👪

Inheritance

2

Autosomal dominant inheritance HP:0000006

The familial form of PLCA caused by OSMR or IL31RA missense variants is inherited in an autosomal dominant manner. Most PLCA overall is sporadic, but a substantial minority of cases in South America and Southeast Asia are familial.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:18179886 SUPPORT Human Clinical

"Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis."

States autosomal dominant inheritance for the OSMR-related familial form.

Autosomal recessive inheritance HP:0000007

Amyloidosis cutis dyschromica, the generalized dyschromic form of primary cutaneous amyloidosis, is inherited in an autosomal recessive manner through biallelic GPNMB loss-of-function alleles.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:29336782 SUPPORT Human Clinical

"We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD."

States autosomal recessive inheritance for the GPNMB-related dyschromic form.

◆

Subtypes

7

Lichen (papular) amyloidosis MONDO:0018856

The most common form of PLCA. Presents as intensely pruritic, discrete, firm, hyperkeratotic hyperpigmented papules, classically on the extensor shins but also the forearms and back, often coalescing into rippled plaques. Amyloid is keratin-derived and deposited in the dermal papillae; the epidermis shows hyperkeratosis and acanthosis. Strongly associated with chronic friction and scratching.

Show evidence (1 reference)

PMID:40151750 SUPPORT Human Clinical

"LA is strongly associated with chronic friction and pruritus, whereas MA presents with asymptomatic hyperpigmentation."

Distinguishes lichen amyloidosis from macular amyloidosis on the basis of pruritus and chronic friction, the defining features of this subtype.

Macular amyloidosis MONDO:0015303

Presents as greyish-brown, often rippled or reticulated hyperpigmented macules, characteristically over the upper back (interscapular region) and extensor arms, typically with little or no papule formation and less pruritus than lichen amyloidosis. Histologically the amyloid deposits in the papillary dermis are smaller than in the lichen form, but tinctorially and immunohistochemically the two are indistinguishable, supporting the view that they are two ends of one keratin-derived process.

Show evidence (1 reference)

PMID:1930004 SUPPORT Human Clinical

"Histologically, PA differed from MA by the larger size of amyloid deposits in the papillary dermis. There was no difference in their tinctorial and immunohistochemical characteristics."

Establishes that macular amyloidosis differs from the papular (lichen) form mainly by deposit size, with identical staining characteristics - the basis for treating them as one overlapping process.

Biphasic (mixed lichen and macular) amyloidosis

Coexistence of lichenoid papules and macular pigmentation in the same patient, reflecting the overlapping nature of the two keratin-derived forms rather than a mechanistically separate entity.

Show evidence (1 reference)

PMID:40151750 SUPPORT Human Clinical

"It includes lichen amyloidosis (LA), macular amyloidosis (MA), and biphasic amyloidosis."

Names biphasic amyloidosis as a recognized subtype of PLCA alongside the lichen and macular forms.

Primary localized cutaneous nodular amyloidosis MONDO:0015302

Mechanistically distinct from the keratin-derived forms. Presents as solitary or few waxy nodules or plaques, most often on the limbs, face, or trunk. The amyloid is AL (immunoglobulin light chain) type, produced by a light-chain-restricted plasma-cell population within the lesion - in effect a localized cutaneous plasma-cell dyscrasia. It carries a small risk of representing or evolving into systemic amyloidosis, so systemic screening is warranted. It has been reported in association with Sjogren syndrome; that association rests on small uncontrolled case series without a denominator, so it is recorded here as a reported association rather than as established over-representation.

Show evidence (3 references)

PMID:41528921 SUPPORT Other

"Primary cutaneous amyloidosis has been classified into three groups: macular, lichen, and nodular, the former two being one often overlapping process, and the latter a localized plasma dyscrasia with a small risk of representing a systemic disease."

Establishes nodular amyloidosis as a localized plasma-cell dyscrasia, mechanistically separate from the overlapping macular/lichen keratin-derived process, and notes the systemic risk.

PMID:6184423 SUPPORT Human Clinical

"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."

Directly demonstrates that nodular amyloid, unlike lichen and macular amyloid, is NOT keratin-derived - the immunohistochemical basis for treating it as a separate subtype.

PMID:18576343 SUPPORT Human Clinical

"SS should be considered in patients with cutaneous amyloidosis."

Supports an awareness/screening recommendation for Sjogren syndrome in cutaneous amyloidosis. Recorded as PARTIAL because this is an 8-patient convenience series drawn from three amyloidosis-centre databases with no denominator and no comparison group - the paper's own title asks "coincidence or a distinct clinical entity?" - so it does not establish epidemiological over-representation.

Amyloidosis cutis dyschromica (GPNMB-related, autosomal recessive) MONDO:0017906

GPNMB hgnc:4462 Autosomal recessive inheritance

A distinct, generalized, early-onset form characterized by widespread reticulate hyperpigmentation mottled with small hypopigmented macules on the trunk and limbs, with little or no pruritus. Caused by biallelic (homozygous or compound heterozygous) truncating or missense variants in GPNMB (glycoprotein NMB), inherited in an autosomal recessive manner and reported predominantly in East and Southeast Asian and South Asian families. The dyschromia reflects loss of melanocytes in the depigmented macules.

Show evidence (1 reference)

PMID:29336782 SUPPORT Human Clinical

"Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs."

Defines amyloidosis cutis dyschromica as a distinct clinical form of primary cutaneous amyloidosis with a characteristic dyschromic presentation.

Familial primary localized cutaneous amyloidosis (OSMR / IL31RA) MONDO:0007101

OSMR hgnc:8507 IL31RA hgnc:18969 Autosomal dominant inheritance

Autosomal dominant familial form, typically presenting with lichen and/or macular lesions, caused by heterozygous missense variants in OSMR (encoding oncostatin M receptor beta) or, less commonly, IL31RA (interleukin-31 receptor A). Both genes lie in the linked 5p13.1-q11.2 interval and encode subunits of the shared oncostatin M type II / IL-31 receptor system; the pathogenic substitutions cluster in the extracellular fibronectin type III-like domains required for receptor dimerization. Familial PLCA is especially prevalent in Taiwanese, southern Chinese, and South American (Brazilian) populations.

Show evidence (1 reference)

PMID:19690585 SUPPORT Human Clinical

"PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5."

Establishes the two-gene (OSMR and IL31RA) genetic basis of familial PLCA.

Cutaneous lichen amyloidosis in MEN2A (RET)

RET hgnc:9967

Cutaneous lichen amyloidosis occurring as a recognized variant feature of multiple endocrine neoplasia type 2A, caused by germline gain-of-function variants in the RET proto-oncogene (classically codon 634). The lesions are typically localized to the interscapular region and may precede the endocrine manifestations, making them a clinical clue that should prompt RET testing. This is the single most actionable fact in the entry: nearly all MEN2A patients eventually develop medullary thyroid carcinoma, so recognising the skin lesion can bring forward RET testing and prophylactic thyroidectomy in an at-risk kindred (see the RET cascade-testing entry under diagnosis). Included here because the cutaneous lesion is genuinely a primary cutaneous amyloidosis, but the driver gene and syndromic context are distinct from OSMR/IL31RA familial PLCA.

Show evidence (4 references)

PMID:42194535 SUPPORT Human Clinical

"In MEN2A, CLA is typically localized to the interscapular region and linked to RET codon 634 variants, whereas generalized forms are rare."

Establishes cutaneous lichen amyloidosis as a RET-associated feature of MEN2A with a characteristic interscapular distribution.

PMID:30085596 SUPPORT Other

"Further evaluation of affected families with MEN2A led to the identification of the following 4 variants: Classical MEN2A. MEN2A with cutaneous lichen amyloidosis (CLA)."

Confirms MEN2A with cutaneous lichen amyloidosis as a formally recognized MEN2A variant.

PMID:30085596 SUPPORT Other

"In both subtypes, nearly 100% of patients eventually develop medullary thyroid cancer (MTC), and up to 50% develop pheochromocytomas."

Quantifies the near-complete MTC penetrance in MEN2A that makes recognition of the cutaneous lichen amyloidosis lesion clinically actionable. Evidence source is OTHER because this is a StatPearls review chapter.

+ 1 more reference

?

Discussions and Knowledge Gaps

2

Is the small-fibre neuropathy of PLCA a cause of the pruritus, or a consequence of chronic scratching and amyloid deposition?

KNOWLEDGE GAP OPEN plca_sfn_cause_or_consequence

Attached to

pathophysiology#Pruritus and the Itch-Scratch-Friction Cycle

The itch-scratch-friction cycle is modelled here as a closed loop, which makes the direction of the nerve-fibre abnormality genuinely ambiguous. Reduced intraepidermal nerve fibre density with raised warm detection thresholds could reflect a primary sensory neuropathy that generates itch, or secondary nerve-fibre loss from repeated mechanical trauma and dermal amyloid. The literature is directly conflicting: some studies report wider cutaneous innervation in familial PLCA while others show the opposite in general lichen amyloidosis. Resolving the direction matters therapeutically, since a primary neuropathic mechanism would favour neuromodulatory over anti-inflammatory treatment.

Proposed experiments

Longitudinal intraepidermal nerve fibre density in pre-lesional OSMR carriers

plca_prelesional_ienf_longitudinal

Serial intraepidermal nerve fibre density measurement and quantitative sensory testing in clinically unaffected skin of OSMR-variant carriers, followed to lesion onset, to establish whether the small-fibre neuropathy precedes amyloid deposition.

Supporting outcome

Reduced nerve fibre density or raised warm detection thresholds detected before any amyloid lesion appears would support the neuropathy as a primary cause of pruritus.

Refuting outcome

Normal pre-lesional innervation and sensory thresholds would indicate the neuropathy is secondary to established lesions.

Within-patient lesional versus perilesional versus distant skin innervation

plca_lesional_vs_distant_ienf

Comparison of intraepidermal nerve fibre density in lesional, perilesional, and anatomically distant unaffected skin within the same patient, to separate a generalized sensory phenotype from locally trauma-induced fibre loss.

Supporting outcome

Uniformly reduced innervation across all three sites would support a generalized primary sensory neuropathy.

Refuting outcome

Fibre loss confined to lesional and perilesional skin would support locally trauma- and amyloid-induced secondary nerve damage.

Show evidence (1 reference)

PMID:42029085 SUPPORT Other

"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."

Explicitly documents the conflicting innervation findings that constitute this knowledge gap. Evidence source is OTHER because this is a narrative review.

Why does Osmr knockout in mice fail to reproduce the human PLCA amyloid phenotype, and does this limit the validity of the mouse model for the amyloid arm of the disease?

HUMAN MODEL MISMATCH OPEN plca_osmr_null_mouse_mismatch

Attached to

pathophysiology#OSM/IL-31 Receptor Signaling Failure pathophysiology#Keratin Misfolding and Beta-Sheet Oligomerization

Osmr-null mice recapitulate the proximal cellular abnormality of human PLCA - enhanced basal keratinocyte differentiation and proliferation with increased epidermal thickness - but develop no PLCA-like lesions and no cutaneous amyloid, even under UVA exposure and itch challenge. The model therefore validates the OSM/STAT5/KLF7 arm of the mechanism while leaving the critical step (conversion of shed keratin into dermal amyloid) untested. Candidate explanations include species differences in keratin composition or amyloid propensity, the absence in caged mice of the decades of frictional trauma that human patients sustain, or a requirement for a specific missense effect that a null allele does not model - human disease is caused by missense variants, and no dominant negative effect was detected for the tested alleles. Evidence exists in the model; its translational validity for the amyloid step is the open question.

Proposed experiments

OSMR missense knock-in mouse

plca_osmr_knockin_missense_mouse

Generate mice carrying the human OSMR missense alleles p.P694L or p.G513D in place of a null allele, and assess for spontaneous cutaneous amyloid.

Supporting outcome

Cutaneous amyloid in missense knock-in but not null mice would show that the specific human substitutions, rather than loss of OSMR per se, are required.

Refuting outcome

Absence of amyloid in missense knock-in mice would point to a species difference rather than an allele-type difference.

Chronic mechanical friction challenge of Osmr-mutant mouse skin

plca_chronic_friction_challenge

Apply sustained, long-duration mechanical friction to the skin of Osmr-mutant mice to test whether the missing environmental co-factor accounts for the absent amyloid phenotype.

Supporting outcome

Emergence of dermal amyloid under chronic friction would confirm friction as a necessary co-factor and validate the itch-scratch-friction loop.

Refuting outcome

Persistent absence of amyloid despite chronic friction would favour an intrinsic species difference in keratin amyloidogenicity.

Comparative aggregation propensity of murine versus human keratins

plca_keratin_aggregation_propensity

Proteomic and in vitro aggregation comparison of murine versus human shed epidermal keratins (including the keratin 5/14 pair) for cross-beta fibril formation propensity.

Supporting outcome

Substantially lower cross-beta propensity of murine keratins would explain the model mismatch as a species property of the precursor.

Refuting outcome

Comparable aggregation propensity would move the explanation to the tissue environment or amyloid clearance rather than the precursor.

Show evidence (2 references)

PMID:33502684 SUPPORT Model Organism

"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)."

Directly documents the failure of the Osmr-null mouse to reproduce the human PLCA phenotype, the mismatch at issue.

PMID:33502684 SUPPORT Model Organism

"These results suggest that Osmr knockout enhances basal keratinocyte differentiation and proliferation in mice."

Shows the model does recapitulate the proximal keratinocyte abnormality, establishing that the mismatch is specific to the amyloid step rather than total.

⚙

Pathophysiology

10

Keratinocyte Damage and Amyloidogenic Keratin Release

The disease-specific trigger of primary cutaneous amyloidosis. Epidermal keratinocytes - injured by chronic friction and scratching, or destabilized by a genetic lesion in the OSM/IL-31 receptor system - undergo filamentous degeneration and apoptosis, dropping their keratin intermediate filaments into the underlying papillary dermis. Keratin is therefore the amyloidogenic precursor protein in the lichen and macular forms; the classic immunohistochemical study concluded only that "at least some" of the amyloid is keratinocyte-derived, and the specific identification of the basal keratin pair 5/14 comes from proteomic subtyping of OSMR-mutant familial disease, so it should not yet be generalized to all sporadic PLCA. This is the disease-specific substitution for the generic amyloidogenic precursor of the amyloidogenesis module: unlike the circulating precursors of systemic amyloidosis (transthyretin, free light chain, serum amyloid A), the PLCA precursor is generated locally by the epithelium immediately overlying the deposit.

keratinocyte CL:0000312

keratinocyte apoptotic process GO:0097283 ↑ INCREASED protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Keratin Misfolding and Beta-Sheet Oligomerization Keratin filaments shed from degenerating keratinocytes into the papillary dermis depart their native conformation and assemble into beta-sheet-rich aggregation-prone species.

Show evidence (2 references)

PMID:6184423 SUPPORT Human Clinical

"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."

The classic immunohistochemical demonstration that the amyloid precursor in cutaneous amyloidosis is keratin released from degenerating keratinocytes - the disease-specific precursor substituted into this module node.

PMID:34459039 SUPPORT Human Clinical

"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"

Proteomic (LC-MS/MS) and immuno-electron subtyping identify keratins 5/14 as the specific deposited amyloid protein in OSMR-mutant familial PLCA. Quoted from the article title, which is the only text in the PubMed record for this correspondence item (no abstract is published).

OSM/IL-31 Receptor Signaling Failure

In familial PLCA, heterozygous missense variants in OSMR or IL31RA - located in the extracellular fibronectin type III-like domains critical for receptor dimerization - impair signal transduction through the shared oncostatin M type II and IL-31 receptor complexes. Patient keratinocytes show reduced JAK/STAT, MAPK, and PI3K/Akt activation after OSM or IL-31 stimulation. Because OSM signaling through OSMRbeta/STAT5/KLF7 normally restrains keratinocyte differentiation, loss of this brake produces basal keratinocyte hyperproliferation and overdifferentiation, increasing the pool of keratinocytes available to degenerate and shed keratin. This node is the genetic entry point into the trigger.

keratinocyte CL:0000312 basal cell of epidermis CL:0002187

oncostatin-M-mediated signaling pathway GO:0038165 ↓ DECREASED cell surface receptor signaling pathway via JAK-STAT GO:0007259 ↓ DECREASED keratinocyte differentiation GO:0030216 ↑ INCREASED keratinocyte proliferation GO:0043616 ↑ INCREASED

Downstream

Keratinocyte Damage and Amyloidogenic Keratin Release Defective OSM/IL-31 receptor signaling increases keratinocyte turnover and apoptosis, enlarging the pool of amyloidogenic keratin released into the papillary dermis.

Pruritus and the Itch-Scratch-Friction Cycle OSMRbeta and IL-31RA are the receptor subunits for the pruritogenic cytokine IL-31, and their epidermal expression is increased in PLCA lesions, contributing to cutaneous nerve-fibre hypersensitivity and itch. The intermediates are genuinely unknown, and the direction is not straightforward: this node is LOSS of receptor signal transduction, whereas the lesional finding is INCREASED receptor expression, so the connection is not a simple direct consequence.

Show evidence (5 references)

PMID:18179886 SUPPORT Human Clinical

"we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. 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..."

Establishes OSMR missense variants as the cause of familial PLCA and demonstrates the resulting signal-transduction failure in patient keratinocytes.

PMID:18179886 SUPPORT Human Clinical

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

Localizes the pathogenic substitutions to the dimerization-critical FNIII domains, giving the structural mechanism of the signaling failure.

PMID:42029085 SUPPORT Other

"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."

Names the STAT5-KLF7 axis downstream of OSMRbeta and confirms that pathogenic OSMR variants suppress signal transduction by disrupting dimerization. Evidence source is OTHER because this is a narrative review.

+ 2 more references

Keratin Misfolding and Beta-Sheet Oligomerization

Keratin filaments released into the papillary dermis lose their native coiled-coil conformation and convert into beta-sheet-rich, aggregation-prone species that nucleate further aggregation. This is the disorder-specific instance of the conserved misfolding/oligomerization amplifier step of amyloidogenesis, operating on keratin rather than on a circulating serum precursor.

protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Papillary Dermal Amyloid Fibril Deposition Beta-sheet keratin oligomers nucleate and elongate into cross-beta amyloid fibrils deposited in the dermal papillae.

Show evidence (2 references)

PMID:6184423 SUPPORT Human Clinical

"Amyloids in lichenoid and macular amyloidoses, and in basal cell epithelioma had an identical antigenicity with epidermal keratin"

The antigenic identity between epidermal keratin and the deposited amyloid establishes that keratin itself is the protein that converts to the amyloid conformation in this disease.

PMID:1930004 SUPPORT Human Clinical

"A few cases exhibited positively for cytokeratin. Strong immunoreactivity for AP protein was observed. PA and MA appear chemically similar and are likely to be of epidermal origin."

Supports the epidermal (keratin) origin of the deposits, though this series found only partial cytokeratin immunoreactivity - epitope masking on conversion to the amyloid fold is one explanation, so the support is recorded as PARTIAL.

Papillary Dermal Amyloid Fibril Deposition

The central effector of the disease and the key conformance point with the amyloidogenesis module - the step at which both upstream precursor routes converge. Beta-sheet oligomers assemble into insoluble cross-beta amyloid fibrils that deposit extracellularly in the dermis, where they are demonstrated by Congo red staining with apple-green birefringence under polarized light. In the keratin-derived lichen and macular forms - which dominate the disease - deposition is confined to the papillary dermis (the dermal papillae) immediately beneath the epidermis that generated the precursor; in the AL/nodular form the light-chain-derived deposits are typically deeper and more nodular, extending into the reticular dermis and subcutis. The disease-specific substitution relative to the generic module is therefore the anatomical site: the amyloid stays local to the skin rather than being distributed to distant organs by the circulation.

amyloid fibril formation GO:1990000 ↑ INCREASED

Downstream

Impaired Amyloid Clearance and Progressive Cutaneous Accumulation Deposited fibrils that outpace macrophage-mediated clearance accumulate progressively in the dermal papillae.

Show evidence (2 references)

PMID:40151750 SUPPORT Human Clinical

"Histopathological analysis revealed amyloid deposits in the papillary dermis, epidermal hyperplasia, and inflammatory infiltration in LA. Congo red staining demonstrated characteristic apple-green birefringence under polarized light, confirming amyloid deposition."

Directly documents papillary-dermal amyloid deposition confirmed by Congo red apple-green birefringence, the central effector of this entry.

PMID:42029085 SUPPORT Other

"Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatological disorder characterized by amyloid deposits in the papillary dermis, significantly impairing patients' quality of life."

Locates the amyloid deposits of PLCA specifically in the papillary dermis. Evidence source is OTHER because this is a narrative review.

Impaired Amyloid Clearance and Progressive Cutaneous Accumulation

Amyloid burden in the skin reflects the balance between deposition and clearance. Dermal macrophages infiltrate lesional skin and remove amyloid, but this clearance is limited - and, in IL31RA-variant disease, is further impaired by dysregulated MCP-1 (monocyte chemoattractant protein-1) expression that reduces monocyte-mediated removal of fibrils. When clearance is outpaced, amyloid accumulates progressively in the dermal papillae, converting a molecular deposition event into a persistent, clinically visible structural lesion of the skin.

macrophage CL:0000235

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Chronic Cutaneous Lesion Formation and Dysfunction Accumulated papillary-dermal amyloid, with the overlying reactive epidermal changes, produces the persistent papules, plaques, and pigmentary change of PLCA.

Pruritus and the Itch-Scratch-Friction Cycle Accumulated papillary-dermal amyloid is itself associated with the cutaneous small-fibre neuropathy that generates itch, closing the amplification loop without requiring a germline receptor lesion. This edge matters because roughly two-thirds of sporadic Chinese PLCA is OSMR-wildtype, so the loop must be enterable from the deposit itself and not only from the genetic node. The intermediates are unresolved - whether the deposit causes the nerve-fibre change or merely accompanies it is the open question recorded in the plca_sfn_cause_or_consequence discussion.

Show evidence (2 references)

PMID:42029085 SUPPORT Other

"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."

Directly establishes impaired monocyte-mediated amyloid clearance, driven by an IL31RA variant via MCP-1, as a mechanism of pathological amyloid retention. Evidence source is OTHER because this is a narrative review.

PMID:29336782 SUPPORT INDIRECT Human Clinical

"Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules."

Documents keratin-positive papillary-dermal amyloid accumulation together with a macrophage infiltrate. Recorded as INDIRECT because this is a co-occurrence only: more macrophages where there is more amyloid is equally consistent with ACTIVE clearance, and the study does not demonstrate that clearance is impaired. The impaired-clearance claim of this node rests on the IL31RA/MCP-1 evidence above.

Chronic Cutaneous Lesion Formation and Dysfunction

The organ-level end state of the module, specialized to the skin. Persistent papillary-dermal amyloid, together with reactive epidermal hyperplasia, hyperkeratosis, pigmentary incontinence, and dermal inflammatory infiltration, produces the chronic hyperkeratotic papules, plaques, and hyperpigmented macules of PLCA. Unlike the systemic amyloidoses, organ dysfunction here is confined to the skin: in the keratin-derived lichen and macular forms there is no cardiac, renal, or neurological amyloid involvement, but the lesions are disfiguring, persistent, and (through intractable pruritus) markedly impair quality of life. The AL/nodular form is the exception that proves the rule - it remains skin-limited in most patients but carries a small risk of harbouring or progressing to systemic AL amyloidosis, which is why it is screened for.

Show evidence (2 references)

PMID:40151750 SUPPORT Human Clinical

"Primary Localized Cutaneous Amyloidosis (PLCA) is a rare disorder characterized by amyloid deposition in the skin without systemic involvement."

Establishes that the consequence of the amyloidogenesis chain in this disease is confined to the skin, with no systemic organ involvement.

PMID:42029085 SUPPORT Other

"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."

Links the molecular cascade to the tissue-level outcome of stratum corneum thickening alongside amyloid deposition. Evidence source is OTHER because this is a narrative review.

Pruritus and the Itch-Scratch-Friction Cycle

A self-reinforcing amplifier loop that is arguably the defining clinical mechanism of lichen amyloidosis. Lesional skin shows small-fibre neuropathy with reduced intraepidermal nerve fibre density and elevated warm detection thresholds that correlate with itch severity, together with increased epidermal expression of the IL-31 receptor subunits OSMRbeta and IL-31RA - a pattern of cutaneous nerve-fibre hypersensitivity rather than simple nerve-fibre excess. The resulting intractable pruritus drives chronic scratching and frictional trauma, which damages keratinocytes and feeds more amyloidogenic keratin back into the papillary dermis, closing the loop. This node is a disease-specific addition beyond the amyloidogenesis module, which has no equivalent feedback arm.

keratinocyte CL:0000312

cytokine-mediated signaling pathway GO:0019221 ↑ INCREASED

Downstream

Keratinocyte Damage and Amyloidogenic Keratin Release Chronic scratching and frictional trauma damage keratinocytes, releasing more amyloidogenic keratin into the papillary dermis and closing the self-reinforcing loop.

Show evidence (3 references)

PMID:26748444 SUPPORT Human Clinical

"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."

Directly establishes small-fibre neuropathy and increased epidermal IL-31 receptor expression as the mechanism of PLCA pruritus, and identifies the IL-31 receptor as a therapeutic target.

PMID:26748444 SUPPORT Human Clinical

"WDT was significantly higher in patients at all sites and correlated with itch scores (r = 0·59; P < 0·01)."

Quantifies the sensory abnormality (raised warm detection threshold correlating with itch severity) underlying the itch arm of the cycle.

PMID:40151750 SUPPORT Human Clinical

"The pathogenesis is linked to chronic friction, keratinocyte damage, and in some cases, genetic predisposition."

Links chronic friction to keratinocyte damage, closing the scratch arm of the itch-scratch-deposition cycle.

Local Plasma Cell Light-Chain Production

The mechanistically separate route to cutaneous amyloid seen in primary localized cutaneous nodular amyloidosis. A light-chain-restricted (clonal) plasma-cell population resident within the skin lesion secretes an amyloidogenic immunoglobulin light chain locally, which misfolds and deposits as AL amyloid in the dermis and subcutis. The precursor is therefore an immunoglobulin light chain, not keratin, and the deposit lacks keratin antigenicity - this is a localized cutaneous plasma-cell dyscrasia. It shares the amyloidogenic-precursor node of the module but substitutes a completely different precursor, which is why nodular disease carries a real (if small) risk of underlying or evolving systemic AL amyloidosis and warrants systemic screening.

plasma cell CL:0000786

protein folding GO:0006457 ⚠ ABNORMAL

Downstream

Papillary Dermal Amyloid Fibril Deposition Locally produced amyloidogenic light chain misfolds and deposits as dermal AL amyloid.

Show evidence (2 references)

PMID:18576343 SUPPORT Human Clinical

"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."

Directly demonstrates a local light-chain-restricted plasma-cell population adjacent to AL-type amyloid deposits in nodular cutaneous amyloidosis - the trigger of this alternative route.

PMID:6184423 SUPPORT Human Clinical

"whereas amyloids in nodular amyloidosis and systemic amyloidosis did not have this identity"

Confirms that nodular amyloid is not keratin-derived, distinguishing this trigger from the keratinocyte route.

GPNMB Loss of Function

The molecular lesion specific to amyloidosis cutis dyschromica. Biallelic loss-of-function of GPNMB - a transmembrane glycoprotein normally expressed throughout the epidermis and most highly in melanocytes, with roles in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation - removes that protein's function from lesional skin. This is a distinct genetic entry into the shared downstream amyloid chain, and it drives two separable consequences: a keratinocyte arm feeding amyloid deposition, and a melanocyte arm producing the dyschromia.

melanocyte CL:0000148 keratinocyte CL:0000312

Downstream

Keratinocyte Damage and Amyloidogenic Keratin Release GPNMB loss promotes keratinocyte fibrillary aggregation and degeneration, feeding the shared keratin-amyloid chain.

Melanocyte Depletion Loss of GPNMB, which is expressed most highly in melanocytes and is implicated in melanosome formation, results in loss of melanocytes from the depigmented lesions.

Show evidence (2 references)

PMID:29336782 SUPPORT Human Clinical

"Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals."

Establishes GPNMB expression in epidermis and melanocytes and its loss in lesional skin, the proximal lesion of this route.

PMID:29336782 SUPPORT Human Clinical

"Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis."

Provides the two-arm mechanism - melanocyte loss causing depigmentation and intracytoplasmic keratinocyte fibrillary aggregates feeding amyloid deposition.

Melanocyte Depletion

The pigmentary arm of amyloidosis cutis dyschromica, and the reason that disease looks unlike any other primary cutaneous amyloidosis. Melanocytes are lost from the depigmented lesions, producing the small hypopigmented macules that stipple the generalized reticulate hyperpigmentation. This arm is separate from - and not a prerequisite for - the amyloid deposition arm: both descend independently from the same GPNMB lesion, which is why the entry models them as sibling consequences rather than a chain.

melanocyte CL:0000148

Downstream

Hypopigmented Macules Melanocyte loss produces the clinically visible hypopigmented macules of amyloidosis cutis dyschromica.

Show evidence (1 reference)

PMID:29336782 SUPPORT Human Clinical

"Depigmentation of the lesions was attributable to loss of melanocytes."

Directly attributes the depigmented lesions of amyloidosis cutis dyschromica to melanocyte loss, the content of this node.

✶

Histopathology

1

Papillary Dermal Amyloid with Congo Red Birefringence

The diagnostic histopathological finding: globular, eosinophilic amyloid deposits confined to the dermal papillae, staining with Congo red and showing apple-green birefringence under polarized light (also positive with crystal violet). The overlying epidermis shows hyperkeratosis and acanthosis, and there is a variable superficial dermal inflammatory infiltrate with pigmentary incontinence. In lichen amyloidosis the deposits are larger than in the macular form, but the two are tinctorially and immunohistochemically identical. Absence of amyloid elsewhere distinguishes PLCA from systemic amyloidosis with skin involvement.

Show evidence (2 references)

PMID:40151750 SUPPORT Human Clinical

"Congo red staining demonstrated characteristic apple-green birefringence under polarized light, confirming amyloid deposition."

Documents the diagnostic Congo red apple-green birefringence.

PMID:1930004 SUPPORT Human Clinical

"Deposits were permanganate-resistant and negative for AA protein, immunoglobulin light chains and keratin."

Records the tinctorial and immunohistochemical profile of the deposits, including the negative AA and light-chain staining that excludes those amyloid types in the lichen/macular forms. Recorded honestly: this same series ALSO found the deposits negative for keratin on routine immunohistochemistry (with only "a few cases" cytokeratin-positive), which cuts against the keratin-origin thesis. The usual reconciliation is epitope masking on conversion to the amyloid fold - later proteomic subtyping (LC-MS/MS, PMID:34459039) does identify keratins 5/14 in the deposits - but the discrepancy is real and is not resolved by this paper.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

11

Integument 5

Pruritus HP:0000989

Temporal: CHRONIC

Show evidence (2 references)

PMID:42029085 SUPPORT Other

"Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatological disorder characterized by amyloid deposits in the papillary dermis"

Defines PLCA as a chronic pruritic disorder. Evidence source is OTHER because this is a narrative review.

PMID:40151750 SUPPORT Human Clinical

"Pruritus was exclusively seen in LA, while hyperpigmentation was present in all cases."

Documents pruritus in the lichen subtype specifically, and notes its absence in the macular cases of this series.

Hyperpigmentation of the Skin VERY_FREQUENT HP:0000953

Show evidence (1 reference)

PMID:40151750 SUPPORT Human Clinical

"Pruritus was exclusively seen in LA, while hyperpigmentation was present in all cases."

Reports hyperpigmentation in 9/9 (100%) of the biopsy-confirmed cases of this series. Note this is a deliberate departure from the default mapping: "in all cases" would map to OBLIGATE, but the band is recorded as VERY_FREQUENT (80-99%) because the cohort is a small single-centre series of nine patients and hyperpigmentation is not an obligate feature of PLCA in larger series - notably it is absent by definition from the hypopigmented macules of amyloidosis cutis dyschromica.

Hypopigmented Macules Hypopigmentation of the skin HP:0001010

Show evidence (1 reference)

PMID:29336782 SUPPORT Human Clinical

"Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs."

Documents the hypopigmented macules as a defining feature of amyloidosis cutis dyschromica.

Lichenification HP:0100725

Show evidence (1 reference)

PMID:40151750 SUPPORT Human Clinical

"LA is strongly associated with chronic friction and pruritus"

Supports the chronic friction and scratching that produce lichenification; recorded as PARTIAL because the abstract documents the friction/pruritus association rather than naming lichenification explicitly.

Epidermal Hyperplasia Hyperkeratosis HP:0000962

Show evidence (2 references)

PMID:40151750 SUPPORT Human Clinical

"Histopathological analysis revealed amyloid deposits in the papillary dermis, epidermal hyperplasia, and inflammatory infiltration in LA."

Directly documents epidermal hyperplasia accompanying the papillary-dermal amyloid.

PMID:37100691 SUPPORT Human Clinical

"Primary localized cutaneous amyloidosis (PLCA) is a chronic skin disease characterized by aberrant keratinocyte differentiation, epidermal hyperproliferation, and amyloid deposits."

Names epidermal hyperproliferation and aberrant keratinocyte differentiation as defining features of PLCA, giving the mechanism behind the hyperplasia.

Other 6

Cutaneous Amyloidosis HP:0012309

Show evidence (1 reference)

PMID:40151750 SUPPORT Human Clinical

"Congo red staining demonstrated characteristic apple-green birefringence under polarized light, confirming amyloid deposition."

Documents Congo-red-confirmed cutaneous amyloid deposition in this biopsy-confirmed series. No `frequency:` is recorded deliberately: demonstrating cutaneous amyloid is the diagnostic entry criterion for PLCA, so any observed rate is fixed at 100% by ascertainment and would carry no information.

Hyperkeratotic Papules HP:0045059

Show evidence (1 reference)

PMID:42194535 SUPPORT Human Clinical

"Cutaneous lichen amyloidosis (CLA) is a rare dermatological condition characterized by amyloid deposition in the skin, presenting as pruritic, hyperkeratotic papules."

Defines the hyperkeratotic papule as the presenting lesion of cutaneous lichen amyloidosis.

Reticulated Skin Pigmentation HP:0007427

Show evidence (1 reference)

PMID:15569011 SUPPORT Human Clinical

"It is characterized by a reticulated or rippled pattern of pigmentation mostly in the upper back."

Directly characterizes macular amyloidosis by its reticulated/rippled pigmentation pattern and upper-back distribution, in a 100-patient clinical series.

Cutaneous Lichen Amyloidosis HP:0032346

Show evidence (1 reference)

PMID:42194535 SUPPORT Human Clinical

"Cutaneous lichen amyloidosis (CLA) is a rare dermatological condition characterized by amyloid deposition in the skin, presenting as pruritic, hyperkeratotic papules."

Defines cutaneous lichen amyloidosis as a distinct clinical sign characterized by pruritic hyperkeratotic papules with cutaneous amyloid deposition.

Cutaneous Macular Amyloidosis HP:0032347

Show evidence (1 reference)

PMID:15569011 SUPPORT Human Clinical

"Macular amyloidosis is a relatively common cutaneous disease in Asia and the Middle East. It is characterized by a reticulated or rippled pattern of pigmentation mostly in the upper back."

Defines macular amyloidosis as a distinct clinical entity with its characteristic reticulated pigmentation and upper-back distribution.

Cutaneous Nodular Amyloidosis HP:0032348

Show evidence (2 references)

PMID:41528921 SUPPORT Other

"Primary cutaneous amyloidosis has been classified into three groups: macular, lichen, and nodular, the former two being one often overlapping process, and the latter a localized plasma dyscrasia with a small risk of representing a systemic disease."

Establishes nodular cutaneous amyloidosis as one of the three recognized presentations and as a localized plasma dyscrasia. Evidence source is OTHER because this is a review.

PMID:18576343 SUPPORT Human Clinical

"The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients."

Confirms the immunoglobulin light-chain (AL) composition of the amyloid in nodular cutaneous amyloidosis lesions.

🧬

Genetic Associations

4

OSMR

Gene: OSMR hgnc:8507 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:18179886 SUPPORT Human Clinical

"FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families."

The original identification of OSMR as the familial PLCA disease gene.

PMID:19690585 SUPPORT Human Clinical

"Here, 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)."

Documents the recurrent heterozygous OSMR missense alleles in a large Taiwanese pedigree series.

PMID:30734345 SUPPORT Human Clinical

"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)."

Documents an OSMR-genotype-dependent sex skew: the female excess is concentrated in biallelic carriers, while OSMR-wildtype patients were male-predominant in this series. This is a dosage-correlated observation whose mechanism is unexplained.

IL31RA

Gene: IL31RA hgnc:18969 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:19690585 SUPPORT Human Clinical

"In one family, we identified a point mutation in the IL31RA gene, c.1562C>T that results in a missense mutation, p.S521F, which is also sited within a fibronectin type III-like repeat domain as observed in the OSMR mutations."

Identifies the causal IL31RA missense variant and its location in the same FNIII domain class as the OSMR variants.

GPNMB

Gene: GPNMB hgnc:4462 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:29336782 SUPPORT Human Clinical

"Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD."

Documents the biallelic GPNMB truncating alleles in affected individuals.

PMID:33687658 SUPPORT Human Clinical

"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."

Independent replication of GPNMB as the amyloidosis cutis dyschromica gene in consanguineous Pakistani families, extending the allelic spectrum beyond truncating alleles to homozygous missense variants.

RET

Gene: RET hgnc:9967 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:42194535 SUPPORT Human Clinical

"Although most cases are sporadic, CLA has been associated with multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome caused by germline alterations in the RET proto-oncogene."

Establishes the RET-MEN2A association with cutaneous lichen amyloidosis.

💊

Medical Actions

7

High-Potency Topical Corticosteroids

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

The current standard of care and first-line symptomatic therapy. High-potency topical corticosteroids reduce pruritus and the inflammatory component, thereby interrupting the itch-scratch-friction cycle that drives ongoing keratinocyte damage and amyloid deposition. They provide symptomatic relief but do not clear established amyloid deposits.

Mechanism Target:

INHIBITS Pruritus and the Itch-Scratch-Friction Cycle — Suppressing pruritus and cutaneous inflammation breaks the scratching arm of the self-reinforcing cycle, reducing further keratinocyte damage.

Show evidence (1 reference)

PMID:41528921 SUPPORT Other

"The current standard of care, high-potency corticosteroids, can provide symptomatic relief."

Establishes high-potency corticosteroids as the current standard of care and characterizes the benefit as symptomatic. Evidence source is OTHER because this is a review.

Dupilumab

Action: Pharmacotherapy NCIT:C15986

Agent: dupilumab NCIT:C162455

A fully human monoclonal antibody against the IL-4 receptor alpha subunit that blocks IL-4 and IL-13 signalling and downregulates cutaneous type 2 cytokines including IL-31, the principal pruritogen implicated in PLCA. Used off-label for refractory lichen amyloidosis - particularly in patients with coexisting atopic dermatitis - with reported improvement in pruritus and lesions in case reports and small series. Not an approved indication; the evidence remains at case-report level.

Mechanism Target:

INHIBITS Pruritus and the Itch-Scratch-Friction Cycle — IL-4Ralpha blockade lowers cutaneous type 2 cytokine tone including IL-31, reducing the pruritus that drives the scratch-damage-deposition loop.

Show evidence (1 reference)

PMID:39975679 SUPPORT Human Clinical

"This article reported two cases of refractory LA successfully treated with dupilumab and reviewed publications reporting dupilumab treatment for PCA."

Documents clinical response of refractory lichen amyloidosis to dupilumab, the case-level evidence for this off-label use.

Nemolizumab (IL-31 Receptor Blockade)

Action: Pharmacotherapy NCIT:C15986

Agent: nemolizumab NCIT:C170211

Anti-IL-31RA monoclonal antibody, and the most mechanistically on-target agent available for PLCA: it blocks the very receptor subunit whose epidermal overexpression is documented in PLCA lesions. The related agent vixarelimab targets the partner subunit OSMRbeta. This is an emerging, mechanism-anchored strategy rather than an established therapy - the cited itch benefit is demonstrated across chronic pruritic dermatoses generally, not in PLCA-specific randomized trials.

Mechanism Target:

INHIBITS Pruritus and the Itch-Scratch-Friction Cycle — Blocking IL-31RA or OSMRbeta interrupts IL-31-driven cutaneous nerve-fibre sensitization, the proximal mechanism of PLCA pruritus.

Show evidence (2 references)

PMID:26748444 SUPPORT Human Clinical

"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."

The PLCA-specific rationale: increased epidermal IL-31 receptor expression makes the IL-31 receptor a candidate therapeutic target in this disease.

PMID:42220857 SUPPORT Other

"Blocking IL-31RA with nemolizumab or targeting OSMRβ with vixarelimab has led to clinically significant improvements in itch severity, patient-reported quality of life, and sleep disturbance."

Documents clinical itch benefit from IL-31RA and OSMRbeta blockade across chronic pruritic dermatoses; recorded as PARTIAL because the benefit is reported for the dermatosis group as a whole (a group whose scope this systematic review states includes PLCA) rather than from PLCA-specific trials.

Tofacitinib (JAK Inhibition)

Action: Pharmacotherapy NCIT:C15986

Agent: tofacitinib CHEBI:71200

Oral Janus kinase inhibitor used off-label for PLCA. The rationale is directly mechanistic: OSMRbeta and IL-31RA signal through the JAK/STAT cascade, and the IL-4/IL-13/IL-31 itch axis is JAK-dependent, so JAK inhibition targets the same node from downstream. In a retrospective series of 24 patients treated with tofacitinib 10 mg/day, body surface area, peak pruritus NRS, and Investigator Global Assessment all improved significantly with good tolerability. Evidence remains retrospective and uncontrolled; the authors call for randomized trials. Note the apparent paradox that PLCA involves LOSS of OSM/OSMRbeta signal transduction yet responds to JAK inhibition - the therapeutic target is the pruritogenic type 2 / IL-31 arm of JAK signalling rather than the deficient OSM-STAT5 differentiation brake.

Mechanism Target:

INHIBITS Pruritus and the Itch-Scratch-Friction Cycle — JAK inhibition blocks the downstream signalling of the pruritogenic type 2 and IL-31 cytokines, reducing itch and hence the scratching that drives further keratinocyte damage.

Show evidence (2 references)

PMID:40908738 SUPPORT Human Clinical

"We conducted a retrospective study of 24 patients with PLCA treated with tofacitinib (10 mg/day) at our dermatology clinic. Disease severity was assessed using body surface area (BSA), Peak Pruritus Numerical Rating Scale (PP-NRS), and Investigator Global Assessment (IGA) scores. Significant..."

Reports the efficacy outcome directly: significant improvement in body surface area, peak pruritus NRS, and Investigator Global Assessment in a 24-patient retrospective series on tofacitinib 10 mg/day. (The quote stops mid-sentence because the cached PubMed abstract itself is truncated at that point.)

PMID:40908738 SUPPORT Human Clinical

"The findings of this study suggest that tofacitinib could be an appealing approach for treating PLCA. Further large-scale, randomized controlled trials are necessary to confirm its long-term efficacy and safety."

The authors' own qualification that the evidence is suggestive rather than definitive; recorded as PARTIAL to avoid overstating an uncontrolled retrospective result.

Friction Avoidance and Skin-Directed Supportive Care

Action: Supportive Care NCIT:C15747

Behavioral supportive care aimed directly at the environmental driver of this entry's itch-scratch-friction cycle: stopping habitual scratching and rubbing, discontinuing nylon towels, backscratchers and abrasive scrubs, and using barrier measures such as hydrocolloid dressings and emollients. Mechanistically it is the most direct intervention available - it removes the frictional keratinocyte injury that supplies amyloidogenic keratin - and it is low-risk and free, though the supporting evidence is consensus-level rather than trial based and it is typically combined with antipruritic therapy rather than used alone.

Mechanism Target:

INHIBITS Pruritus and the Itch-Scratch-Friction Cycle — Removing frictional and scratch trauma breaks the scratch arm of the self-reinforcing cycle at its environmental source.

INHIBITS Keratinocyte Damage and Amyloidogenic Keratin Release — Less mechanical injury to the epidermis means fewer degenerating keratinocytes shedding keratin into the papillary dermis.

Show evidence (2 references)

PMID:28342017 SUPPORT Other

"A variety of treatment options for PLCA were reported including retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D3 analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, laser..."

Places hydrocolloid dressings (the barrier arm of this entry) in the catalogued PLCA armamentarium. Recorded as PARTIAL because the review catalogues rather than validates it, and does not separately evaluate friction avoidance. Evidence source is OTHER because this is a systematic review of predominantly case-level reports.

PMID:40151750 SUPPORT Human Clinical

"The pathogenesis is linked to chronic friction, keratinocyte damage, and in some cases, genetic predisposition."

Supplies the mechanistic rationale for friction avoidance by naming chronic friction as a pathogenic driver. Recorded as PARTIAL because it establishes the target, not the efficacy of the intervention.

Phototherapy

Action: Phototherapy NCIT:C15301

Ultraviolet phototherapy (PUVA, narrowband UVB, UVB) used to reduce pruritus and pigmentation in non-nodular PLCA. In the systematic review of procedural treatments, phototherapy showed benefit with PUVA superior to UVB for pruritus specifically. Outcomes across series are variable and no standardized protocol exists.

Mechanism Target:

INHIBITS Pruritus and the Itch-Scratch-Friction Cycle — Phototherapy reduces pruritus, interrupting the scratching that perpetuates keratinocyte damage.

Show evidence (1 reference)

PMID:41389140 SUPPORT Other

"Microneedling and phototherapy (PUVA/UVB) also showed benefits, with PUVA being superior for pruritus."

Establishes phototherapy benefit and the PUVA-over-UVB ordering for pruritus, from a PRISMA systematic review of 16 studies and 432 patients. Evidence source is OTHER because this is a systematic review.

Laser and Procedural Therapy

Action: Laser Therapy NCIT:C15466

Ablative and non-ablative laser and device-based treatments - fractional CO2 laser, Nd:YAG, Er:YAG, and microneedling - directed at the pigmentation, pruritus, and amyloid burden of non-nodular PLCA. Fractional CO2 laser, particularly combined with topical corticosteroids or vitamin C, has the strongest reported results. Note the subtype split in the meta-analysis evidence: laser therapy is recommended for non-nodular disease, whereas surgical excision is the most effective option for nodular amyloidosis. Complete-response rates remain low even where partial response is common.

Mechanism Target:

INHIBITS Impaired Amyloid Clearance and Progressive Cutaneous Accumulation — Ablative resurfacing physically removes papillary-dermal amyloid and the overlying hyperkeratotic epidermis, reducing the accumulated deposit burden rather than acting on precursor supply.

Show evidence (2 references)

PMID:41389140 SUPPORT Other

"Fractional CO₂ laser, especially with corticosteroids or vitamin C, showed the most effective results for pigmentation, pruritus, and amyloid reduction in PLCA."

Identifies fractional CO2 laser as the most effective procedural modality including for amyloid reduction, supporting the deposit-directed target_mechanisms link. Evidence source is OTHER because this is a systematic review.

PMID:39957318 SUPPORT Other

"This study suggests that surgery is the most effective treatment option for NA, and laser therapy is recommended for patients with non-NA."

Supplies the subtype split - laser for non-nodular disease, surgery for nodular - from a meta-analysis of 116 studies and 534 patients. Evidence source is OTHER because this is a systematic review and meta-analysis.

🌍

Environmental Factors

1

Chronic Friction and Scratching

Long-standing mechanical trauma to the skin - habitual scratching, rubbing, and friction from nylon brushes, towels, or backscratchers - is the principal environmental contributor to PLCA and explains the characteristic distribution over accessible extensor surfaces (shins, forearms, interscapular back). Friction damages keratinocytes and drives the release of amyloidogenic keratin, forming the closing arm of the itch-scratch-friction cycle.

Show evidence (1 reference)

PMID:40151750 SUPPORT Human Clinical

"The pathogenesis is linked to chronic friction, keratinocyte damage, and in some cases, genetic predisposition."

Names chronic friction as a pathogenic contributor acting through keratinocyte damage.

🔬

Diagnosis

6

Skin Biopsy with Congo Red Staining

The diagnostic cornerstone and the definitive test. A lesional skin biopsy is stained with Congo red and examined under polarized light; apple-green birefringence in the papillary dermis confirms amyloid. Crystal violet is a useful adjunct. Because PLCA is defined histopathologically, clinical appearance alone is insufficient and the condition is frequently misdiagnosed without biopsy.

Skin Biopsy NCIT:C51692

Results: Positive: globular eosinophilic deposits in the dermal papillae showing apple-green birefringence with Congo red under polarized light, with overlying hyperkeratosis and acanthosis. Absence of amyloid does not exclude clinically early disease but excludes the diagnosis as formally defined.

Show evidence (2 references)

PMID:40151750 SUPPORT Human Clinical

"Histopathological examination remains the gold standard for diagnosis."

States histopathological examination as the diagnostic gold standard for PLCA.

PMID:40151750 SUPPORT Human Clinical

"Congo red and crystal violet stains remain indispensable for diagnosis."

Confirms Congo red and crystal violet as the indispensable confirmatory stains.

Amyloid Typing (Proteomic and Immunohistochemical)

Determining which protein the deposit is made of, which is what separates the keratin-derived lichen/macular forms from AL-type nodular disease and from skin involvement by a systemic amyloidosis. Laser-capture LC-MS/MS proteomic subtyping with immuno-electron microscopy identifies keratins 5/14 in OSMR-mutant familial disease; kappa/lambda light-chain immunohistochemistry identifies the AL deposits of nodular disease. Typing changes management because AL-typed cutaneous amyloid mandates a systemic workup.

Histopathologic Examination NCIT:C18190

Results: Keratin-positive (keratins 5/14) in lichen/macular disease; immunoglobulin light-chain restricted in nodular disease. Note that routine anti-keratin immunohistochemistry may be negative in lichen/macular deposits despite their keratin origin, plausibly through epitope masking on conversion to the amyloid fold - proteomic typing is more reliable than IHC for this question.

Show evidence (2 references)

PMID:34459039 SUPPORT Human Clinical

"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"

Demonstrates proteomic (LC-MS/MS) plus immuno-electron subtyping as the method that establishes deposit composition. Quoted from the article title, which is the only text in the PubMed record for this correspondence item (no abstract is published).

PMID:18576343 SUPPORT Human Clinical

"The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients."

Demonstrates light-chain typing distinguishing AL-type nodular cutaneous amyloid from the keratin-derived forms.

Dermoscopy

A non-invasive adjunct that supports clinical recognition and helps discriminate PLCA from the other dyschromatoses, particularly in amyloidosis cutis dyschromica where the differential includes dyschromatosis universalis hereditaria, Dowling-Degos disease and xeroderma pigmentosum. It supplements but does not replace biopsy.

Dermoscopy NCIT:C116478

Results: In amyloidosis cutis dyschromica, hyperpigmented macules show brown dots and globules in a honeycomb pattern; hypopigmented lesions show a pebbled appearance with radial furrows, corresponding to amyloid deposits, melanophages, and dilated vessels.

Show evidence (1 reference)

PMID:39119323 SUPPORT Human Clinical

"There are very few case reports highlighting the dermoscopic findings of ACD which would help in diagnosing and differentiating with similar conditions."

Establishes the diagnostic and differential-diagnostic role of dermoscopy in amyloidosis cutis dyschromica, while indicating the evidence base is case-level.

Systemic AL Amyloidosis Screening in Nodular Disease

Because nodular cutaneous amyloidosis is a localized plasma-cell dyscrasia producing AL amyloid, and a small proportion of patients harbour or later develop systemic AL amyloidosis, patients with the nodular subtype should be evaluated for systemic involvement and kept under follow-up. This is risk stratification, not an expectation of progression: in the largest reported Sjogren-associated series no patient progressed over a median 3.5 years. Screening does not modify the local plasma-cell clone; it determines whether that clone is skin-confined or part of a systemic dyscrasia, which changes management entirely.

Disease Screening NCIT:C15419

Results: Serum and urine immunofixation, serum free light chains, and assessment for cardiac and renal involvement. A positive clonal screen in a patient with AL-typed cutaneous amyloid moves the diagnosis toward systemic AL amyloidosis.

Show evidence (2 references)

PMID:41528921 SUPPORT Other

"the latter a localized plasma dyscrasia with a small risk of representing a systemic disease."

Establishes the small systemic risk of nodular cutaneous amyloidosis that motivates screening. Evidence source is OTHER because this is a review.

PMID:18576343 SUPPORT Human Clinical

"Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years."

Tempers the systemic risk - no progression in this series - which is why screening is framed as risk stratification rather than expected progression. Recorded as PARTIAL because it qualifies rather than straightforwardly supports the screening recommendation.

RET Cascade Testing in Cutaneous Lichen Amyloidosis

The highest-consequence diagnostic action in this entry. Cutaneous lichen amyloidosis - classically interscapular, but also in generalized form - is a recognized variant feature of MEN2A and can present before the endocrine manifestations. Because nearly all MEN2A patients eventually develop medullary thyroid carcinoma, recognising the skin lesion and proceeding to germline RET testing (with cascade testing of relatives if positive) can bring forward surveillance and prophylactic thyroidectomy in an at-risk kindred. Codon 634 is the classic association, but the reported allelic spectrum is wider.

Genetic Testing NCIT:C15709

Results: A pathogenic germline RET variant establishes MEN2A and triggers MTC and pheochromocytoma surveillance plus cascade testing of first-degree relatives. A negative result in isolated PLCA is expected and does not argue against the diagnosis of primary cutaneous amyloidosis.

Show evidence (2 references)

PMID:42194535 SUPPORT Human Clinical

"This case may contribute to understanding genotype-phenotype correlations in MEN2A and suggests that atypical or generalized CLA may be an early clinical clue warranting consideration of RET genetic testing."

Directly recommends RET genetic testing on the basis of the cutaneous lichen amyloidosis presentation - the action this diagnosis entry encodes.

PMID:30085596 SUPPORT Other

"In both subtypes, nearly 100% of patients eventually develop medullary thyroid cancer (MTC), and up to 50% develop pheochromocytomas."

Quantifies the near-complete MTC penetrance that makes cascade testing urgent once MEN2A is suspected. Evidence source is OTHER because this is a StatPearls review chapter.

OSMR and IL31RA Genetic Testing

Molecular confirmation of familial PLCA. OSMR is the highest-yield first test: in a mainland Chinese series OSMR missense variants were found in 63.9% of familial cases, and notably also in 34.4% of apparently sporadic cases, so a negative family history does not exclude a molecular diagnosis. IL31RA is the second-tier gene for OSMR-negative pedigrees, and biallelic GPNMB testing is indicated for the dyschromic presentation.

Genetic Testing NCIT:C15709

Results: Heterozygous OSMR or IL31RA missense variants in the extracellular fibronectin type III-like domains confirm familial PLCA. Genotype carries prognostic information: homozygous OSMR carriers had a median onset of 20 years versus 32 years in heterozygotes and wild-type.

Show evidence (2 references)

PMID:30734345 SUPPORT Human Clinical

"Sequence analysis of OSMR exons demonstrated that the OSMR missense mutation rate in patients with fPLCA (63.89%) was significantly higher than that in patients with sPLCA (34.38%)."

Quantifies the diagnostic yield of OSMR sequencing in both familial and sporadic PLCA, supporting an OSMR-first testing strategy.

PMID:19690585 SUPPORT Human Clinical

"PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in two biologically associated cytokine receptor genes located on chromosome 5."

Justifies testing IL31RA in addition to OSMR, given the demonstrated two-gene heterogeneity.

📈

Progression

2

Adult-onset chronic progressive skin disease

Age: Typically adult onset; median 32 years in OSMR-heterozygous and OSMR-wildtype Chinese patients, and earlier (median 20 years) in OSMR homozygotes. Amyloidosis cutis dyschromica is the exception, with prepubertal onset.

PLCA is chronic and slowly progressive and essentially never remits spontaneously; lesions persist for years to decades. Genotype modifies onset age, with biallelic OSMR carriers presenting about a decade earlier than heterozygotes.

Show evidence (2 references)

PMID:30734345 SUPPORT Human Clinical

"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)."

Provides the genotype-stratified median ages of onset quoted above.

PMID:39119323 SUPPORT Human Clinical

"Amyloidosis cutis dyschromica is a very rare form of primary cutaneous amyloidosis characterized by prepubertal onset of hyper and hypopigmented spots and amyloid deposits in the papillary dermis."

Establishes the prepubertal onset that distinguishes amyloidosis cutis dyschromica from the adult-onset lichen and macular forms.

Nodular disease - surveillance for systemic progression

Nodular Amyloidosis

Nodular cutaneous amyloidosis is the only subtype with a route out of the skin. Reported progression to systemic AL amyloidosis is uncommon, and the largest Sjogren-associated series observed none over a median 3.5 years, but the risk is non-zero and justifies ongoing surveillance rather than discharge.

Show evidence (2 references)

PMID:18576343 SUPPORT Human Clinical

"Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years."

The observed progression rate in the largest reported series - zero over a median 3.5 years - which bounds the risk without eliminating it.

PMID:41528921 SUPPORT Other

"the latter a localized plasma dyscrasia with a small risk of representing a systemic disease."

Confirms the residual systemic risk that motivates continued surveillance. Evidence source is OTHER because this is a review.

📊

Prevalence

3

Chinese, Malay, and Indian ethnic groups in Malaysia

Cases In Literature Unknown

A consecutive biopsy series of 85 Malaysian patients found PLCA more frequent in the Chinese than in other major ethnic groups, with the papular (lichen) form outnumbering the macular form roughly 3:1. This is a clinic-based case series, so it supports the ethnic-distribution claim but does not yield a population rate.

Show evidence (1 reference)

PMID:1930004 SUPPORT Human Clinical

"A review of consecutive biopsies from 85 Malaysian patients with primary localised cutaneous amyloidosis (PLCA) revealed 63 with papular amyloidosis (PA) and 22 with macular amyloidosis (MA). PLCA appeared to affect the Chinese more frequently than the other major ethnic groups but MA was more..."

Documents the ethnic distribution and the relative frequency of papular versus macular disease in a Southeast Asian biopsy series.

Iranian dermatology-clinic macular amyloidosis cohort (n=100)

Cases In Literature Unknown

Sex and age distribution rather than a population rate. This clinic series found a marked female predominance (9:1 female:male) and clustering between ages 21 and 50, with female patients presenting on average about 10 years later than male patients. The authors flag that their sex ratio "differed dramatically from most of the previous reports", so the magnitude of the skew is unsettled even though a female excess is consistently reported.

Show evidence (1 reference)

PMID:15569011 SUPPORT Human Clinical

"Although the sex distribution (9 : 1, female : male ratio) differed dramatically from most of the previous reports, it was consistent with few other series. Eighty one percent of patients were between 21 and 50 years of age."

Provides the sex ratio and age distribution, with the authors' own caveat that the ratio is an outlier relative to prior reports.

Southeast Asia and South America

Unknown Unknown

PLCA is consistently described as relatively common in Southeast Asian and South American populations compared with Europe and North America; no quantitative population rate is reported in the cited source.

Show evidence (1 reference)

PMID:19690585 SUPPORT Human Clinical

"Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America."

Supports the geographic concentration of PLCA without asserting a numeric rate.

{ }

Source YAML

click to show

name: Primary Cutaneous Amyloidosis
creation_date: "2026-08-01T00:00:00Z"
category: Complex
disease_term:
  preferred_term: primary cutaneous amyloidosis
  term:
    id: MONDO:0015301
    label: primary cutaneous amyloidosis
parents:
- Amyloidosis
description: >-
  Primary localized cutaneous amyloidosis (PLCA) is a group of chronic,
  skin-limited amyloidoses in which amyloid is deposited in the papillary dermis
  without any systemic amyloid involvement and without an underlying plasma-cell
  or inflammatory systemic disease. In the two commonest forms - lichen
  amyloidosis and macular amyloidosis - the deposited amyloid is derived from
  degenerating epidermal keratinocytes, so the amyloidogenic precursor is
  keratin rather than a circulating serum protein (proteomic subtyping has
  identified keratins 5/14 specifically, so far in OSMR-mutant familial disease). This
  keratinocyte origin makes PLCA a mechanistically distinctive amyloidosis: the
  precursor is generated locally, in situ, by the same epithelium that overlies
  the deposit. Chronic pruritus with scratching and frictional epidermal damage
  is both a cardinal symptom and a putative driver, producing a self-reinforcing
  itch-scratch-deposition cycle. A minority of cases are familial, following
  autosomal dominant inheritance with pathogenic missense variants in OSMR
  (oncostatin M receptor beta) or IL31RA (interleukin-31 receptor A) - two
  subunits of the shared oncostatin M / IL-31 receptor system - and an
  autosomal recessive form (amyloidosis cutis dyschromica) caused by biallelic
  loss of GPNMB. Nodular cutaneous amyloidosis is mechanistically separate: its
  amyloid is AL (immunoglobulin light chain) produced by a local cutaneous
  plasma-cell clone, and it is not keratin-derived. Cutaneous lichen amyloidosis
  is also a recognized feature of a RET-driven MEN2A variant.
synonyms:
- primary localized cutaneous amyloidosis
- PLCA
- primary localised cutaneous amyloidosis
- familial primary localized cutaneous amyloidosis
- cutaneous amyloidosis
notes: >-
  Deep-research provenance: the falcon (Edison) provider named in the originating
  issue was unavailable in this curation environment - no EDISON_API_KEY /
  FUTUREHOUSE_API_KEY was configured and deep-research-client reported claude_code
  as the only available provider - so claude_code was used instead. All evidence in
  this entry was independently verified against PubMed-cached abstracts rather than
  taken from any deep-research summary. Disease associations that are not modelled
  as separate slots: cutaneous lichen amyloidosis is a recognized variant feature of
  RET-driven MEN2A (see the MEN2A-Associated Cutaneous Lichen Amyloidosis subtype),
  and nodular cutaneous amyloidosis has been reported in association with Sjogren
  syndrome (see the Nodular Amyloidosis subtype). The Sjogren association rests on
  small uncontrolled case series without a denominator and is recorded as a reported
  association, not as established over-representation.

has_subtypes:
- name: Lichen Amyloidosis
  display_name: Lichen (papular) amyloidosis
  subtype_term:
    preferred_term: lichen amyloidosis
    term:
      id: MONDO:0018856
      label: lichen amyloidosis
  description: >-
    The most common form of PLCA. Presents as intensely pruritic, discrete,
    firm, hyperkeratotic hyperpigmented papules, classically on the extensor
    shins but also the forearms and back, often coalescing into rippled plaques.
    Amyloid is keratin-derived and deposited in the dermal papillae; the
    epidermis shows hyperkeratosis and acanthosis. Strongly associated with
    chronic friction and scratching.
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LA is strongly associated with chronic friction and pruritus, whereas MA
      presents with asymptomatic hyperpigmentation.
    explanation: >-
      Distinguishes lichen amyloidosis from macular amyloidosis on the basis of
      pruritus and chronic friction, the defining features of this subtype.

- name: Macular Amyloidosis
  display_name: Macular amyloidosis
  subtype_term:
    preferred_term: macular amyloidosis
    term:
      id: MONDO:0015303
      label: macular amyloidosis
  description: >-
    Presents as greyish-brown, often rippled or reticulated hyperpigmented
    macules, characteristically over the upper back (interscapular region) and
    extensor arms, typically with little or no papule formation and less pruritus
    than lichen amyloidosis. Histologically the amyloid deposits in the papillary
    dermis are smaller than in the lichen form, but tinctorially and
    immunohistochemically the two are indistinguishable, supporting the view that
    they are two ends of one keratin-derived process.
  evidence:
  - reference: PMID:1930004
    reference_title: "Primary localised cutaneous amyloidosis in Malaysians."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologically, PA differed from MA by the larger size of amyloid deposits
      in the papillary dermis. There was no difference in their tinctorial and
      immunohistochemical characteristics.
    explanation: >-
      Establishes that macular amyloidosis differs from the papular (lichen) form
      mainly by deposit size, with identical staining characteristics - the basis
      for treating them as one overlapping process.

- name: Biphasic Amyloidosis
  display_name: Biphasic (mixed lichen and macular) amyloidosis
  description: >-
    Coexistence of lichenoid papules and macular pigmentation in the same
    patient, reflecting the overlapping nature of the two keratin-derived forms
    rather than a mechanistically separate entity.
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It includes lichen amyloidosis (LA), macular amyloidosis (MA), and biphasic
      amyloidosis.
    explanation: >-
      Names biphasic amyloidosis as a recognized subtype of PLCA alongside the
      lichen and macular forms.

- name: Nodular Amyloidosis
  display_name: Primary localized cutaneous nodular amyloidosis
  subtype_term:
    preferred_term: nodular cutaneous amyloidosis
    term:
      id: MONDO:0015302
      label: nodular cutaneous amyloidosis
  description: >-
    Mechanistically distinct from the keratin-derived forms. Presents as solitary
    or few waxy nodules or plaques, most often on the limbs, face, or trunk. The
    amyloid is AL (immunoglobulin light chain) type, produced by a
    light-chain-restricted plasma-cell population within the lesion - in effect a
    localized cutaneous plasma-cell dyscrasia. It carries a small risk of
    representing or evolving into systemic amyloidosis, so systemic screening is
    warranted. It has been reported in association with Sjogren syndrome; that
    association rests on small uncontrolled case series without a denominator, so
    it is recorded here as a reported association rather than as established
    over-representation.
  evidence:
  - reference: PMID:41528921
    reference_title: "Cutaneous Amyloidosis: An Updated Approach Focusing on Macular Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary cutaneous amyloidosis has been classified into three groups:
      macular, lichen, and nodular, the former two being one often overlapping
      process, and the latter a localized plasma dyscrasia with a small risk of
      representing a systemic disease.
    explanation: >-
      Establishes nodular amyloidosis as a localized plasma-cell dyscrasia,
      mechanistically separate from the overlapping macular/lichen keratin-derived
      process, and notes the systemic risk.
  - reference: PMID:6184423
    reference_title: "Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Directly demonstrates that nodular amyloid, unlike lichen and macular
      amyloid, is NOT keratin-derived - the immunohistochemical basis for treating
      it as a separate subtype.
  - reference: PMID:18576343
    reference_title: "Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SS should be considered in patients with cutaneous amyloidosis.
    explanation: >-
      Supports an awareness/screening recommendation for Sjogren syndrome in
      cutaneous amyloidosis. Recorded as PARTIAL because this is an 8-patient
      convenience series drawn from three amyloidosis-centre databases with no
      denominator and no comparison group - the paper's own title asks
      "coincidence or a distinct clinical entity?" - so it does not establish
      epidemiological over-representation.

- name: Amyloidosis Cutis Dyschromica
  display_name: Amyloidosis cutis dyschromica (GPNMB-related, autosomal recessive)
  subtype_term:
    preferred_term: amyloidosis cutis dyschromica
    term:
      id: MONDO:0017906
      label: amyloidosis cutis dyschromia
  description: >-
    A distinct, generalized, early-onset form characterized by widespread
    reticulate hyperpigmentation mottled with small hypopigmented macules on the
    trunk and limbs, with little or no pruritus. Caused by biallelic (homozygous
    or compound heterozygous) truncating or missense variants in GPNMB
    (glycoprotein NMB), inherited in an autosomal recessive manner and reported
    predominantly in East and Southeast Asian and South Asian families. The
    dyschromia reflects loss of melanocytes in the depigmented macules.
  genes:
  - preferred_term: GPNMB
    term:
      id: hgnc:4462
      label: GPNMB
  inheritance:
  - name: Autosomal recessive inheritance
    description: >-
      Amyloidosis cutis dyschromica segregates as an autosomal recessive trait,
      with affected individuals carrying homozygous or compound heterozygous
      GPNMB loss-of-function alleles.
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:29336782
      reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report here that the compound heterozygosity or homozygosity of GPNMB
        truncating alleles is the cause of autosomal-recessive ACD.
      explanation: >-
        Establishes autosomal recessive inheritance via biallelic GPNMB truncating
        alleles.
  evidence:
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous
      amyloidosis characterized by generalized hyperpigmentation mottled with
      small hypopigmented macules on the trunks and limbs.
    explanation: >-
      Defines amyloidosis cutis dyschromica as a distinct clinical form of primary
      cutaneous amyloidosis with a characteristic dyschromic presentation.

- name: Familial PLCA
  display_name: Familial primary localized cutaneous amyloidosis (OSMR / IL31RA)
  subtype_term:
    preferred_term: familial primary localized cutaneous amyloidosis
    term:
      id: MONDO:0007101
      label: familial primary localized cutaneous amyloidosis
  description: >-
    Autosomal dominant familial form, typically presenting with lichen and/or
    macular lesions, caused by heterozygous missense variants in OSMR (encoding
    oncostatin M receptor beta) or, less commonly, IL31RA (interleukin-31
    receptor A). Both genes lie in the linked 5p13.1-q11.2 interval and encode
    subunits of the shared oncostatin M type II / IL-31 receptor system; the
    pathogenic substitutions cluster in the extracellular fibronectin type
    III-like domains required for receptor dimerization. Familial PLCA is
    especially prevalent in Taiwanese, southern Chinese, and South American
    (Brazilian) populations.
  genes:
  - preferred_term: OSMR
    term:
      id: hgnc:8507
      label: OSMR
  - preferred_term: IL31RA
    term:
      id: hgnc:18969
      label: IL31RA
  inheritance:
  - name: Autosomal dominant inheritance
    description: >-
      Familial PLCA segregates as an autosomal dominant trait with heterozygous
      missense variants in OSMR or IL31RA.
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:18179886
      reference_title: "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Familial primary localized cutaneous amyloidosis (FPLCA) is an
        autosomal-dominant disorder associated with chronic skin itching and
        deposition of epidermal keratin filament-associated amyloid material in
        the dermis.
      explanation: >-
        States the autosomal dominant inheritance of familial PLCA.
  evidence:
  - reference: PMID:19690585
    reference_title: "Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PCA is a genetically heterogeneous disorder but our study shows that it can
      be caused by mutations in two biologically associated cytokine receptor
      genes located on chromosome 5.
    explanation: >-
      Establishes the two-gene (OSMR and IL31RA) genetic basis of familial PLCA.

- name: MEN2A-Associated Cutaneous Lichen Amyloidosis
  display_name: Cutaneous lichen amyloidosis in MEN2A (RET)
  description: >-
    Cutaneous lichen amyloidosis occurring as a recognized variant feature of
    multiple endocrine neoplasia type 2A, caused by germline gain-of-function
    variants in the RET proto-oncogene (classically codon 634). The lesions are
    typically localized to the interscapular region and may precede the endocrine
    manifestations, making them a clinical clue that should prompt RET testing.
    This is the single most actionable fact in the entry: nearly all MEN2A patients
    eventually develop medullary thyroid carcinoma, so recognising the skin lesion
    can bring forward RET testing and prophylactic thyroidectomy in an at-risk
    kindred (see the RET cascade-testing entry under diagnosis).
    Included here because the cutaneous lesion is genuinely a primary cutaneous
    amyloidosis, but the driver gene and syndromic context are distinct from
    OSMR/IL31RA familial PLCA.
  genes:
  - preferred_term: RET
    term:
      id: hgnc:9967
      label: RET
  evidence:
  - reference: PMID:42194535
    reference_title: "Generalized Cutaneous Lichen Amyloidosis in a Patient with an Ultra-Rare RET Y806C Variant Associated with MEN2A: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In MEN2A, CLA is typically localized to the interscapular region and linked
      to RET codon 634 variants, whereas generalized forms are rare.
    explanation: >-
      Establishes cutaneous lichen amyloidosis as a RET-associated feature of
      MEN2A with a characteristic interscapular distribution.
  - reference: PMID:30085596
    reference_title: "Multiple Endocrine Neoplasias Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Further evaluation of affected families with MEN2A led to the
      identification of the following 4 variants: Classical MEN2A. MEN2A with
      cutaneous lichen amyloidosis (CLA).
    explanation: >-
      Confirms MEN2A with cutaneous lichen amyloidosis as a formally recognized
      MEN2A variant.
  - reference: PMID:30085596
    reference_title: "Multiple Endocrine Neoplasias Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In both subtypes, nearly 100% of patients eventually develop medullary
      thyroid cancer (MTC), and up to 50% develop pheochromocytomas.
    explanation: >-
      Quantifies the near-complete MTC penetrance in MEN2A that makes recognition
      of the cutaneous lichen amyloidosis lesion clinically actionable. Evidence
      source is OTHER because this is a StatPearls review chapter.
  - reference: PMID:42194535
    reference_title: "Generalized Cutaneous Lichen Amyloidosis in a Patient with an Ultra-Rare RET Y806C Variant Associated with MEN2A: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male patient with MEN2A and a generalized form of CLA that
      preceded the diagnosis of primary hyperparathyroidism (PHPT) and medullary
      thyroid carcinoma (MTC).
    explanation: >-
      Documents the cutaneous lesion preceding the endocrine neoplasia in a
      RET-variant patient - the temporal ordering that makes CLA a useful early
      clinical clue. Note this is a single case report, so it establishes that
      precedence can occur, not a typical lead time.

inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The familial form of PLCA caused by OSMR or IL31RA missense variants is
    inherited in an autosomal dominant manner. Most PLCA overall is sporadic,
    but a substantial minority of cases in South America and Southeast Asia are
    familial.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:18179886
    reference_title: "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial primary localized cutaneous amyloidosis (FPLCA) is an
      autosomal-dominant disorder associated with chronic skin itching and
      deposition of epidermal keratin filament-associated amyloid material in
      the dermis.
    explanation: >-
      States autosomal dominant inheritance for the OSMR-related familial form.
- name: Autosomal recessive inheritance
  description: >-
    Amyloidosis cutis dyschromica, the generalized dyschromic form of primary
    cutaneous amyloidosis, is inherited in an autosomal recessive manner through
    biallelic GPNMB loss-of-function alleles.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here that the compound heterozygosity or homozygosity of GPNMB
      truncating alleles is the cause of autosomal-recessive ACD.
    explanation: >-
      States autosomal recessive inheritance for the GPNMB-related dyschromic
      form.

pathophysiology:
- name: Keratinocyte Damage and Amyloidogenic Keratin Release
  description: >-
    The disease-specific trigger of primary cutaneous amyloidosis. Epidermal
    keratinocytes - injured by chronic friction and scratching, or destabilized
    by a genetic lesion in the OSM/IL-31 receptor system - undergo filamentous
    degeneration and apoptosis, dropping their keratin intermediate filaments
    into the underlying papillary dermis. Keratin is therefore the amyloidogenic
    precursor protein in the lichen and macular forms; the classic
    immunohistochemical study concluded only that "at least some" of the amyloid
    is keratinocyte-derived, and the specific identification of the basal keratin
    pair 5/14 comes from proteomic subtyping of OSMR-mutant familial disease, so
    it should not yet be generalized to all sporadic PLCA. This is the disease-specific substitution for the
    generic amyloidogenic precursor of the amyloidogenesis module: unlike the
    circulating precursors of systemic amyloidosis (transthyretin, free light
    chain, serum amyloid A), the PLCA precursor is generated locally by the
    epithelium immediately overlying the deposit.
  role: trigger
  biological_scale: CELLULAR
  conforms_to: amyloidogenesis#Amyloidogenic Precursor Protein
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte apoptotic process
    term:
      id: GO:0097283
      label: keratinocyte apoptotic process
    modifier: INCREASED
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:6184423
    reference_title: "Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The classic immunohistochemical demonstration that the amyloid precursor in
      cutaneous amyloidosis is keratin released from degenerating keratinocytes -
      the disease-specific precursor substituted into this module node.
  - reference: PMID:34459039
    reference_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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      Proteomic (LC-MS/MS) and immuno-electron subtyping identify keratins 5/14 as
      the specific deposited amyloid protein in OSMR-mutant familial PLCA. Quoted
      from the article title, which is the only text in the PubMed record for this
      correspondence item (no abstract is published).
  downstream:
  - target: Keratin Misfolding and Beta-Sheet Oligomerization
    causal_link_type: DIRECT
    description: >-
      Keratin filaments shed from degenerating keratinocytes into the papillary
      dermis depart their native conformation and assemble into beta-sheet-rich
      aggregation-prone species.

- name: OSM/IL-31 Receptor Signaling Failure
  description: >-
    In familial PLCA, heterozygous missense variants in OSMR or IL31RA - located
    in the extracellular fibronectin type III-like domains critical for receptor
    dimerization - impair signal transduction through the shared oncostatin M
    type II and IL-31 receptor complexes. Patient keratinocytes show reduced
    JAK/STAT, MAPK, and PI3K/Akt activation after OSM or IL-31 stimulation.
    Because OSM signaling through OSMRbeta/STAT5/KLF7 normally restrains
    keratinocyte differentiation, loss of this brake produces basal keratinocyte
    hyperproliferation and overdifferentiation, increasing the pool of
    keratinocytes available to degenerate and shed keratin. This node is the
    genetic entry point into the trigger.
  role: trigger
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: basal cell of epidermis
    term:
      id: CL:0002187
      label: basal cell of epidermis
  biological_processes:
  - preferred_term: oncostatin-M-mediated signaling pathway
    term:
      id: GO:0038165
      label: oncostatin-M-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: INCREASED
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:18179886
    reference_title: "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified missense mutations in the OSMR gene, encoding oncostatin
      M-specific receptor beta (OSMRbeta), in three families. 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.
    explanation: >-
      Establishes OSMR missense variants as the cause of familial PLCA and
      demonstrates the resulting signal-transduction failure in patient
      keratinocytes.
  - reference: PMID:18179886
    reference_title: "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenic amino acid substitutions are located within the
      extracellular fibronectin type III-like (FNIII) domains, regions critical
      for receptor dimerization and function.
    explanation: >-
      Localizes the pathogenic substitutions to the dimerization-critical FNIII
      domains, giving the structural mechanism of the signaling failure.
  - reference: PMID:42029085
    reference_title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: >-
      Names the STAT5-KLF7 axis downstream of OSMRbeta and confirms that
      pathogenic OSMR variants suppress signal transduction by disrupting
      dimerization. Evidence source is OTHER because this is a narrative review.
  - reference: PMID:33502684
    reference_title: "OSMRβ mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the expression levels of epidermal keratinocyte differentiation-related
      genes were significantly decreased in the OSM-treated HaCaT cells or primary
      keratinocytes
    explanation: >-
      The in vitro arm: OSM stimulation of HaCaT and primary human keratinocytes
      suppresses differentiation-marker expression, establishing OSM as a negative
      regulator of keratinocyte differentiation.
  - reference: PMID:33502684
    reference_title: "OSMRβ mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that Osmr knockout enhances basal keratinocyte
      differentiation and proliferation in mice.
    explanation: >-
      The in vivo arm of the same study: Osmr-null mice reproduce the basal
      keratinocyte hyperdifferentiation and hyperproliferation, showing the axis
      operates in intact skin. Split from the in vitro item so each evidence item
      carries a single evidence_source, per the repo SOP.
  downstream:
  - target: Keratinocyte Damage and Amyloidogenic Keratin Release
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of the OSM/STAT5/KLF7 brake on keratinocyte differentiation
    - AHNAK upregulation driving basal keratinocyte hyperproliferation and overdifferentiation
    - Bcl-xL suppression increasing keratinocyte apoptosis
    description: >-
      Defective OSM/IL-31 receptor signaling increases keratinocyte turnover and
      apoptosis, enlarging the pool of amyloidogenic keratin released into the
      papillary dermis.
    evidence:
    - reference: PMID:37100691
      reference_title: "AHNAK, regulated by the OSM/OSMR signaling, involved in the development of primary localized cutaneous amyloidosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Taken together, these data indicated that the elevated expression of
        AHNAK by OSMR mutations led to hyperproliferation and overdifferentiation
        of keratinocytes, and the discovered mechanism might provide insights
        into potential therapeutic targets for PLCA.
      explanation: >-
        Provides the AHNAK-mediated intermediate linking OSMR mutation to
        keratinocyte hyperproliferation and overdifferentiation. Tagged IN_VITRO
        for the HaCaT / primary keratinocyte / 3D human epidermis experiments that
        carry this conclusion; the same paper's gene-edited mouse arm is captured
        separately below.
    - reference: PMID:37100691
      reference_title: "AHNAK, regulated by the OSM/OSMR signaling, involved in the development of primary localized cutaneous amyloidosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Similar results were obtained in wild-type and OSMR knockout mice.
      explanation: >-
        The in vivo arm: OSMR-knockout mice reproduce the loss of OSM-mediated
        AHNAK downregulation seen in the cell and 3D-skin systems.
    - reference: PMID:42029085
      reference_title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        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
      explanation: >-
        Supplies both named intermediates (AHNAK elevation and Bcl-xL suppression)
        and their consequences of accelerated differentiation and apoptosis.
        Evidence source is OTHER because this is a narrative review.
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      OSMRbeta and IL-31RA are the receptor subunits for the pruritogenic cytokine
      IL-31, and their epidermal expression is increased in PLCA lesions,
      contributing to cutaneous nerve-fibre hypersensitivity and itch. The
      intermediates are genuinely unknown, and the direction is not
      straightforward: this node is LOSS of receptor signal transduction, whereas
      the lesional finding is INCREASED receptor expression, so the connection is
      not a simple direct consequence.
    evidence:
    - reference: PMID:26748444
      reference_title: "Pathophysiology of pruritus in primary localized cutaneous amyloidosis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        increased epidermal expression of OSMRβ (P < 0·01) and IL-31RA (P <
        0·01)
      explanation: >-
        Documents significantly increased lesional epidermal expression of both
        IL-31 receptor subunits, OSMRbeta and IL-31RA - the receptor link between
        this node and the pruritus node. Recorded as INDIRECT: the 20 patients were
        unselected Chinese PLCA cases who were not OSMR-genotyped, so this
        cross-sectional receptor upregulation in largely sporadic disease supports
        an IL-31-receptor contribution to pruritus but does not establish it as a
        consequence of the germline signalling-failure lesion. Note also that in
        the same study cutaneous IL-31 ligand staining was NOT significantly
        increased, so the signal is receptor upregulation, not ligand excess.

- name: Keratin Misfolding and Beta-Sheet Oligomerization
  description: >-
    Keratin filaments released into the papillary dermis lose their native
    coiled-coil conformation and convert into beta-sheet-rich, aggregation-prone
    species that nucleate further aggregation. This is the disorder-specific
    instance of the conserved misfolding/oligomerization amplifier step of
    amyloidogenesis, operating on keratin rather than on a circulating serum
    precursor.
  role: amplifier
  biological_scale: MOLECULAR
  conforms_to: amyloidogenesis#Protein Misfolding and Beta-Sheet Oligomerization
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:6184423
    reference_title: "Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloids in lichenoid and macular amyloidoses, and in basal cell
      epithelioma had an identical antigenicity with epidermal keratin
    explanation: >-
      The antigenic identity between epidermal keratin and the deposited amyloid
      establishes that keratin itself is the protein that converts to the amyloid
      conformation in this disease.
  - reference: PMID:1930004
    reference_title: "Primary localised cutaneous amyloidosis in Malaysians."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A few cases exhibited positively for cytokeratin. Strong immunoreactivity
      for AP protein was observed. PA and MA appear chemically similar and are
      likely to be of epidermal origin.
    explanation: >-
      Supports the epidermal (keratin) origin of the deposits, though this series
      found only partial cytokeratin immunoreactivity - epitope masking on
      conversion to the amyloid fold is one explanation, so the support is
      recorded as PARTIAL.
  downstream:
  - target: Papillary Dermal Amyloid Fibril Deposition
    causal_link_type: DIRECT
    description: >-
      Beta-sheet keratin oligomers nucleate and elongate into cross-beta amyloid
      fibrils deposited in the dermal papillae.

- name: Papillary Dermal Amyloid Fibril Deposition
  description: >-
    The central effector of the disease and the key conformance point with the
    amyloidogenesis module - the step at which both upstream precursor routes
    converge. Beta-sheet oligomers assemble into insoluble cross-beta amyloid
    fibrils that deposit extracellularly in the dermis, where they are
    demonstrated by Congo red staining with apple-green birefringence under
    polarized light. In the keratin-derived lichen and macular forms - which
    dominate the disease - deposition is confined to the papillary dermis (the
    dermal papillae) immediately beneath the epidermis that generated the
    precursor; in the AL/nodular form the light-chain-derived deposits are
    typically deeper and more nodular, extending into the reticular dermis and
    subcutis. The disease-specific substitution relative to the generic module is
    therefore the anatomical site: the amyloid stays local to the skin rather than
    being distributed to distant organs by the circulation.
  role: central_effector
  biological_scale: TISSUE
  conforms_to: amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological analysis revealed amyloid deposits in the papillary
      dermis, epidermal hyperplasia, and inflammatory infiltration in LA. Congo
      red staining demonstrated characteristic apple-green birefringence under
      polarized light, confirming amyloid deposition.
    explanation: >-
      Directly documents papillary-dermal amyloid deposition confirmed by Congo
      red apple-green birefringence, the central effector of this entry.
  - reference: PMID:42029085
    reference_title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic
      dermatological disorder characterized by amyloid deposits in the papillary
      dermis, significantly impairing patients' quality of life.
    explanation: >-
      Locates the amyloid deposits of PLCA specifically in the papillary dermis.
      Evidence source is OTHER because this is a narrative review.
  downstream:
  - target: Impaired Amyloid Clearance and Progressive Cutaneous Accumulation
    causal_link_type: DIRECT
    description: >-
      Deposited fibrils that outpace macrophage-mediated clearance accumulate
      progressively in the dermal papillae.

- name: Impaired Amyloid Clearance and Progressive Cutaneous Accumulation
  description: >-
    Amyloid burden in the skin reflects the balance between deposition and
    clearance. Dermal macrophages infiltrate lesional skin and remove amyloid,
    but this clearance is limited - and, in IL31RA-variant disease, is further
    impaired by dysregulated MCP-1 (monocyte chemoattractant protein-1)
    expression that reduces monocyte-mediated removal of fibrils. When clearance
    is outpaced, amyloid accumulates progressively in the dermal papillae,
    converting a molecular deposition event into a persistent, clinically visible
    structural lesion of the skin.
  role: effector
  biological_scale: TISSUE
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:42029085
    reference_title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: >-
      Directly establishes impaired monocyte-mediated amyloid clearance, driven by
      an IL31RA variant via MCP-1, as a mechanism of pathological amyloid
      retention. Evidence source is OTHER because this is a narrative review.
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperpigmented lesions exhibited significantly increased amounts of
      DNA/keratin-positive amyloid deposits in the papillary dermis and
      infiltrating macrophages compared with hypo- or depigmented macules.
    explanation: >-
      Documents keratin-positive papillary-dermal amyloid accumulation together
      with a macrophage infiltrate. Recorded as INDIRECT because this is a
      co-occurrence only: more macrophages where there is more amyloid is equally
      consistent with ACTIVE clearance, and the study does not demonstrate that
      clearance is impaired. The impaired-clearance claim of this node rests on
      the IL31RA/MCP-1 evidence above.
  downstream:
  - target: Chronic Cutaneous Lesion Formation and Dysfunction
    causal_link_type: DIRECT
    description: >-
      Accumulated papillary-dermal amyloid, with the overlying reactive epidermal
      changes, produces the persistent papules, plaques, and pigmentary change of
      PLCA.
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Accumulated papillary-dermal amyloid is itself associated with the cutaneous
      small-fibre neuropathy that generates itch, closing the amplification loop
      without requiring a germline receptor lesion. This edge matters because
      roughly two-thirds of sporadic Chinese PLCA is OSMR-wildtype, so the loop
      must be enterable from the deposit itself and not only from the genetic
      node. The intermediates are unresolved - whether the deposit causes the
      nerve-fibre change or merely accompanies it is the open question recorded in
      the plca_sfn_cause_or_consequence discussion.
    evidence:
    - reference: PMID:26748444
      reference_title: "Pathophysiology of pruritus in primary localized cutaneous amyloidosis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SFN is present in PLCA. Pruritus in PLCA is likely associated with
        hypersensitivity of cutaneous nerve fibres
      explanation: >-
        Establishes small-fibre neuropathy and itch in an unselected,
        predominantly sporadic PLCA cohort, showing the pruritus arm does not
        depend on an OSMR genotype. Recorded as INDIRECT because the study is
        cross-sectional and cannot establish that the amyloid deposit causes the
        neuropathy.

- name: Chronic Cutaneous Lesion Formation and Dysfunction
  description: >-
    The organ-level end state of the module, specialized to the skin. Persistent
    papillary-dermal amyloid, together with reactive epidermal hyperplasia,
    hyperkeratosis, pigmentary incontinence, and dermal inflammatory infiltration,
    produces the chronic hyperkeratotic papules, plaques, and hyperpigmented
    macules of PLCA. Unlike the systemic amyloidoses, organ dysfunction here is
    confined to the skin: in the keratin-derived lichen and macular forms there is
    no cardiac, renal, or neurological amyloid involvement, but the lesions are
    disfiguring, persistent, and (through intractable pruritus) markedly impair
    quality of life. The AL/nodular form is the exception that proves the rule - it
    remains skin-limited in most patients but carries a small risk of harbouring or
    progressing to systemic AL amyloidosis, which is why it is screened for.
  role: consequence
  biological_scale: ORGANISM
  conforms_to: amyloidogenesis#Organ Dysfunction
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary Localized Cutaneous Amyloidosis (PLCA) is a rare disorder
      characterized by amyloid deposition in the skin without systemic
      involvement.
    explanation: >-
      Establishes that the consequence of the amyloidogenesis chain in this
      disease is confined to the skin, with no systemic organ involvement.
  - reference: PMID:42029085
    reference_title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: >-
      Links the molecular cascade to the tissue-level outcome of stratum corneum
      thickening alongside amyloid deposition. Evidence source is OTHER because
      this is a narrative review.

- name: Pruritus and the Itch-Scratch-Friction Cycle
  description: >-
    A self-reinforcing amplifier loop that is arguably the defining clinical
    mechanism of lichen amyloidosis. Lesional skin shows small-fibre neuropathy
    with reduced intraepidermal nerve fibre density and elevated warm detection
    thresholds that correlate with itch severity, together with increased
    epidermal expression of the IL-31 receptor subunits OSMRbeta and IL-31RA -
    a pattern of cutaneous nerve-fibre hypersensitivity rather than simple
    nerve-fibre excess. The resulting intractable pruritus drives chronic
    scratching and frictional trauma, which damages keratinocytes and feeds more
    amyloidogenic keratin back into the papillary dermis, closing the loop. This
    node is a disease-specific addition beyond the amyloidogenesis module, which
    has no equivalent feedback arm.
  role: amplifier
  biological_scale: TISSUE
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:26748444
    reference_title: "Pathophysiology of pruritus in primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Directly establishes small-fibre neuropathy and increased epidermal IL-31
      receptor expression as the mechanism of PLCA pruritus, and identifies the
      IL-31 receptor as a therapeutic target.
  - reference: PMID:26748444
    reference_title: "Pathophysiology of pruritus in primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WDT was significantly higher in patients at all sites and correlated with
      itch scores (r = 0·59; P < 0·01).
    explanation: >-
      Quantifies the sensory abnormality (raised warm detection threshold
      correlating with itch severity) underlying the itch arm of the cycle.
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenesis is linked to chronic friction, keratinocyte damage, and in
      some cases, genetic predisposition.
    explanation: >-
      Links chronic friction to keratinocyte damage, closing the scratch arm of
      the itch-scratch-deposition cycle.
  downstream:
  - target: Keratinocyte Damage and Amyloidogenic Keratin Release
    causal_link_type: DIRECT
    description: >-
      Chronic scratching and frictional trauma damage keratinocytes, releasing
      more amyloidogenic keratin into the papillary dermis and closing the
      self-reinforcing loop.
    evidence:
    - reference: PMID:40151750
      reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        LA is strongly associated with chronic friction and pruritus, whereas MA
        presents with asymptomatic hyperpigmentation.
      explanation: >-
        Associates chronic friction and pruritus with the lichen form, supporting
        the friction-to-keratinocyte-damage edge.

- name: Local Plasma Cell Light-Chain Production
  description: >-
    The mechanistically separate route to cutaneous amyloid seen in primary
    localized cutaneous nodular amyloidosis. A light-chain-restricted (clonal)
    plasma-cell population resident within the skin lesion secretes an
    amyloidogenic immunoglobulin light chain locally, which misfolds and deposits
    as AL amyloid in the dermis and subcutis. The precursor is therefore an
    immunoglobulin light chain, not keratin, and the deposit lacks keratin
    antigenicity - this is a localized cutaneous plasma-cell dyscrasia. It shares
    the amyloidogenic-precursor node of the module but substitutes a completely
    different precursor, which is why nodular disease carries a real (if small)
    risk of underlying or evolving systemic AL amyloidosis and warrants systemic
    screening.
  role: trigger
  biological_scale: CELLULAR
  conforms_to: amyloidogenesis#Amyloidogenic Precursor Protein
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18576343
    reference_title: "Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Directly demonstrates a local light-chain-restricted plasma-cell population
      adjacent to AL-type amyloid deposits in nodular cutaneous amyloidosis - the
      trigger of this alternative route.
  - reference: PMID:6184423
    reference_title: "Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whereas amyloids in nodular amyloidosis and systemic amyloidosis did not
      have this identity
    explanation: >-
      Confirms that nodular amyloid is not keratin-derived, distinguishing this
      trigger from the keratinocyte route.
  downstream:
  - target: Papillary Dermal Amyloid Fibril Deposition
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Local secretion of an amyloidogenic immunoglobulin light chain by the cutaneous plasma-cell clone
    - Light-chain misfolding into beta-sheet-rich oligomers
    - Nucleation of AL-type fibrils, typically deeper and more nodular than the keratin-derived papillary deposits
    description: >-
      Locally produced amyloidogenic light chain misfolds and deposits as dermal
      AL amyloid.

- name: GPNMB Loss of Function
  description: >-
    The molecular lesion specific to amyloidosis cutis dyschromica. Biallelic
    loss-of-function of GPNMB - a transmembrane glycoprotein normally expressed
    throughout the epidermis and most highly in melanocytes, with roles in
    melanosome formation, autophagy, phagocytosis, tissue repair, and negative
    regulation of inflammation - removes that protein's function from lesional
    skin. This is a distinct genetic entry into the shared downstream amyloid
    chain, and it drives two separable consequences: a keratinocyte arm feeding
    amyloid deposition, and a melanocyte arm producing the dyschromia.
  role: trigger
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed
      in all epidermal cells, with the highest staining observed in melanocytes.
      GPNMB staining is significantly reduced in the lesional skin of affected
      individuals.
    explanation: >-
      Establishes GPNMB expression in epidermis and melanocytes and its loss in
      lesional skin, the proximal lesion of this route.
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Depigmentation of the lesions was attributable to loss of melanocytes.
      Intracytoplasmic fibrillary aggregates were observed in keratinocytes
      scattered in the lesional epidermis.
    explanation: >-
      Provides the two-arm mechanism - melanocyte loss causing depigmentation and
      intracytoplasmic keratinocyte fibrillary aggregates feeding amyloid
      deposition.
  downstream:
  - target: Keratinocyte Damage and Amyloidogenic Keratin Release
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired GPNMB-dependent autophagy and phagocytosis in epidermal cells
    - Intracytoplasmic fibrillary aggregation within lesional keratinocytes
    - Degeneration of the affected keratinocytes with release of keratin into the papillary dermis
    description: >-
      GPNMB loss promotes keratinocyte fibrillary aggregation and degeneration,
      feeding the shared keratin-amyloid chain.
  - target: Melanocyte Depletion
    causal_link_type: DIRECT
    description: >-
      Loss of GPNMB, which is expressed most highly in melanocytes and is
      implicated in melanosome formation, results in loss of melanocytes from the
      depigmented lesions.

- name: Melanocyte Depletion
  description: >-
    The pigmentary arm of amyloidosis cutis dyschromica, and the reason that
    disease looks unlike any other primary cutaneous amyloidosis. Melanocytes are
    lost from the depigmented lesions, producing the small hypopigmented macules
    that stipple the generalized reticulate hyperpigmentation. This arm is
    separate from - and not a prerequisite for - the amyloid deposition arm: both
    descend independently from the same GPNMB lesion, which is why the entry
    models them as sibling consequences rather than a chain.
  role: consequence
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  evidence:
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Depigmentation of the lesions was attributable to loss of melanocytes.
    explanation: >-
      Directly attributes the depigmented lesions of amyloidosis cutis dyschromica
      to melanocyte loss, the content of this node.
  downstream:
  - target: Hypopigmented Macules
    causal_link_type: DIRECT
    description: >-
      Melanocyte loss produces the clinically visible hypopigmented macules of
      amyloidosis cutis dyschromica.

phenotypes:
- name: Pruritus
  category: Dermatological
  description: >-
    Chronic, often intractable itch, the cardinal symptom of lichen amyloidosis
    and the driver of the itch-scratch-friction cycle. Mediated by cutaneous
    small-fibre neuropathy with increased epidermal IL-31 receptor expression.
    Characteristically absent or minimal in macular amyloidosis and in
    amyloidosis cutis dyschromica.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
    temporality: CHRONIC
  evidence:
  - reference: PMID:42029085
    reference_title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic
      dermatological disorder characterized by amyloid deposits in the papillary
      dermis
    explanation: >-
      Defines PLCA as a chronic pruritic disorder. Evidence source is OTHER
      because this is a narrative review.
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pruritus was exclusively seen in LA, while hyperpigmentation was present in
      all cases.
    explanation: >-
      Documents pruritus in the lichen subtype specifically, and notes its absence
      in the macular cases of this series.

- name: Cutaneous Amyloidosis
  category: Dermatological
  description: >-
    Extracellular amyloid deposition confined to the skin - specifically the
    papillary dermis - demonstrable on biopsy by Congo red staining with
    apple-green birefringence under polarized light. This is the defining
    pathological phenotype of the disease and, by definition, occurs without
    systemic amyloid involvement.
  phenotype_term:
    preferred_term: Cutaneous amyloidosis
    term:
      id: HP:0012309
      label: Cutaneous amyloidosis
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congo red staining demonstrated characteristic apple-green birefringence
      under polarized light, confirming amyloid deposition.
    explanation: >-
      Documents Congo-red-confirmed cutaneous amyloid deposition in this
      biopsy-confirmed series. No `frequency:` is recorded deliberately:
      demonstrating cutaneous amyloid is the diagnostic entry criterion for PLCA,
      so any observed rate is fixed at 100% by ascertainment and would carry no
      information.

- name: Hyperkeratotic Papules
  category: Dermatological
  description: >-
    Discrete, firm, dome-shaped hyperkeratotic papules, typically 2-5 mm, that
    coalesce into rippled or corrugated plaques. Classically over the extensor
    shins, forearms, and back. The defining lesion of lichen amyloidosis.
  subtype: Lichen Amyloidosis
  phenotype_term:
    preferred_term: Hyperkeratotic papule
    term:
      id: HP:0045059
      label: Hyperkeratotic papule
  evidence:
  - reference: PMID:42194535
    reference_title: "Generalized Cutaneous Lichen Amyloidosis in a Patient with an Ultra-Rare RET Y806C Variant Associated with MEN2A: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous lichen amyloidosis (CLA) is a rare dermatological condition
      characterized by amyloid deposition in the skin, presenting as pruritic,
      hyperkeratotic papules.
    explanation: >-
      Defines the hyperkeratotic papule as the presenting lesion of cutaneous
      lichen amyloidosis.

- name: Hyperpigmentation of the Skin
  category: Dermatological
  description: >-
    Greyish-brown hyperpigmentation, often in a rippled or reticulate pattern,
    typically over the interscapular back and extensor limbs. The defining lesion
    of macular amyloidosis and a near-universal accompaniment of the lichen form;
    it reflects pigmentary incontinence with melanin in the papillary dermis
    alongside the amyloid.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pruritus was exclusively seen in LA, while hyperpigmentation was present in
      all cases.
    explanation: >-
      Reports hyperpigmentation in 9/9 (100%) of the biopsy-confirmed cases of
      this series. Note this is a deliberate departure from the default mapping:
      "in all cases" would map to OBLIGATE, but the band is recorded as
      VERY_FREQUENT (80-99%) because the cohort is a small single-centre series of
      nine patients and hyperpigmentation is not an obligate feature of PLCA in
      larger series - notably it is absent by definition from the hypopigmented
      macules of amyloidosis cutis dyschromica.

- name: Hypopigmented Macules
  category: Dermatological
  description: >-
    Small hypopigmented or depigmented macules interspersed within generalized
    reticulate hyperpigmentation, giving the characteristic dyschromic
    (salt-and-pepper) appearance of amyloidosis cutis dyschromica. Attributable to
    loss of melanocytes.
  subtype: Amyloidosis Cutis Dyschromica
  phenotype_term:
    preferred_term: Hypopigmentation of the skin
    term:
      id: HP:0001010
      label: Hypopigmentation of the skin
  evidence:
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous
      amyloidosis characterized by generalized hyperpigmentation mottled with
      small hypopigmented macules on the trunks and limbs.
    explanation: >-
      Documents the hypopigmented macules as a defining feature of amyloidosis
      cutis dyschromica.

- name: Reticulated Skin Pigmentation
  category: Dermatological
  description: >-
    A rippled or reticulated (net-like) pattern of grey-brown pigmentation,
    characteristic of macular amyloidosis over the upper back and extensor
    surfaces of the arms and legs, and also the pattern of the generalized
    hyperpigmentation in amyloidosis cutis dyschromica.
  subtype: Macular Amyloidosis
  phenotype_term:
    preferred_term: Reticulated skin pigmentation
    term:
      id: HP:0007427
      label: Reticulated skin pigmentation
  evidence:
  - reference: PMID:15569011
    reference_title: "Macular amyloidosis: an assessment of prevalence, sex, and age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by a reticulated or rippled pattern of pigmentation
      mostly in the upper back.
    explanation: >-
      Directly characterizes macular amyloidosis by its reticulated/rippled
      pigmentation pattern and upper-back distribution, in a 100-patient clinical
      series.

- name: Cutaneous Lichen Amyloidosis
  category: Dermatological
  description: >-
    The specific dermatological sign of lichen amyloidosis - pruritic,
    hyperkeratotic, often pigmented papules on the trunk and extremities,
    especially the shins, with amyloid in the papillary dermis. Recorded as a
    distinct HPO sign so the subtype is machine-queryable at the phenotype level
    as well as through the MONDO subtype binding.
  subtype: Lichen Amyloidosis
  phenotype_term:
    preferred_term: Cutaneous lichen amyloidosis
    term:
      id: HP:0032346
      label: Cutaneous lichen amyloidosis
  evidence:
  - reference: PMID:42194535
    reference_title: "Generalized Cutaneous Lichen Amyloidosis in a Patient with an Ultra-Rare RET Y806C Variant Associated with MEN2A: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous lichen amyloidosis (CLA) is a rare dermatological condition
      characterized by amyloid deposition in the skin, presenting as pruritic,
      hyperkeratotic papules.
    explanation: >-
      Defines cutaneous lichen amyloidosis as a distinct clinical sign
      characterized by pruritic hyperkeratotic papules with cutaneous amyloid
      deposition.

- name: Cutaneous Macular Amyloidosis
  category: Dermatological
  description: >-
    The specific dermatological sign of macular amyloidosis - greyish-brown
    hyperkeratotic macules in a rippled or reticulated pattern, typically over the
    upper back and extensor arms and legs, with keratin-derived amyloid in the
    papillary dermis. Recorded as a distinct HPO sign alongside its lichen and
    nodular siblings so all three presentations are queryable at the phenotype
    level as well as through their MONDO subtype bindings.
  subtype: Macular Amyloidosis
  phenotype_term:
    preferred_term: Cutaneous macular amyloidosis
    term:
      id: HP:0032347
      label: Cutaneous macular amyloidosis
  evidence:
  - reference: PMID:15569011
    reference_title: "Macular amyloidosis: an assessment of prevalence, sex, and age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Macular amyloidosis is a relatively common cutaneous disease in Asia and the
      Middle East. It is characterized by a reticulated or rippled pattern of
      pigmentation mostly in the upper back.
    explanation: >-
      Defines macular amyloidosis as a distinct clinical entity with its
      characteristic reticulated pigmentation and upper-back distribution.

- name: Cutaneous Nodular Amyloidosis
  category: Dermatological
  description: >-
    Waxy nodules or plaques containing immunoglobulin-derived (AL) amyloid
    produced by a local clonal plasma-cell population, the rarest of the primary
    cutaneous amyloidosis presentations and the only one that is not
    keratin-derived.
  subtype: Nodular Amyloidosis
  phenotype_term:
    preferred_term: Cutaneous nodular amyloidosis
    term:
      id: HP:0032348
      label: Cutaneous nodular amyloidosis
  evidence:
  - reference: PMID:41528921
    reference_title: "Cutaneous Amyloidosis: An Updated Approach Focusing on Macular Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary cutaneous amyloidosis has been classified into three groups:
      macular, lichen, and nodular, the former two being one often overlapping
      process, and the latter a localized plasma dyscrasia with a small risk of
      representing a systemic disease.
    explanation: >-
      Establishes nodular cutaneous amyloidosis as one of the three recognized
      presentations and as a localized plasma dyscrasia. Evidence source is OTHER
      because this is a review.
  - reference: PMID:18576343
    reference_title: "Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of the immunoglobulin light chain type of amyloid (AL amyloid)
      was confirmed in 4 patients.
    explanation: >-
      Confirms the immunoglobulin light-chain (AL) composition of the amyloid in
      nodular cutaneous amyloidosis lesions.

- name: Lichenification
  category: Dermatological
  description: >-
    Thickening of the skin with accentuated skin markings resulting from chronic
    scratching and rubbing, a visible marker of the itch-scratch-friction cycle
    and typically found on the shins in lichen amyloidosis.
  subtype: Lichen Amyloidosis
  phenotype_term:
    preferred_term: Lichenification
    term:
      id: HP:0100725
      label: Lichenification
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LA is strongly associated with chronic friction and pruritus
    explanation: >-
      Supports the chronic friction and scratching that produce lichenification;
      recorded as PARTIAL because the abstract documents the friction/pruritus
      association rather than naming lichenification explicitly.

- name: Epidermal Hyperplasia
  category: Histopathological
  description: >-
    Acanthosis and hyperkeratosis of the epidermis overlying the amyloid deposits,
    reflecting the keratinocyte hyperproliferation and overdifferentiation driven
    by loss of the OSM/STAT5/KLF7 brake and by chronic frictional stimulation.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological analysis revealed amyloid deposits in the papillary
      dermis, epidermal hyperplasia, and inflammatory infiltration in LA.
    explanation: >-
      Directly documents epidermal hyperplasia accompanying the papillary-dermal
      amyloid.
  - reference: PMID:37100691
    reference_title: "AHNAK, regulated by the OSM/OSMR signaling, involved in the development of primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary localized cutaneous amyloidosis (PLCA) is a chronic skin disease
      characterized by aberrant keratinocyte differentiation, epidermal
      hyperproliferation, and amyloid deposits.
    explanation: >-
      Names epidermal hyperproliferation and aberrant keratinocyte differentiation
      as defining features of PLCA, giving the mechanism behind the hyperplasia.

genetic:
- name: OSMR
  notes: >-
    OSMR encodes oncostatin M receptor beta (OSMRbeta), a shared signalling
    subunit of both the oncostatin M type II receptor (with gp130) and the IL-31
    receptor (with IL-31RA). Heterozygous missense variants clustering in the
    extracellular fibronectin type III-like domains cause autosomal dominant
    familial PLCA by disrupting receptor dimerization and downstream JAK/STAT
    (notably STAT5/KLF7), MAPK, and PI3K/Akt signalling. Recurrent alleles include
    p.I691T, p.G618A, p.D647V, p.P694L, p.K697T, and p.G513D. OSMR variants are
    found not only in familial disease but also in a substantial minority of
    apparently sporadic cases.
  gene_term:
    preferred_term: OSMR
    term:
      id: hgnc:8507
      label: OSMR
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:18179886
    reference_title: "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we
      identified missense mutations in the OSMR gene, encoding oncostatin
      M-specific receptor beta (OSMRbeta), in three families.
    explanation: >-
      The original identification of OSMR as the familial PLCA disease gene.
  - reference: PMID:19690585
    reference_title: "Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, 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).
    explanation: >-
      Documents the recurrent heterozygous OSMR missense alleles in a large
      Taiwanese pedigree series.
  - reference: PMID:30734345
    reference_title: "Clinical and genetic features of Chinese patients with lichen and macular primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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).
    explanation: >-
      Documents an OSMR-genotype-dependent sex skew: the female excess is
      concentrated in biallelic carriers, while OSMR-wildtype patients were
      male-predominant in this series. This is a dosage-correlated observation
      whose mechanism is unexplained.
  case_fractions:
  - population: Chinese familial PLCA (fPLCA) patients, mainland China
    case_fraction_percent: 63.89
    cohort_size: 36
    notes: >-
      OSMR missense mutation rate among 36 patients with familial PLCA in a
      mainland Chinese series.
    evidence:
    - reference: PMID:30734345
      reference_title: "Clinical and genetic features of Chinese patients with lichen and macular primary localized cutaneous amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sequence analysis of OSMR exons demonstrated that the OSMR missense
        mutation rate in patients with fPLCA (63.89%) was significantly higher
        than that in patients with sPLCA (34.38%).
      explanation: >-
        Quantifies the OSMR mutation share among familial PLCA cases.
  - population: Chinese sporadic PLCA (sPLCA) patients, mainland China
    case_fraction_percent: 34.38
    cohort_size: 64
    notes: >-
      OSMR missense mutation rate among 64 patients with sporadic PLCA in the same
      mainland Chinese series - evidence that OSMR contributes to sporadic as well
      as familial disease.
    evidence:
    - reference: PMID:30734345
      reference_title: "Clinical and genetic features of Chinese patients with lichen and macular primary localized cutaneous amyloidosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sequence analysis of OSMR exons demonstrated that the OSMR missense
        mutation rate in patients with fPLCA (63.89%) was significantly higher
        than that in patients with sPLCA (34.38%).
      explanation: >-
        Quantifies the OSMR mutation share among sporadic PLCA cases.

- name: IL31RA
  notes: >-
    IL31RA encodes interleukin-31 receptor A, which heterodimerizes with OSMRbeta
    to form the IL-31 receptor. It lies in the same linked 5p13.1-q11.2 interval
    as OSMR. A missense variant p.S521F, sited - like the OSMR variants - within a
    fibronectin type III-like repeat domain, causes familial PLCA in a subset of
    pedigrees without OSMR variants. IL31RA-variant disease is additionally
    associated with dysregulated MCP-1 expression that impairs monocyte-mediated
    amyloid clearance.
  gene_term:
    preferred_term: IL31RA
    term:
      id: hgnc:18969
      label: IL31RA
  relationship_type: CAUSATIVE
  subtype: Familial PLCA
  evidence:
  - reference: PMID:19690585
    reference_title: "Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In one family, we identified a point mutation in the IL31RA gene, c.1562C>T
      that results in a missense mutation, p.S521F, which is also sited within a
      fibronectin type III-like repeat domain as observed in the OSMR mutations.
    explanation: >-
      Identifies the causal IL31RA missense variant and its location in the same
      FNIII domain class as the OSMR variants.

- name: GPNMB
  notes: >-
    GPNMB encodes glycoprotein NMB, a transmembrane glycoprotein expressed
    throughout the epidermis and most strongly in melanocytes, with roles in
    melanosome formation, autophagy, phagocytosis, tissue repair, and negative
    regulation of inflammation. Biallelic nonsense, frameshift, or missense
    variants predicted to destabilize or otherwise disrupt the protein cause
    autosomal recessive amyloidosis cutis dyschromica, reported predominantly in
    East/Southeast Asian and South Asian (including consanguineous Pakistani)
    families. Note that the two Pakistani missense alleles are not straightforward
    loss-of-function: structural modelling predicted p.Ile174Met to destabilize
    GPNMB but p.Gly363Val to ENHANCE its stability, so the missense mechanism is
    not simply reduced protein abundance.
  gene_term:
    preferred_term: GPNMB
    term:
      id: hgnc:4462
      label: GPNMB
  relationship_type: CAUSATIVE
  subtype: Amyloidosis Cutis Dyschromica
  evidence:
  - reference: PMID:29336782
    reference_title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six nonsense or frameshift mutations were identified in nine individuals
      diagnosed with ACD.
    explanation: >-
      Documents the biallelic GPNMB truncating alleles in affected individuals.
  - reference: PMID:33687658
    reference_title: "Two missense mutations in GPNMB cause autosomal recessive amyloidosis cutis dyschromica in the consanguineous pakistani families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Independent replication of GPNMB as the amyloidosis cutis dyschromica gene
      in consanguineous Pakistani families, extending the allelic spectrum beyond
      truncating alleles to homozygous missense variants.

- name: RET
  notes: >-
    Germline gain-of-function variants in the RET proto-oncogene cause multiple
    endocrine neoplasia type 2A, one recognized variant of which is MEN2A with
    cutaneous lichen amyloidosis. The cutaneous lesion is classically
    interscapular and linked to codon 634 variants, and may precede the endocrine
    manifestations. RET is therefore a syndromic susceptibility driver for
    cutaneous lichen amyloidosis rather than a cause of isolated PLCA.
  gene_term:
    preferred_term: RET
    term:
      id: hgnc:9967
      label: RET
  relationship_type: SUSCEPTIBILITY
  subtype: MEN2A-Associated Cutaneous Lichen Amyloidosis
  evidence:
  - reference: PMID:42194535
    reference_title: "Generalized Cutaneous Lichen Amyloidosis in a Patient with an Ultra-Rare RET Y806C Variant Associated with MEN2A: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although most cases are sporadic, CLA has been associated with multiple
      endocrine neoplasia type 2A (MEN2A), a hereditary syndrome caused by
      germline alterations in the RET proto-oncogene.
    explanation: >-
      Establishes the RET-MEN2A association with cutaneous lichen amyloidosis.

environmental:
- name: Chronic Friction and Scratching
  description: >-
    Long-standing mechanical trauma to the skin - habitual scratching, rubbing,
    and friction from nylon brushes, towels, or backscratchers - is the principal
    environmental contributor to PLCA and explains the characteristic distribution
    over accessible extensor surfaces (shins, forearms, interscapular back).
    Friction damages keratinocytes and drives the release of amyloidogenic
    keratin, forming the closing arm of the itch-scratch-friction cycle.
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenesis is linked to chronic friction, keratinocyte damage, and in
      some cases, genetic predisposition.
    explanation: >-
      Names chronic friction as a pathogenic contributor acting through
      keratinocyte damage.

prevalence:
- population: Chinese, Malay, and Indian ethnic groups in Malaysia
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    A consecutive biopsy series of 85 Malaysian patients found PLCA more frequent
    in the Chinese than in other major ethnic groups, with the papular (lichen)
    form outnumbering the macular form roughly 3:1. This is a clinic-based case
    series, so it supports the ethnic-distribution claim but does not yield a
    population rate.
  evidence:
  - reference: PMID:1930004
    reference_title: "Primary localised cutaneous amyloidosis in Malaysians."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A review of consecutive biopsies from 85 Malaysian patients with primary
      localised cutaneous amyloidosis (PLCA) revealed 63 with papular amyloidosis
      (PA) and 22 with macular amyloidosis (MA). PLCA appeared to affect the
      Chinese more frequently than the other major ethnic groups but MA was more
      common than expected among the Indians.
    explanation: >-
      Documents the ethnic distribution and the relative frequency of papular
      versus macular disease in a Southeast Asian biopsy series.
- population: Iranian dermatology-clinic macular amyloidosis cohort (n=100)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Sex and age distribution rather than a population rate. This clinic series
    found a marked female predominance (9:1 female:male) and clustering between
    ages 21 and 50, with female patients presenting on average about 10 years
    later than male patients. The authors flag that their sex ratio "differed
    dramatically from most of the previous reports", so the magnitude of the skew
    is unsettled even though a female excess is consistently reported.
  evidence:
  - reference: PMID:15569011
    reference_title: "Macular amyloidosis: an assessment of prevalence, sex, and age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the sex distribution (9 : 1, female : male ratio) differed
      dramatically from most of the previous reports, it was consistent with few
      other series. Eighty one percent of patients were between 21 and 50 years of
      age.
    explanation: >-
      Provides the sex ratio and age distribution, with the authors' own caveat
      that the ratio is an outlier relative to prior reports.

- population: Southeast Asia and South America
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    PLCA is consistently described as relatively common in Southeast Asian and
    South American populations compared with Europe and North America; no
    quantitative population rate is reported in the cited source.
  evidence:
  - reference: PMID:19690585
    reference_title: "Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated
      with amyloid deposits in the superficial dermis. The disease is relatively
      common in Southeast Asia and South America.
    explanation: >-
      Supports the geographic concentration of PLCA without asserting a numeric
      rate.

progression:
- phase: Adult-onset chronic progressive skin disease
  age_range: >-
    Typically adult onset; median 32 years in OSMR-heterozygous and OSMR-wildtype
    Chinese patients, and earlier (median 20 years) in OSMR homozygotes.
    Amyloidosis cutis dyschromica is the exception, with prepubertal onset.
  notes: >-
    PLCA is chronic and slowly progressive and essentially never remits
    spontaneously; lesions persist for years to decades. Genotype modifies onset
    age, with biallelic OSMR carriers presenting about a decade earlier than
    heterozygotes.
  evidence:
  - reference: PMID:30734345
    reference_title: "Clinical and genetic features of Chinese patients with lichen and macular primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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).
    explanation: >-
      Provides the genotype-stratified median ages of onset quoted above.
  - reference: PMID:39119323
    reference_title: "Dermoscopy of Amyloidosis Cutis Dyschromica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloidosis cutis dyschromica is a very rare form of primary cutaneous
      amyloidosis characterized by prepubertal onset of hyper and hypopigmented
      spots and amyloid deposits in the papillary dermis.
    explanation: >-
      Establishes the prepubertal onset that distinguishes amyloidosis cutis
      dyschromica from the adult-onset lichen and macular forms.
- phase: Nodular disease - surveillance for systemic progression
  subtype: Nodular Amyloidosis
  notes: >-
    Nodular cutaneous amyloidosis is the only subtype with a route out of the
    skin. Reported progression to systemic AL amyloidosis is uncommon, and the
    largest Sjogren-associated series observed none over a median 3.5 years, but
    the risk is non-zero and justifies ongoing surveillance rather than discharge.
  evidence:
  - reference: PMID:18576343
    reference_title: "Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progression to systemic amyloidosis was not observed in any patient during a
      median followup of 3.5 years.
    explanation: >-
      The observed progression rate in the largest reported series - zero over a
      median 3.5 years - which bounds the risk without eliminating it.
  - reference: PMID:41528921
    reference_title: "Cutaneous Amyloidosis: An Updated Approach Focusing on Macular Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the latter a localized plasma dyscrasia with a small risk of representing a
      systemic disease.
    explanation: >-
      Confirms the residual systemic risk that motivates continued surveillance.
      Evidence source is OTHER because this is a review.

histopathology:
- name: Papillary Dermal Amyloid with Congo Red Birefringence
  description: >-
    The diagnostic histopathological finding: globular, eosinophilic amyloid
    deposits confined to the dermal papillae, staining with Congo red and showing
    apple-green birefringence under polarized light (also positive with crystal
    violet). The overlying epidermis shows hyperkeratosis and acanthosis, and
    there is a variable superficial dermal inflammatory infiltrate with pigmentary
    incontinence. In lichen amyloidosis the deposits are larger than in the
    macular form, but the two are tinctorially and immunohistochemically
    identical. Absence of amyloid elsewhere distinguishes PLCA from systemic
    amyloidosis with skin involvement.
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congo red staining demonstrated characteristic apple-green birefringence
      under polarized light, confirming amyloid deposition.
    explanation: >-
      Documents the diagnostic Congo red apple-green birefringence.
  - reference: PMID:1930004
    reference_title: "Primary localised cutaneous amyloidosis in Malaysians."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deposits were permanganate-resistant and negative for AA protein,
      immunoglobulin light chains and keratin.
    explanation: >-
      Records the tinctorial and immunohistochemical profile of the deposits,
      including the negative AA and light-chain staining that excludes those
      amyloid types in the lichen/macular forms. Recorded honestly: this same
      series ALSO found the deposits negative for keratin on routine
      immunohistochemistry (with only "a few cases" cytokeratin-positive), which
      cuts against the keratin-origin thesis. The usual reconciliation is epitope
      masking on conversion to the amyloid fold - later proteomic subtyping
      (LC-MS/MS, PMID:34459039) does identify keratins 5/14 in the deposits - but
      the discrepancy is real and is not resolved by this paper.

diagnosis:
- name: Skin Biopsy with Congo Red Staining
  diagnosis_term:
    preferred_term: Skin Biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  description: >-
    The diagnostic cornerstone and the definitive test. A lesional skin biopsy is
    stained with Congo red and examined under polarized light; apple-green
    birefringence in the papillary dermis confirms amyloid. Crystal violet is a
    useful adjunct. Because PLCA is defined histopathologically, clinical
    appearance alone is insufficient and the condition is frequently misdiagnosed
    without biopsy.
  results: >-
    Positive: globular eosinophilic deposits in the dermal papillae showing
    apple-green birefringence with Congo red under polarized light, with overlying
    hyperkeratosis and acanthosis. Absence of amyloid does not exclude clinically
    early disease but excludes the diagnosis as formally defined.
  evidence:
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological examination remains the gold standard for diagnosis.
    explanation: >-
      States histopathological examination as the diagnostic gold standard for
      PLCA.
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congo red and crystal violet stains remain indispensable for diagnosis.
    explanation: >-
      Confirms Congo red and crystal violet as the indispensable confirmatory
      stains.

- name: Amyloid Typing (Proteomic and Immunohistochemical)
  diagnosis_term:
    preferred_term: Histopathologic Examination
    term:
      id: NCIT:C18190
      label: Histopathologic Examination
  description: >-
    Determining which protein the deposit is made of, which is what separates the
    keratin-derived lichen/macular forms from AL-type nodular disease and from
    skin involvement by a systemic amyloidosis. Laser-capture LC-MS/MS proteomic
    subtyping with immuno-electron microscopy identifies keratins 5/14 in
    OSMR-mutant familial disease; kappa/lambda light-chain immunohistochemistry
    identifies the AL deposits of nodular disease. Typing changes management
    because AL-typed cutaneous amyloid mandates a systemic workup.
  results: >-
    Keratin-positive (keratins 5/14) in lichen/macular disease; immunoglobulin
    light-chain restricted in nodular disease. Note that routine anti-keratin
    immunohistochemistry may be negative in lichen/macular deposits despite their
    keratin origin, plausibly through epitope masking on conversion to the amyloid
    fold - proteomic typing is more reliable than IHC for this question.
  evidence:
  - reference: PMID:34459039
    reference_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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      Demonstrates proteomic (LC-MS/MS) plus immuno-electron subtyping as the
      method that establishes deposit composition. Quoted from the article title,
      which is the only text in the PubMed record for this correspondence item
      (no abstract is published).
  - reference: PMID:18576343
    reference_title: "Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of the immunoglobulin light chain type of amyloid (AL amyloid)
      was confirmed in 4 patients.
    explanation: >-
      Demonstrates light-chain typing distinguishing AL-type nodular cutaneous
      amyloid from the keratin-derived forms.

- name: Dermoscopy
  diagnosis_term:
    preferred_term: Dermoscopy
    term:
      id: NCIT:C116478
      label: Dermoscopy
  description: >-
    A non-invasive adjunct that supports clinical recognition and helps
    discriminate PLCA from the other dyschromatoses, particularly in amyloidosis
    cutis dyschromica where the differential includes dyschromatosis universalis
    hereditaria, Dowling-Degos disease and xeroderma pigmentosum. It supplements
    but does not replace biopsy.
  results: >-
    In amyloidosis cutis dyschromica, hyperpigmented macules show brown dots and
    globules in a honeycomb pattern; hypopigmented lesions show a pebbled
    appearance with radial furrows, corresponding to amyloid deposits,
    melanophages, and dilated vessels.
  evidence:
  - reference: PMID:39119323
    reference_title: "Dermoscopy of Amyloidosis Cutis Dyschromica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are very few case reports highlighting the dermoscopic findings of ACD
      which would help in diagnosing and differentiating with similar conditions.
    explanation: >-
      Establishes the diagnostic and differential-diagnostic role of dermoscopy in
      amyloidosis cutis dyschromica, while indicating the evidence base is
      case-level.

- name: Systemic AL Amyloidosis Screening in Nodular Disease
  diagnosis_term:
    preferred_term: Disease Screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  description: >-
    Because nodular cutaneous amyloidosis is a localized plasma-cell dyscrasia
    producing AL amyloid, and a small proportion of patients harbour or later
    develop systemic AL amyloidosis, patients with the nodular subtype should be
    evaluated for systemic involvement and kept under follow-up. This is
    risk stratification, not an expectation of progression: in the largest
    reported Sjogren-associated series no patient progressed over a median 3.5
    years. Screening does not modify the local plasma-cell clone; it determines
    whether that clone is skin-confined or part of a systemic dyscrasia, which
    changes management entirely.
  results: >-
    Serum and urine immunofixation, serum free light chains, and assessment for
    cardiac and renal involvement. A positive clonal screen in a patient with
    AL-typed cutaneous amyloid moves the diagnosis toward systemic AL amyloidosis.
  evidence:
  - reference: PMID:41528921
    reference_title: "Cutaneous Amyloidosis: An Updated Approach Focusing on Macular Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the latter a localized plasma dyscrasia with a small risk of representing a
      systemic disease.
    explanation: >-
      Establishes the small systemic risk of nodular cutaneous amyloidosis that
      motivates screening. Evidence source is OTHER because this is a review.
  - reference: PMID:18576343
    reference_title: "Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progression to systemic amyloidosis was not observed in any patient during a
      median followup of 3.5 years.
    explanation: >-
      Tempers the systemic risk - no progression in this series - which is why
      screening is framed as risk stratification rather than expected progression.
      Recorded as PARTIAL because it qualifies rather than straightforwardly
      supports the screening recommendation.

- name: RET Cascade Testing in Cutaneous Lichen Amyloidosis
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    The highest-consequence diagnostic action in this entry. Cutaneous lichen
    amyloidosis - classically interscapular, but also in generalized form - is a
    recognized variant feature of MEN2A and can present before the endocrine
    manifestations. Because nearly all MEN2A patients eventually develop medullary
    thyroid carcinoma, recognising the skin lesion and proceeding to germline RET
    testing (with cascade testing of relatives if positive) can bring forward
    surveillance and prophylactic thyroidectomy in an at-risk kindred. Codon 634
    is the classic association, but the reported allelic spectrum is wider.
  results: >-
    A pathogenic germline RET variant establishes MEN2A and triggers MTC and
    pheochromocytoma surveillance plus cascade testing of first-degree relatives.
    A negative result in isolated PLCA is expected and does not argue against the
    diagnosis of primary cutaneous amyloidosis.
  evidence:
  - reference: PMID:42194535
    reference_title: "Generalized Cutaneous Lichen Amyloidosis in a Patient with an Ultra-Rare RET Y806C Variant Associated with MEN2A: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case may contribute to understanding genotype-phenotype correlations in
      MEN2A and suggests that atypical or generalized CLA may be an early clinical
      clue warranting consideration of RET genetic testing.
    explanation: >-
      Directly recommends RET genetic testing on the basis of the cutaneous lichen
      amyloidosis presentation - the action this diagnosis entry encodes.
  - reference: PMID:30085596
    reference_title: "Multiple Endocrine Neoplasias Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In both subtypes, nearly 100% of patients eventually develop medullary
      thyroid cancer (MTC), and up to 50% develop pheochromocytomas.
    explanation: >-
      Quantifies the near-complete MTC penetrance that makes cascade testing
      urgent once MEN2A is suspected. Evidence source is OTHER because this is a
      StatPearls review chapter.

- name: OSMR and IL31RA Genetic Testing
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Molecular confirmation of familial PLCA. OSMR is the highest-yield first test:
    in a mainland Chinese series OSMR missense variants were found in 63.9% of
    familial cases, and notably also in 34.4% of apparently sporadic cases, so a
    negative family history does not exclude a molecular diagnosis. IL31RA is the
    second-tier gene for OSMR-negative pedigrees, and biallelic GPNMB testing is
    indicated for the dyschromic presentation.
  results: >-
    Heterozygous OSMR or IL31RA missense variants in the extracellular fibronectin
    type III-like domains confirm familial PLCA. Genotype carries prognostic
    information: homozygous OSMR carriers had a median onset of 20 years versus 32
    years in heterozygotes and wild-type.
  evidence:
  - reference: PMID:30734345
    reference_title: "Clinical and genetic features of Chinese patients with lichen and macular primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of OSMR exons demonstrated that the OSMR missense
      mutation rate in patients with fPLCA (63.89%) was significantly higher
      than that in patients with sPLCA (34.38%).
    explanation: >-
      Quantifies the diagnostic yield of OSMR sequencing in both familial and
      sporadic PLCA, supporting an OSMR-first testing strategy.
  - reference: PMID:19690585
    reference_title: "Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PCA is a genetically heterogeneous disorder but our study shows that it can
      be caused by mutations in two biologically associated cytokine receptor
      genes located on chromosome 5.
    explanation: >-
      Justifies testing IL31RA in addition to OSMR, given the demonstrated
      two-gene heterogeneity.

treatments:
- name: High-Potency Topical Corticosteroids
  description: >-
    The current standard of care and first-line symptomatic therapy. High-potency
    topical corticosteroids reduce pruritus and the inflammatory component,
    thereby interrupting the itch-scratch-friction cycle that drives ongoing
    keratinocyte damage and amyloid deposition. They provide symptomatic relief
    but do not clear established amyloid deposits.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    treatment_effect: INHIBITS
    description: >-
      Suppressing pruritus and cutaneous inflammation breaks the scratching arm of
      the self-reinforcing cycle, reducing further keratinocyte damage.
  evidence:
  - reference: PMID:41528921
    reference_title: "Cutaneous Amyloidosis: An Updated Approach Focusing on Macular Amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The current standard of care, high-potency corticosteroids, can provide
      symptomatic relief.
    explanation: >-
      Establishes high-potency corticosteroids as the current standard of care and
      characterizes the benefit as symptomatic. Evidence source is OTHER because
      this is a review.

- name: Dupilumab
  description: >-
    A fully human monoclonal antibody against the IL-4 receptor alpha subunit that
    blocks IL-4 and IL-13 signalling and downregulates cutaneous type 2 cytokines
    including IL-31, the principal pruritogen implicated in PLCA. Used off-label
    for refractory lichen amyloidosis - particularly in patients with coexisting
    atopic dermatitis - with reported improvement in pruritus and lesions in case
    reports and small series. Not an approved indication; the evidence remains at
    case-report level.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dupilumab
      term:
        id: NCIT:C162455
        label: Dupilumab
  target_mechanisms:
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    treatment_effect: INHIBITS
    description: >-
      IL-4Ralpha blockade lowers cutaneous type 2 cytokine tone including IL-31,
      reducing the pruritus that drives the scratch-damage-deposition loop.
  evidence:
  - reference: PMID:39975679
    reference_title: "Dupilumab for treatment of primary cutaneous amyloidosis in adults: two case reports and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This article reported two cases of refractory LA successfully treated with dupilumab
      and reviewed publications reporting dupilumab treatment for PCA.
    explanation: >-
      Documents clinical response of refractory lichen amyloidosis to dupilumab,
      the case-level evidence for this off-label use.

- name: Nemolizumab (IL-31 Receptor Blockade)
  description: >-
    Anti-IL-31RA monoclonal antibody, and the most mechanistically on-target agent
    available for PLCA: it blocks the very receptor subunit whose epidermal
    overexpression is documented in PLCA lesions. The related agent vixarelimab
    targets the partner subunit OSMRbeta. This is an emerging, mechanism-anchored
    strategy rather than an established therapy - the cited itch benefit is
    demonstrated across chronic pruritic dermatoses generally, not in
    PLCA-specific randomized trials.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nemolizumab
      term:
        id: NCIT:C170211
        label: Nemolizumab
  target_mechanisms:
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    treatment_effect: INHIBITS
    description: >-
      Blocking IL-31RA or OSMRbeta interrupts IL-31-driven cutaneous nerve-fibre
      sensitization, the proximal mechanism of PLCA pruritus.
  evidence:
  - reference: PMID:26748444
    reference_title: "Pathophysiology of pruritus in primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The PLCA-specific rationale: increased epidermal IL-31 receptor expression
      makes the IL-31 receptor a candidate therapeutic target in this disease.
  - reference: PMID:42220857
    reference_title: "Convergent Oncostatin M and IL-31 Signaling in Chronic Pruritic Dermatoses: A Neuroimmune Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) Perspective."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Blocking IL-31RA with nemolizumab or targeting OSMRβ with vixarelimab has
      led to clinically significant improvements in itch severity, patient-reported
      quality of life, and sleep disturbance.
    explanation: >-
      Documents clinical itch benefit from IL-31RA and OSMRbeta blockade across
      chronic pruritic dermatoses; recorded as PARTIAL because the benefit is
      reported for the dermatosis group as a whole (a group whose scope this
      systematic review states includes PLCA) rather than from PLCA-specific
      trials.

- name: Tofacitinib (JAK Inhibition)
  description: >-
    Oral Janus kinase inhibitor used off-label for PLCA. The rationale is
    directly mechanistic: OSMRbeta and IL-31RA signal through the JAK/STAT
    cascade, and the IL-4/IL-13/IL-31 itch axis is JAK-dependent, so JAK
    inhibition targets the same node from downstream. In a retrospective series
    of 24 patients treated with tofacitinib 10 mg/day, body surface area, peak
    pruritus NRS, and Investigator Global Assessment all improved significantly
    with good tolerability. Evidence remains retrospective and uncontrolled; the
    authors call for randomized trials. Note the apparent paradox that PLCA
    involves LOSS of OSM/OSMRbeta signal transduction yet responds to JAK
    inhibition - the therapeutic target is the pruritogenic type 2 / IL-31 arm of
    JAK signalling rather than the deficient OSM-STAT5 differentiation brake.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tofacitinib
      term:
        id: CHEBI:71200
        label: tofacitinib
  target_mechanisms:
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    treatment_effect: INHIBITS
    description: >-
      JAK inhibition blocks the downstream signalling of the pruritogenic type 2
      and IL-31 cytokines, reducing itch and hence the scratching that drives
      further keratinocyte damage.
  evidence:
  - reference: PMID:40908738
    reference_title: "Tofacitinib for the Treatment of Primary Localized Cutaneous Amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conducted a retrospective study of 24 patients with PLCA treated with
      tofacitinib (10 mg/day) at our dermatology clinic. Disease severity was
      assessed using body surface area (BSA), Peak Pruritus Numerical Rating Scale
      (PP-NRS), and Investigator Global Assessment (IGA) scores. Significant
      improvements were observed in BSA (p < 0.05), PP-NRS
    explanation: >-
      Reports the efficacy outcome directly: significant improvement in body
      surface area, peak pruritus NRS, and Investigator Global Assessment in a
      24-patient retrospective series on tofacitinib 10 mg/day. (The quote stops
      mid-sentence because the cached PubMed abstract itself is truncated at that
      point.)
  - reference: PMID:40908738
    reference_title: "Tofacitinib for the Treatment of Primary Localized Cutaneous Amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings of this study suggest that tofacitinib could be an appealing
      approach for treating PLCA. Further large-scale, randomized controlled
      trials are necessary to confirm its long-term efficacy and safety.
    explanation: >-
      The authors' own qualification that the evidence is suggestive rather than
      definitive; recorded as PARTIAL to avoid overstating an uncontrolled
      retrospective result.

- name: Friction Avoidance and Skin-Directed Supportive Care
  description: >-
    Behavioral supportive care aimed directly at the environmental driver of this
    entry's itch-scratch-friction cycle: stopping habitual scratching and rubbing,
    discontinuing nylon towels, backscratchers and abrasive scrubs, and using
    barrier measures such as hydrocolloid dressings and emollients. Mechanistically
    it is the most direct intervention available - it removes the frictional
    keratinocyte injury that supplies amyloidogenic keratin - and it is low-risk
    and free, though the supporting evidence is consensus-level rather than trial
    based and it is typically combined with antipruritic therapy rather than used
    alone.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    treatment_effect: INHIBITS
    description: >-
      Removing frictional and scratch trauma breaks the scratch arm of the
      self-reinforcing cycle at its environmental source.
  - target: Keratinocyte Damage and Amyloidogenic Keratin Release
    treatment_effect: INHIBITS
    description: >-
      Less mechanical injury to the epidermis means fewer degenerating
      keratinocytes shedding keratin into the papillary dermis.
  evidence:
  - reference: PMID:28342017
    reference_title: "Primary Localized Cutaneous Amyloidosis: A Systematic Treatment Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A variety of treatment options for PLCA were reported including retinoids,
      corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine,
      cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D3 analogs, capsaicin,
      menthol, hydrocolloid dressings, surgical modalities, laser treatment, and
      phototherapy.
    explanation: >-
      Places hydrocolloid dressings (the barrier arm of this entry) in the
      catalogued PLCA armamentarium. Recorded as PARTIAL because the review
      catalogues rather than validates it, and does not separately evaluate
      friction avoidance. Evidence source is OTHER because this is a systematic
      review of predominantly case-level reports.
  - reference: PMID:40151750
    reference_title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenesis is linked to chronic friction, keratinocyte damage, and in
      some cases, genetic predisposition.
    explanation: >-
      Supplies the mechanistic rationale for friction avoidance by naming chronic
      friction as a pathogenic driver. Recorded as PARTIAL because it establishes
      the target, not the efficacy of the intervention.

- name: Phototherapy
  description: >-
    Ultraviolet phototherapy (PUVA, narrowband UVB, UVB) used to reduce pruritus
    and pigmentation in non-nodular PLCA. In the systematic review of procedural
    treatments, phototherapy showed benefit with PUVA superior to UVB for pruritus
    specifically. Outcomes across series are variable and no standardized protocol
    exists.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Phototherapy
    term:
      id: NCIT:C15301
      label: Phototherapy
  target_mechanisms:
  - target: Pruritus and the Itch-Scratch-Friction Cycle
    treatment_effect: INHIBITS
    description: >-
      Phototherapy reduces pruritus, interrupting the scratching that perpetuates
      keratinocyte damage.
  evidence:
  - reference: PMID:41389140
    reference_title: "A systematic review of procedural treatment for primary localized cutaneous amyloidosis: focus on efficacy, safety, treatment durability in comparison and combination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Microneedling and phototherapy (PUVA/UVB) also showed benefits, with PUVA
      being superior for pruritus.
    explanation: >-
      Establishes phototherapy benefit and the PUVA-over-UVB ordering for
      pruritus, from a PRISMA systematic review of 16 studies and 432 patients.
      Evidence source is OTHER because this is a systematic review.

- name: Laser and Procedural Therapy
  description: >-
    Ablative and non-ablative laser and device-based treatments - fractional CO2
    laser, Nd:YAG, Er:YAG, and microneedling - directed at the pigmentation,
    pruritus, and amyloid burden of non-nodular PLCA. Fractional CO2 laser,
    particularly combined with topical corticosteroids or vitamin C, has the
    strongest reported results. Note the subtype split in the meta-analysis
    evidence: laser therapy is recommended for non-nodular disease, whereas
    surgical excision is the most effective option for nodular amyloidosis.
    Complete-response rates remain low even where partial response is common.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Laser Therapy
    term:
      id: NCIT:C15466
      label: Laser Therapy
  target_mechanisms:
  - target: Impaired Amyloid Clearance and Progressive Cutaneous Accumulation
    treatment_effect: INHIBITS
    description: >-
      Ablative resurfacing physically removes papillary-dermal amyloid and the
      overlying hyperkeratotic epidermis, reducing the accumulated deposit burden
      rather than acting on precursor supply.
  evidence:
  - reference: PMID:41389140
    reference_title: "A systematic review of procedural treatment for primary localized cutaneous amyloidosis: focus on efficacy, safety, treatment durability in comparison and combination."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Fractional CO₂ laser, especially with corticosteroids or vitamin C, showed
      the most effective results for pigmentation, pruritus, and amyloid reduction
      in PLCA.
    explanation: >-
      Identifies fractional CO2 laser as the most effective procedural modality
      including for amyloid reduction, supporting the deposit-directed
      target_mechanisms link. Evidence source is OTHER because this is a
      systematic review.
  - reference: PMID:39957318
    reference_title: "Systematic review and meta-analysis of treatments and outcomes in primary localized cutaneous amyloidosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This study suggests that surgery is the most effective treatment option for
      NA, and laser therapy is recommended for patients with non-NA.
    explanation: >-
      Supplies the subtype split - laser for non-nodular disease, surgery for
      nodular - from a meta-analysis of 116 studies and 534 patients. Evidence
      source is OTHER because this is a systematic review and meta-analysis.

discussions:
- discussion_id: plca_sfn_cause_or_consequence
  prompt: >-
    Is the small-fibre neuropathy of PLCA a cause of the pruritus, or a
    consequence of chronic scratching and amyloid deposition?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Pruritus and the Itch-Scratch-Friction Cycle
  rationale: >-
    The itch-scratch-friction cycle is modelled here as a closed loop, which makes
    the direction of the nerve-fibre abnormality genuinely ambiguous. Reduced
    intraepidermal nerve fibre density with raised warm detection thresholds could
    reflect a primary sensory neuropathy that generates itch, or secondary
    nerve-fibre loss from repeated mechanical trauma and dermal amyloid. The
    literature is directly conflicting: some studies report wider cutaneous
    innervation in familial PLCA while others show the opposite in general lichen
    amyloidosis. Resolving the direction matters therapeutically, since a primary
    neuropathic mechanism would favour neuromodulatory over anti-inflammatory
    treatment.
  proposed_experiments:
  - experiment_id: plca_prelesional_ienf_longitudinal
    name: Longitudinal intraepidermal nerve fibre density in pre-lesional OSMR carriers
    description: >-
      Serial intraepidermal nerve fibre density measurement and quantitative
      sensory testing in clinically unaffected skin of OSMR-variant carriers,
      followed to lesion onset, to establish whether the small-fibre neuropathy
      precedes amyloid deposition.
    supporting_outcome:
    - Reduced nerve fibre density or raised warm detection thresholds detected before any amyloid lesion appears would support the neuropathy as a primary cause of pruritus.
    refuting_outcome:
    - Normal pre-lesional innervation and sensory thresholds would indicate the neuropathy is secondary to established lesions.
  - experiment_id: plca_lesional_vs_distant_ienf
    name: Within-patient lesional versus perilesional versus distant skin innervation
    description: >-
      Comparison of intraepidermal nerve fibre density in lesional, perilesional,
      and anatomically distant unaffected skin within the same patient, to separate
      a generalized sensory phenotype from locally trauma-induced fibre loss.
    supporting_outcome:
    - Uniformly reduced innervation across all three sites would support a generalized primary sensory neuropathy.
    refuting_outcome:
    - Fibre loss confined to lesional and perilesional skin would support locally trauma- and amyloid-induced secondary nerve damage.
  evidence:
  - reference: PMID:42029085
    reference_title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: >-
      Explicitly documents the conflicting innervation findings that constitute
      this knowledge gap. Evidence source is OTHER because this is a narrative
      review.

- discussion_id: plca_osmr_null_mouse_mismatch
  prompt: >-
    Why does Osmr knockout in mice fail to reproduce the human PLCA amyloid
    phenotype, and does this limit the validity of the mouse model for the
    amyloid arm of the disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#OSM/IL-31 Receptor Signaling Failure
  - pathophysiology#Keratin Misfolding and Beta-Sheet Oligomerization
  rationale: >-
    Osmr-null mice recapitulate the proximal cellular abnormality of human PLCA -
    enhanced basal keratinocyte differentiation and proliferation with increased
    epidermal thickness - but develop no PLCA-like lesions and no cutaneous
    amyloid, even under UVA exposure and itch challenge. The model therefore
    validates the OSM/STAT5/KLF7 arm of the mechanism while leaving the critical
    step (conversion of shed keratin into dermal amyloid) untested. Candidate
    explanations include species differences in keratin composition or amyloid
    propensity, the absence in caged mice of the decades of frictional trauma that
    human patients sustain, or a requirement for a specific missense effect that a
    null allele does not model - human disease is caused by missense variants, and
    no dominant negative effect was detected for the tested alleles. Evidence
    exists in the model; its translational validity for the amyloid step is the
    open question.
  proposed_experiments:
  - experiment_id: plca_osmr_knockin_missense_mouse
    name: OSMR missense knock-in mouse
    description: >-
      Generate mice carrying the human OSMR missense alleles p.P694L or p.G513D in
      place of a null allele, and assess for spontaneous cutaneous amyloid.
    supporting_outcome:
    - Cutaneous amyloid in missense knock-in but not null mice would show that the specific human substitutions, rather than loss of OSMR per se, are required.
    refuting_outcome:
    - Absence of amyloid in missense knock-in mice would point to a species difference rather than an allele-type difference.
  - experiment_id: plca_chronic_friction_challenge
    name: Chronic mechanical friction challenge of Osmr-mutant mouse skin
    description: >-
      Apply sustained, long-duration mechanical friction to the skin of
      Osmr-mutant mice to test whether the missing environmental co-factor
      accounts for the absent amyloid phenotype.
    supporting_outcome:
    - Emergence of dermal amyloid under chronic friction would confirm friction as a necessary co-factor and validate the itch-scratch-friction loop.
    refuting_outcome:
    - Persistent absence of amyloid despite chronic friction would favour an intrinsic species difference in keratin amyloidogenicity.
  - experiment_id: plca_keratin_aggregation_propensity
    name: Comparative aggregation propensity of murine versus human keratins
    description: >-
      Proteomic and in vitro aggregation comparison of murine versus human shed
      epidermal keratins (including the keratin 5/14 pair) for cross-beta fibril
      formation propensity.
    supporting_outcome:
    - Substantially lower cross-beta propensity of murine keratins would explain the model mismatch as a species property of the precursor.
    refuting_outcome:
    - Comparable aggregation propensity would move the explanation to the tissue environment or amyloid clearance rather than the precursor.
  evidence:
  - reference: PMID:33502684
    reference_title: "OSMRβ mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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).
    explanation: >-
      Directly documents the failure of the Osmr-null mouse to reproduce the human
      PLCA phenotype, the mismatch at issue.
  - reference: PMID:33502684
    reference_title: "OSMRβ mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that Osmr knockout enhances basal keratinocyte
      differentiation and proliferation in mice.
    explanation: >-
      Shows the model does recapitulate the proximal keratinocyte abnormality,
      establishing that the mismatch is specific to the amyloid step rather than
      total.

references:
- reference: PMID:6184423
  title: "Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid."
- reference: PMID:1930004
  title: "Primary localised cutaneous amyloidosis in Malaysians."
- reference: PMID:15569011
  title: "Macular amyloidosis: an assessment of prevalence, sex, and age."
- reference: PMID:18179886
  title: "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis."
- reference: PMID:18576343
  title: "Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?"
- reference: PMID:19690585
  title: "Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis."
- reference: PMID:26748444
  title: "Pathophysiology of pruritus in primary localized cutaneous amyloidosis."
- reference: PMID:29336782
  title: "Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans."
- reference: PMID:30085596
  title: "Multiple Endocrine Neoplasias Type 2."
- reference: PMID:30734345
  title: "Clinical and genetic features of Chinese patients with lichen and macular primary localized cutaneous amyloidosis."
- reference: PMID:33502684
  title: "OSMRβ mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients."
- reference: PMID:33687658
  title: "Two missense mutations in GPNMB cause autosomal recessive amyloidosis cutis dyschromica in the consanguineous pakistani families."
- reference: PMID:34459039
  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."
- reference: PMID:37100691
  title: "AHNAK, regulated by the OSM/OSMR signaling, involved in the development of primary localized cutaneous amyloidosis."
- reference: PMID:39975679
  title: "Dupilumab for treatment of primary cutaneous amyloidosis in adults: two case reports and literature review."
- reference: PMID:40151750
  title: "Histopathological Insights into Primary Localized Cutaneous Amyloidosis: A Case Series."
- reference: PMID:40908738
  title: "Tofacitinib for the Treatment of Primary Localized Cutaneous Amyloidosis."
- reference: PMID:41528921
  title: "Cutaneous Amyloidosis: An Updated Approach Focusing on Macular Amyloidosis."
- reference: PMID:42029085
  title: "Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review."
- reference: PMID:42194535
  title: "Generalized Cutaneous Lichen Amyloidosis in a Patient with an Ultra-Rare RET Y806C Variant Associated with MEN2A: A Case Report and Literature Review."
- reference: PMID:42220857
  title: "Convergent Oncostatin M and IL-31 Signaling in Chronic Pruritic Dermatoses: A Neuroimmune Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) Perspective."

📚

References & Deep Research

References

21

PMID:6184423

Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid.