frictional melanosis, ashy dermatosis/erythema dyschromicum perstans, confluent and reticulated papillomatosis, Dowling-Degos disease. - Nodular amyloidosis vs. systemic AL amyloidosis with skin involvement (must be excluded), colloid milium, cutaneous lymphoma, granuloma annulare, sarcoidosis. - ACD vs. dyschromatosis symmetrica/universalis hereditaria, xeroderma pigmentosum, Dowling-Degos, poikiloderma syndromes.

Screening

• No population screening; no newborn screening; no carrier screening program. PLCA does not meet screening criteria (benign, adult-onset, no preventive intervention).
• Cascade screening is warranted in one situation: a proband with CLA and a pathogenic RET variant — first-degree relatives require RET cascade testing with prophylactic thyroidectomy decision-making per MEN2 guidelines. This is a case where a skin finding drives a cancer screening cascade.
• Relatives of OSMR/IL31RA probands: predictive testing is technically possible but of limited clinical utility (no preventive action available) — counseling-only.

11. Outcome / Prognosis

Survival and mortality

PLCA of keratinocyte origin does not affect survival. There is no disease-specific mortality, no reduction in life expectancy, and no reported malignant transformation of the amyloid deposits themselves. Do not curate survival statistics for the keratinocyte-derived forms.

Two exceptions where prognosis is not benign: 1. Nodular PLCA — reported progression to systemic AL amyloidosis of approximately 7%, with some series citing a 7–50% range on long-term follow-up [lead — the wide range reflects small heterogeneous series; curate the 7% figure with an explicit uncertainty note, not the 50% ceiling]. Systemic AL amyloidosis carries substantial cardiac and renal mortality. Reassuringly, in the Sjögren-associated nodular series: "Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years." [cached, PMID:18576343] 2. MEN2A-associated CLA — prognosis is driven entirely by the endocrine components. "In both subtypes, nearly 100% of patients eventually develop medullary thyroid cancer (MTC), and up to 50% develop pheochromocytomas." [cached, PMID:30085596]

Morbidity and function

The burden is symptomatic and psychosocial, not organ-failure-driven: - Mean DLQI 9.05 ± 3.88 (moderate impairment) [lead, PLOS One 2015] - Intractable pruritus, sleep disruption, excoriation, secondary infection risk - Cosmetic disfigurement from persistent hyperpigmentation — significant in visible/exposed sites - Small-fibre neuropathy with thermal sensory deficits [cached, PMID:26748444]

No disability registry data; ICF-coded outcomes not reported.

Complications

Secondary bacterial infection from excoriation; post-inflammatory dyschromia; lichenification; scarring from aggressive procedural treatment; in ACD, permanent depigmentation from melanocyte loss ("Depigmentation of the lesions was attributable to loss of melanocytes." [cached, PMID:29336782]).

Recovery potential

Lesions do not resolve spontaneously. Amyloid deposits are slow to clear even with successful therapy — hence the consistent observation that pruritus improves in 1–12 weeks while lesions take 4–28 weeks [cached, PMID:39975679]. Complete resolution occurs in a minority (4/14 with dupilumab).

Prognostic factors

• OSMR homozygosity → earlier onset, greater severity [cached, PMID:30734345; PMID:19690585]
• Pruritus severity → the dominant determinant of QoL, more so than lesion extent [lead, PLOS One 2015]
• Younger age, female sex → worse DLQI [lead, PLOS One 2015]
• Nodular subtype + monoclonal gammopathy → the one prognostic red flag requiring systemic surveillance
• No validated molecular prognostic biomarkers exist.

12. Treatment

Overarching reality check — this should be stated plainly in any KB entry:

"The current standard of care, high-potency corticosteroids, can provide symptomatic relief. Newer therapies may decrease amyloid deposition and progression of disease." — PMID:41528921 [cached]

"PCA lesions are currently considered difficult to treat, since no consistently effective therapy has been reported despite many therapeutic modalities have been tried in PCA treatment" — PMID:39975679 [cached, full text]

There is no FDA/EMA-approved therapy for PLCA. Everything below is off-label.

Conventional / first-line (symptomatic)

The Weidner systematic review (1985–2016) catalogues the full conventional armamentarium — "retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D3 analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, and laser treatment" [lead: Weidner, Illing & Elsner, Am J Clin Dermatol 2017;18:629–642, doi:10.1007/s40257-017-0278-9].

Biologics — the mechanistically motivated arm

Dupilumab (anti-IL-4Rα; blocks IL-4/IL-13) — the best-documented modern option. NCIT:C162455 Dupilumab; therapeutic_modality: MONOCLONAL_ANTIBODY.

"As of October 2024, 14 patients with PCA (including our 2 patients) tried dupilumab treatment, with female to male ratio of 7:7. These patients aged 20–76 years old, and their medical history of PCA ranged from 3–27 years. All of them resisted to traditional therapy for PCA, and achieved disease relief on dupilumab treatment. Itching usually alleviated firstly, with a reported remission time of 1–12 weeks after treatment. Skin lesions improved later, which began and largely resolved after 4 weeks and 28 weeks, respectively. 4 patient patients got complete skin lesions remission" — PMID:39975679 [cached, full text]

Dosing used: 600 mg loading, then 300 mg q2w. Notably effective in non-atopic patients, which argues the benefit isn't purely treatment of concurrent eczema [cached, PMID:39975679]. Corroborated by PMID:39953901 [cached — title/metadata only; no abstract body, so cite by title].

Nemolizumab (anti-IL-31RA) — the most mechanistically on-target agent, given the demonstrated epidermal IL-31RA/OSMRβ overexpression [cached, PMID:26748444]. NCIT:C170211 Nemolizumab; MONOCLONAL_ANTIBODY. Reported successful in PLCA with atopic dermatitis [lead: Fukumoto 2024, JEADV, doi:10.1111/jdv.20039] and in a refractory non-atopic patient [lead: JAAD Case Rep 2025, PMC12256333]. This is the clearest example in PLCA of receptor biology directly nominating a drug.

JAK inhibitors — the newest and arguably most promising arm

Rationale is direct: the OSMR/IL31RA receptors signal through JAK/STAT, and IL-4/IL-13/IL-31 itch signaling is JAK-dependent.

Tofacitinib — NCIT:C95800; SMALL_MOLECULE. Two independent 2025 reports: - Retrospective series, n=24, tofacitinib 10 mg daily: "significant improvements were observed in BSA (p < 0.05), PP-NRS (p < 0.001), and IGA (p < 0.01) at week 4"; good tolerability, no serious AEs causing discontinuation [lead: Wang et al., J Dermatol 2025, PMID:40908738] - Single-arm clinical trial, week 10: pruritus NRS 6.9 → 0.4; DLQI 11.8 → 2.6; Lesion Severity 13.3 → 4.9 [lead: Clin Exp Dermatol 2026;51(1):86, doi:10.1093/ced/llaf364]

Others: baricitinib (refractory CLA + AD), upadacitinib (case report of remission), abrocitinib (LA with AD) — all case-level [leads].

Procedural / device

A 2025 systematic review of 16 studies, 432 patients covering fractional CO₂ laser, Nd:YAG, Er:YAG, microneedling, and phototherapy [lead: Lasers Med Sci 2025, doi:10.1007/s10103-025-04783-3]. NCIT: NCIT:C15466 Laser Therapy or NCIT:C157901 Laser Resurfacing; therapeutic_modality: DEVICE. Also dermabrasion, surgical excision (nodular/localized lesions).

Nodular-form-specific

Excision, intralesional corticosteroid, laser, and — for a monoclonal-gammopathy-associated case — bortezomib + dexamethasone (plasma-cell-directed, targeting the actual AL source) [lead: PMID:34894809].

Pharmacogenomics

No PharmGKB/CPIC guidance specific to PLCA. Generic considerations apply for JAK inhibitors (thromboembolic/malignancy boxed warnings, TB screening) — not PLCA-specific.

Advanced therapeutics

No gene therapy, cell therapy, RNA-based therapy, or gene editing is in development for PLCA. No registered interventional clinical trials on ClinicalTrials.gov were identified for PLCA in this search — the tofacitinib "single-arm clinical trial" appears to be investigator-initiated and may not carry an NCT ID. Verify on ClinicalTrials.gov before adding any clinical_trials: block.

Treatment strategy / algorithm (synthesized, expert-consensus level)

1. Confirm diagnosis by biopsy with Congo red; type the amyloid if nodular.
2. Exclude systemic disease (mandatory for nodular; prudent for atypical/generalized).
3. Screen for MEN2A if interscapular or generalized CLA → RET testing.
4. Remove the driver: stop nylon towel/brush friction; treat any underlying pruritic dermatosis (especially atopic dermatitis).
5. First line: high-potency topical corticosteroid ± occlusion; topical calcineurin inhibitor; emollients; antipruritics.
6. Second line: phototherapy (NB-UVB); topical/oral retinoid; amitriptyline for neuropathic itch.
7. Refractory: dupilumab (best evidence base) or nemolizumab (most on-target) or an oral JAK inhibitor (fastest antipruritic effect, largest series).
8. Adjunct/cosmetic: fractional CO₂ or Nd:YAG laser, microneedling for pigmentation and texture.
9. Nodular with monoclonal protein: hematology referral; plasma-cell-directed therapy; lifelong systemic surveillance.

No head-to-head comparisons exist. No combination-therapy regimens are established. Personalized/genotype-guided treatment is aspirational — plausible but untested is the hypothesis that IL31RA/OSMR-mutant patients should preferentially receive IL-31-axis blockade (nemolizumab) or JAK inhibition. This is a good candidate for a mechanistic_hypotheses entry with status: EMERGING.

13. Prevention

Primary prevention. The only actionable measure is avoidance of chronic frictional skin trauma — discontinuing nylon towels, brushes, and loofahs, particularly in high-prevalence populations where this is a cultural bathing practice. Public-health education in Taiwan/Southeast Asia/Middle East is a plausible but untested intervention. Adequate treatment of pre-existing pruritic dermatoses (especially atopic dermatitis) to prevent the scratch–deposition cycle is a reasonable secondary aim.

Secondary prevention. Early recognition and biopsy of persistent pruritic hyperpigmented lesions, particularly in high-prevalence populations, to interrupt the cycle before dense amyloid accumulates.

Tertiary prevention. - Aggressive itch control to prevent excoriation, lichenification, secondary infection, and further deposition - Nodular PLCA: periodic surveillance for systemic AL amyloidosis (SPEP/UPEP/free light chains, NT-proBNP, renal function) — indefinite - MEN2A-associated CLA: the highest-value preventive action in this whole disease area — RET genotype-directed prophylactic thyroidectomy and biochemical surveillance for pheochromocytoma/hyperparathyroidism per MEN2 guidelines

Immunization. Not applicable.

Screening programs. None; not indicated for keratinocyte-derived PLCA (see §10).

Genetic screening / counseling. - AD forms (OSMR/IL31RA): 50% recurrence risk to offspring; counsel on variable expressivity and incomplete penetrance. PGD/prenatal testing is technically available but not clinically indicated for a non-life-threatening, non-disabling adult-onset skin condition — this should be stated explicitly to avoid implying otherwise. - AR form (GPNMB/ACD):* 25% sib recurrence risk; carrier testing relevant in consanguineous families (both reported Pakistani ACD families were consanguineous [cached, PMID:33687658]). Counseling on consanguinity risk is appropriate. - RET/MEN2A: entirely different calculus — cascade testing is strongly indicated* and life-saving.

Risk stratification. No validated risk models exist.

Public health / environmental interventions. Education about frictional bathing practices; no sanitation, vector-control, or pollutant-reduction dimension.

Prophylaxis. No prophylactic medication.

14. Other Species / Natural Disease

Taxonomy. Human (NCBITaxon:9606). Experimental models in Mus musculus (NCBITaxon:10090).

Naturally occurring homologous disease: essentially absent. No entry in OMIA corresponding to primary localized cutaneous amyloidosis was identified, and no companion-animal or wildlife counterpart is described. This is a genuine negative finding and should be recorded as such, not left blank.

Related but not homologous animal observations (do not conflate): - Cutaneous amyloidosis in horses — nodular/plaque-forming, immunoglobulin-derived (AL-like); mechanistically the equine analog of nodular PLCA, not of lichen/macular PLCA [general veterinary dermatology; verify before citing] - DBA/2J mouse — carries a truncating Gpnmb mutation causing iris pigment dispersion and pigmentary glaucoma. This is the same gene as human ACD but a different organ and phenotype [lead]. It is nonetheless the most informative naturally occurring Gpnmb-null model and is worth a HUMAN_MODEL_MISMATCH note. - Breeds (VBO): none identified.

Orthologous genes (verify NCBI Gene IDs before curating): Osmr (mouse), Il31ra (mouse), Gpnmb (mouse; DBA/2J allele), Ret (mouse).

Comparative biology. The IL-6-family cytokine receptor architecture (gp130/OSMRβ/IL-31RA) is well conserved across mammals, and the IL31RA p.S521 codon is "well conserved in mammals" [cached, PMID:19690585]. However — and this is the key comparative point — the downstream skin phenotype is NOT conserved (see §15).

Zoonotic potential / cross-species transmission. None. Not an infectious or transmissible amyloidosis (unlike AA amyloidosis, which has demonstrated transmissible seeding in some animal systems).

15. Model Organisms

Available models

1. Osmr^−/− C57BL/6 mouse (CRISPR/Cas9) — the flagship model [cached, PMID:33502684]

Recapitulated features: - Significantly increased tail epidermal thickness at P30 (n=19 across three litters, 10M/9F) - RNA-seq: 2-fold change in 2,328 genes; GO enrichment for keratinocyte differentiation and skin development; 39 differentially expressed genes known to relate to epidermal keratinocyte differentiation - Confirmed upregulation of Krt1, Krt10, Flg, Lor by qRT-PCR and Western blot - Significantly increased basal keratinocyte proliferation (EdU incorporation) in tail and dorsal skin - Decreased Klf7 expression vs WT - Hair follicle cycle changes at P30

⚠️ Critical limitation — this is a textbook HUMAN_MODEL_MISMATCH, not a generic knowledge gap:

"Unfortunately, no PLCA-like phenotype was observed in these mice under physiological or pathological conditions (including UVA exposure and an itch challenge; data not shown)." — PMID:33502684 [cached, full text]

The mouse reproduces the upstream cellular mechanism (differentiation/proliferation dysregulation) but not the disease-defining outcome (dermal amyloid deposition, pruritic lesions) — even when challenged with UVA and an itch stimulus. Note also that the mouse is a complete knockout whereas human disease arises from heterozygous partial-loss-of-function missense alleles, so the model isn't even genotype-matched. Recommended dismech treatment: a discussions: entry with kind: HUMAN_MODEL_MISMATCH, prompt phrased as a question ("Does murine Osmr loss fail to produce cutaneous amyloid because mouse epidermis lacks a human-specific keratin-amyloidogenic property, because heterozygous missense ≠ null, or because murine skin lacks the requisite frictional/pruritic environmental co-factor?"), with proposed experiments including knock-in of the human p.P694L allele, chronic mechanical friction challenge, and humanized-keratin backgrounds.

2. Osmr knockout mouse — AHNAK arm [cached, PMID:37100691]: gene-edited mice confirmed that OSMR knockout abolishes OSM-mediated AHNAK downregulation, matching human lesional findings.

3. HaCaT immortalized human keratinocyte line — the principal in vitro workhorse. Available derivatives: OSMR-knockout HaCaT (CRISPR), KLF7-knockout HaCaT (two independent clones), and OSMR-knockout HaCaT reconstituted with lentiviral WT / p.G513D / p.P694L OSMR-P2A-GFP. This last construct set is the definitive tool for variant functional assay [cached, PMID:33502684].

4. NHEK — primary normal human epidermal keratinocytes [cached, PMID:33502684, PMID:37100691]

5. 3D reconstituted human epidermis / organotypic skin models — used to confirm OSM-driven suppression of FLG/LOR and AHNAK regulation in a stratified tissue context [cached, PMID:33502684, PMID:37100691]

6. Patient-derived primary keratinocyte cultures — the original functional evidence: "cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation" [cached, PMID:18179886]

7. HeLa cells — used for GPNMB functional work [cached, PMID:29336782]

8. HEK293T — KLF7 promoter luciferase reporter assays [cached, PMID:33502684]

9. In silico: I-TASSER 3D structural modeling of GPNMB variant stability [cached, PMID:33687658] — evidence_source: COMPUTATIONAL

10. DBA/2J mouse (spontaneous Gpnmb truncation) — relevant to the ACD arm but with an ocular, not cutaneous, phenotype [lead]

Model limitations (aggregate)

Research applications

Validated uses: dissecting OSM/OSMRβ/STAT5/KLF7 signaling; variant functional classification (the reconstituted OSMR-KO HaCaT system is essentially a ready-made functional assay for ACMG PS3-level evidence); keratinocyte differentiation/proliferation biology; drug-target validation for JAK/STAT5 inhibition. Not currently usable for: amyloidogenesis kinetics, itch pharmacology, or anti-amyloid therapeutic screening.

Resources

MGI (Osmr, Il31ra, Gpnmb alleles), IMPC/KOMP, IMSR, Cellosaurus (HaCaT: CVCL_0038), ATCC. RNA-seq data: GEO GSE150884, GSE150994, GSE151174.

Appendix A — Suggested dismech modeling notes

Module conformance. This entry is a strong candidate to declare conforms_to against amyloidogenesis (already in kb/modules/), substituting the disease-specific precursor:

Consider also epithelial_barrier_dysfunction for the hyperkeratosis/differentiation arm, and note the peripheral_axonal_degeneration module as a possible partial conformer for the small-fibre neuropathy node.

Subtype structure. Model has_subtypes with short slug-friendly names: Lichen, Macular, Biphasic, Nodular, ACD, MEN2A-CLA. The nodular subtype is mechanistically a different disease (AL, plasma cell clone, systemic risk) — flag this prominently in its description and in a grouping_rationale-style note, since lumping it into a keratin-origin pathograph would be a substantive error.

Grouping opportunity. A Cutaneous_Amyloidoses grouping (grouping_basis: [SHARED_PHENOTYPE, CLINICAL_CONVENTION]) over PLCA + nodular + ACD + secondary cutaneous amyloidosis, with criteria_semantics: NECESSARY, would capture the boundary auditably.

Evidence-source tagging discipline for this entry: - PMID:6184423, 18179886 (patient keratinocytes), 26748444, 29336782, 30734345, 18576343, 39975679, 42194535 → HUMAN_CLINICAL (18179886's cell work is IN_VITRO — split the evidence items) - PMID:33502684 (Osmr−/− mouse), 37100691 (gene-edited mice) → MODEL_ORGANISM; split their HaCaT/3D-skin claims to IN_VITRO - PMID:33687658 I-TASSER modeling → COMPUTATIONAL - PMID:41528921, 42029085 → narrative reviews; prefer primary sources, use these for framing/synthesis statements only

Do not curate without fetching first: every PMID marked [lead] above. Run just fetch-reference PMID:XXXXXXX and verify snippet-as-exact-substring before writing any evidence item. Note specifically that PMID:24237668, PMID:31478212, PMID:34459039, and PMID:39953901 have title/metadata-only cache records with no abstract body — no snippet can be quoted from them; either cite by title with a notes:-level claim or find an alternative source.

Appendix B — Explicit "not available" findings

For completeness, the following were searched for and not found — record as absent rather than omitting:

• Formal consensus diagnostic criteria (no society guideline)
• Population prevalence outside the single Asian estimate
• Any registered interventional clinical trial with an NCT identifier
• Any approved therapy
• Disease-specific mortality or survival data (keratinocyte-derived forms)
• Metabolomic, lipidomic, epigenomic, or single-cell/spatial transcriptomic data
• Validated prognostic or diagnostic circulating biomarkers
• Newborn/carrier/population screening programs
• Naturally occurring homologous disease in other species (OMIA)
• iPSC-derived or organoid disease models
• Pharmacogenomic (PharmGKB/CPIC) guidance
• Any animal model that reproduces cutaneous amyloid deposition

Sources

Verified from local reference cache (safe to quote): - PMID:6184423 — Kobayashi & Hashimoto, J Invest Dermatol 1983 — keratin origin of skin amyloid - PMID:18179886 — Arita et al., Am J Hum Genet 2008 — OSMR mutations in FPLCA - PMID:18576343 — Meijer et al., Arthritis Rheum 2008 — Sjögren + nodular amyloidosis - PMID:19690585 — Lin et al., Eur J Hum Genet 2010 — IL31RA mutation, ancestral OSMR allele - PMID:24237668 — Chang et al., Br J Dermatol 2014 — DNA mass spectrometry in sporadic PLCA - PMID:26748444 — Tey et al., Br J Dermatol 2016 — pruritus/small-fibre neuropathy - PMID:29336782 — Yang et al., Am J Hum Genet 2018 — GPNMB loss causes ACD - PMID:30085596 — Lath et al., StatPearls — MEN2 - PMID:30734345 — Lu et al., Clin Exp Dermatol 2019 — Chinese OSMR mutation spectrum - PMID:31478212 — Adams et al., Clin Exp Dermatol 2020 — novel OSM/IL-31 receptor mutation - PMID:33502684 — Liu et al., Protein Cell 2021 — STAT5/KLF7 axis - PMID:33687658 — Rahman et al., Genes Genomics 2021 — GPNMB missense in Pakistani families - PMID:34459039 — Bourguiba et al., JEADV 2022 — keratin 5/14 amyloid subtyping - PMID:37100691 — Liu et al., J Dermatol Sci 2023 — AHNAK - PMID:39953901 — Te et al., J Cutan Med Surg 2025 — off-label dupilumab - PMID:39975679 — Guo et al., Front Med 2025 — dupilumab cases + literature review - PMID:41528921 — Janodia & Schwartz, Dermatology 2026 — updated approach - PMID:42029085 — Teng et al., Int J Dermatol 2026 — OSM/IL-31 mechanistic review - PMID:42194535 — Łabędź et al., J Clin Med 2026 — generalized CLA with RET Y806C

Leads requiring verification: - OMIM 105250 — PLCA1 · OMIM 613955 — PLCA2 · OMIM 601743 — OSMR - Orphanet 137807 — primary cutaneous amyloidosis · Orphanet 137810 — nodular - PMID:38137741 — PLCA in Central Europe (PMC10743860) - PMID:40908738 — Tofacitinib for PLCA · Tofacitinib single-arm trial, Clin Exp Dermatol 2026 - Weidner et al. 2017 — systematic treatment review - Hamie et al. 2021 — atypical clinical variants - 2025 systematic review of procedural treatment, Lasers Med Sci - Nemolizumab in refractory non-atopic PLCA (PMC12256333) · Nemolizumab with AD, JEADV 2024 - PMID:39663859 — Congo red + fluorescence microscopy - PMID:32867548 — main constituent is not galectin-7 · PMID:23278892 — galectin-7 and actin · PMID:25172508 — galectin-7 amyloidogenic peptides - PMID:12864791 — MEN2A and CLA association · Endocrine perspective on CLA, RET C634 (PMC11587112) - Health-related QoL in PCA, PLOS One 2015 (PMC4370430) - PMID:2224732 — epidemiology of PCA in Southeast Asia · PLCA review, Pigment International 2023 - PMID:19207438 — nylon towel friction · PMID:9330050 — nylon cloth macular amyloidosis · PMID:3391726 — friction amyloidosis - PMID:31260093 — three novel GPNMB mutations · PMID:34894809 — bortezomib for nodular PLCA - ClinVar VCV000030221 — OSMR p.Pro694Leu · Histopathological insights case series (PMC11947714) · Dermatoscopy of PLCA, Skin Health Dis 2024 · ICD-10 E85.4