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Inheritance

2

Autosomal dominant inheritance of the germline mevalonate pathway variant HP:0000006

Familial porokeratosis segregates as an autosomal dominant trait, with affected individuals carrying a monoallelic germline loss-of-function variant in MVK, PMVK, MVD or FDPS. The germline variant alone is not sufficient: clinically apparent lesions require an additional somatic event, which explains the incomplete, age-dependent penetrance. Expressivity is highly variable even within families, and several clinical variants can coexist in one individual.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:22983302 SUPPORT Human Clinical

"Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear."

Establishes the autosomal dominant transmission of the commonest porokeratosis variant.

PMID:31207227 SUPPORT Human Clinical

"Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as MVD or MVK."

Confirms the monoallelic germline state that underlies dominant transmission.

Somatic mosaicism of the second hit HP:0001442

Lesional skin is genetically mosaic. In linear porokeratosis a single post-zygotic second hit occurring in the embryonic period produces a Blaschko-linear clone; in DSAP each lesion carries its own independent postnatal second hit. Non-hereditary localized porokeratosis can arise from purely somatic biallelic FDFT1 promoter hypermethylation with no germline variant at all.

Typified by somatic mosaicism

Show evidence (2 references)

PMID:30942823 SUPPORT Human Clinical

"Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease."

States the mosaic basis of the Blaschko-linear distribution that this inheritance block records.

PMID:31207227 SUPPORT Human Clinical

"The second hits differed among DSAP lesions but were identical in those of congenital LP, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital LP to a single second hit in the embryonic period."

Directly distinguishes the mosaic (prenatal, single-clone) mechanism of linear porokeratosis from the multi-clone postnatal mechanism of DSAP.

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Subtypes

10

Disseminated superficial actinic porokeratosis MONDO:0019212

MVK hgnc:7530 MVD hgnc:7529

The commonest variant. Multiple small annular macules and papules with a fine keratotic rim, distributed symmetrically on sun-exposed extensor limbs, usually appearing in the third to fifth decades and often worsening in summer. Each lesion carries its own independent postnatal second hit, frequently bearing a UV mutational signature, which is why sun protection is a preventive measure.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"the authors show that DSAP lesions result from second-hit somatic mitotic recombination or point mutations with a UV signature, validating the clinical observation that DSAP lesions arise upon sun exposed skin"

Supports both the actinic distribution and the independent-second-hit basis of the DSAP subtype.

Porokeratosis of Mibelli MONDO:0019141

One or a few slowly enlarging brown annular plaques with a sharply defined, prominent keratotic border, often beginning in childhood in hereditary disease. Limbs and trunk predominate, but palms, soles, scalp, face, mucosa and genital skin can be involved. Because Mibelli plaques are typically large and of long standing, they fall into the higher-risk group for malignant transformation identified in the pooled case literature.

Show evidence (2 references)

PMID:8624658 SUPPORT Human Clinical

"Large lesions, those of long-standing duration, and the linear type were at greatest risk."

Supports placing large, long-standing Mibelli plaques in the higher-risk group; the source does not report a Mibelli-specific rate, hence PARTIAL.

PMID:38132857 SUPPORT Human Clinical

"disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar porokeratosis"

Confirms porokeratosis of Mibelli as one of the commonly recognised clinical variants of the porokeratosis group.

Linear porokeratosis MONDO:0023246

PMVK hgnc:9141 MVD hgnc:7529

Congenital or early-onset unilateral streaks of keratotic papules and plaques following the lines of Blaschko. It is the mosaic form: a single second hit in the embryonic period produces one keratinocyte clone whose descendants trace the dorsoventral migration pattern of keratinocyte precursors. Linear porokeratosis carries the highest reported risk of malignant transformation.

Show evidence (1 reference)

PMID:30942823 SUPPORT Human Clinical

"Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway"

Establishes the mosaic, second-hit genetic basis of the linear subtype and its PMVK/MVD gene assignment.

Porokeratosis palmaris et plantaris disseminata MONDO:0008291

Small keratotic papules that begin on the palms and soles, typically in adolescence or early adult life, and later become generalized to involve non-sun-exposed skin. Lesions may be pruritic or painful; nail dystrophy is an uncommon complication.

Show evidence (1 reference)

PMID:31449901 SUPPORT Human Clinical

"2 with porokeratosis palmaris et plantaris disseminata"

Documents PPPD as a distinct, genotyped clinical variant in a porokeratosis patient series.

Punctate porokeratosis (punctate palmoplantar porokeratosis)

A palmoplantar variant consisting of numerous tiny, seed-like keratotic plugs confined to the palms and soles, each of which is a minute cornoid lamella. It is grouped with PPPD under palmoplantar porokeratosis. No distinct non-obsolete MONDO class was identified for the punctate variant at curation time, so no subtype_term is bound.

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"palmoplantar porokeratosis (including porokeratosis palmaris et plantaris disseminata and punctate porokeratosis)"

Confirms punctate porokeratosis as a recognized palmoplantar variant of the porokeratosis group.

Disseminated superficial porokeratosis

The non-actinic counterpart of DSAP: disseminated lesions involving both sun-exposed and covered skin, typically with earlier (often childhood) onset. Distinguished from DSAP by distribution rather than by a different mechanism.

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"disseminated superficial actinic porokeratosis, disseminated superficial porokeratosis, porokeratosis of Mibelli"

Lists disseminated superficial porokeratosis as a recognised variant distinct from DSAP.

Verrucous porokeratosis (porokeratosis ptychotropica / genitogluteal)

Verrucous, often intensely pruritic or burning plaques of the genitogluteal, perianal and intertriginous skin, expanding centrifugally over years. Histology typically shows multiple cornoid lamellae with papillomatosis and psoriasiform hyperplasia. It is notably treatment-resistant.

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"verrucous porokeratosis (also known as genitogluteal porokeratosis)"

Establishes verrucous/genitogluteal porokeratosis as a recognised clinical variant.

Follicular porokeratosis

A rare folliculocentric variant in which the cornoid lamella forms within hair follicle infundibula, producing keratotic follicular plugs. Its genetic basis is less well characterised than that of the classical variants.

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"Commonly recognised variants include disseminated superficial actinic porokeratosis, disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar porokeratosis (including porokeratosis palmaris et plantaris disseminata and punctate porokeratosis), linear porokeratosis,..."

Lists follicular porokeratosis among the recognised variants.

Porokeratoma

A usually solitary keratotic plaque or nodule that lacks the classic annular rim but shows cornoid lamellae histologically, typically presenting in later adult life. It is the variant most easily mistaken for a keratinocyte carcinoma clinically.

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"Commonly recognised variants include disseminated superficial actinic porokeratosis, disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar porokeratosis (including porokeratosis palmaris et plantaris disseminata and punctate porokeratosis), linear porokeratosis,..."

Lists porokeratoma among the recognised variants of the porokeratosis group.

Eruptive / immunosuppression-associated porokeratosis

Sudden appearance of numerous inflammatory, often pruritic porokeratotic lesions in the setting of iatrogenic or disease-related immunosuppression - solid-organ or haematopoietic stem cell transplantation, HIV infection, haematologic malignancy, or immunosuppressive drug therapy. Lesions may partially regress when the immunosuppressive state is corrected. This is an acquired, immunologically gated presentation rather than a distinct genetic entity.

Show evidence (1 reference)

PMID:34418147 SUPPORT Human Clinical

"Here, we discuss a single-institution case series of three children who developed porokeratosis following hematopoietic stem cell transplantation for acute leukemia, and we propose that this presentation be termed localized eruptive porokeratosis (LEP)."

Documents eruptive porokeratosis arising after transplant-associated immunosuppression.

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Pathophysiology

12

Germline Heterozygous Mevalonate Pathway Variant

Affected individuals carry a monoallelic germline loss-of-function variant in one of four mevalonate-pathway genes - MVK (mevalonate kinase), PMVK (phosphomevalonate kinase), MVD (mevalonate diphosphate decarboxylase) or FDPS (farnesyl diphosphate synthase). Heterozygosity alone leaves roughly half-normal enzyme activity in the epidermis and does not by itself produce a lesion; it establishes a field of keratinocytes primed for a second hit. At least one such variant was found in 98% of familial and 73% of sporadic index patients in the defining cohort.

keratinocyte CL:0000312

MVK hgnc:7530 PMVK hgnc:9141 MVD hgnc:7529 FDPS hgnc:3631

mevalonate kinase activity GO:0004496 ↓ DECREASED phosphomevalonate kinase activity GO:0004631 ↓ DECREASED diphosphomevalonate decarboxylase activity GO:0004163 ↓ DECREASED

skin epidermis UBERON:0001003

Downstream

Somatic Second Hit in Lesional Keratinocytes The germline heterozygous allele is the necessary substrate on which a somatic event in the remaining wild-type allele produces biallelic deficiency.

Show evidence (2 references)

PMID:26202976 SUPPORT Human Clinical

"we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway"

Establishes the four canonical causal genes named in this node.

PMID:26202976 SUPPORT Human Clinical

"At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients"

Quantifies the diagnostic yield of the four-gene germline lesion.

Somatic Second Hit in Lesional Keratinocytes

A somatic event inactivates the remaining wild-type allele within a single epidermal keratinocyte, converting the heterozygous state to biallelic deficiency. The two dominant mechanisms are copy-neutral loss of heterozygosity from somatic mitotic (homologous) recombination and C>T transition point mutations bearing a UV signature. Somatic second hits were detected in 81% of patients in a large contemporary cohort, with gene-specific patterns (chromosome 12-wide copy-neutral LOH in MVK disease, 16q in MVD disease). Timing determines the clinical variant: an embryonic second hit gives a single Blaschko-linear clone (linear porokeratosis) whereas many independent postnatal second hits give the disseminated lesions of DSAP.

keratinocyte CL:0000312 keratinocyte stem cell CL:0002337

response to UV GO:0009411

Downstream

Biallelic Mevalonate Pathway Enzyme Deficiency Loss of the wild-type allele leaves the keratinocyte with no functional copy of the affected mevalonate-pathway enzyme.

Photodistribution of Lesions on Sun-Exposed Skin Because the second hit in DSAP is frequently a UV-signature C>T transition, new lesions appear preferentially where UV exposure is greatest.

Show evidence (3 references)

PMID:31207227 SUPPORT Human Clinical

"we showed that each skin lesion of DSAP exhibited an individual second hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop"

The primary evidence that a somatic second hit is required, not merely associated.

PMID:31207227 SUPPORT Human Clinical

"Most skin lesions exhibited one of two principal second hits, either somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele."

Documents the two mechanisms of the second hit described in this node.

PMID:41240373 SUPPORT Human Clinical

"Somatic second-hit changes were identified in 81% (n = 55/68) of patients, mostly copy-neutral loss of heterozygosity (CN-LOH) with gene subtype specificity: most MVK-related porokeratosis showed chromosome 12-wide CN-LOH, while most MVD-related porokeratosis had 16q CN-LOH."

Quantifies second-hit frequency and the gene-specific CN-LOH patterns.

Somatic FDFT1 Promoter Hypermethylation

The alternative, non-hereditary entry point into the same pathway lesion. In solitary or linearly arranged localized porokeratosis, FDFT1 (squalene synthase) is silenced epigenetically rather than mutationally: lesions carry somatic biallelic promoter hypermethylation, or mono-allelic hypermethylation together with a somatic genetic alteration on the opposite allele. Gene-specific hypermethylation is detectable in morphologically normal epidermis immediately adjacent to lesions but not distal to them, indicating an asymptomatic epigenetically mosaic field that predisposes particular skin areas.

keratinocyte CL:0000312

FDFT1 hgnc:3629

skin epidermis UBERON:0001003

Downstream

Biallelic Mevalonate Pathway Enzyme Deficiency Biallelic promoter hypermethylation abolishes FDFT1 expression in the affected clone, producing the same functional pathway block as a biallelic coding lesion.

Show evidence (2 references)

PMID:38653249 SUPPORT Human Clinical

"Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway."

Establishes epigenetic silencing of FDFT1 as an independent, non-germline cause.

PMID:38653249 SUPPORT Human Clinical

"In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes..."

Supports the predisposed epigenetically mosaic field described in this node.

Biallelic Mevalonate Pathway Enzyme Deficiency

The doubly hit keratinocyte has effectively no activity of the affected enzyme, so flux through the mevalonate/isoprenoid pathway falls. A parallel, non-hereditary route to the same state exists: somatic biallelic (or mono-allelic plus somatic variant) promoter hypermethylation of FDFT1, the squalene synthase gene immediately downstream of FDPS, silences that enzyme in localized porokeratosis with no germline variant.

keratinocyte CL:0000312

FDFT1 hgnc:3629

isoprenoid biosynthetic process GO:0008299 ↓ DECREASED

Downstream

Cholesterol and Non-Sterol Isoprenoid Depletion Loss of enzyme activity blocks the pathway, starving the clone of cholesterol and the non-sterol isoprenoid end-products.

Mevalonate Pathway Intermediate Accumulation The same enzymatic block causes substrate and proximal intermediates to build up behind it.

Show evidence (2 references)

PMID:38653249 SUPPORT Human Clinical

"lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis"

Establishes the epigenetic route to the same biallelic pathway-enzyme deficiency.

PMID:38653249 SUPPORT Human Clinical

"Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles."

Restates the trans (opposite-allele) configuration that defines biallelic deficiency.

Cholesterol and Non-Sterol Isoprenoid Depletion

The end-product arm of the metabolic lesion. Flux through the pathway falls, so the clone is starved of cholesterol - an essential membrane constituent and a major component of the extracellular lipid matrix of the stratum corneum - and, for blocks proximal to the prenyl-donor branch point, of the non-sterol isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Which species are depleted depends on where the block sits: an MVK, PMVK or MVD block starves both the sterol and non-sterol branches, whereas an FDFT1 (squalene synthase) block lies below the branch point and depletes cholesterol only, with FPP spared or increased. Ultrastructurally the cholesterol deficit shows up as a reduced number of lamellar bodies and disrupted lamellar bilayer architecture in keratinocytes beneath the cornoid lamella. This is the arm that topical cholesterol replacement addresses.

cholesterol biosynthetic process GO:0006695 ↓ DECREASED

Downstream

Impaired Protein Prenylation and Geranylgeranylation FPP and GGPP are the lipid donors for protein prenylation; their depletion directly reduces prenylation of small GTPases and nuclear lamins. This edge holds for the MVK/PMVK/MVD/FDPS blocks, not for the distal FDFT1 block.

Aberrant Keratinocyte Differentiation and Apoptosis Cholesterol insufficiency perturbs keratinocyte differentiation and lowers the threshold for apoptosis.

Show evidence (3 references)

PMID:31753123 SUPPORT Other

"IPP is the precursor of the sterol isoprenoids (cholesterol and steroid hormones) and the nonsterol isoprenoids (FPP, GGPP, dolichols, and ubiquitone (coenzyme Q))."

Identifies the sterol and non-sterol products depleted downstream of the block.

PMID:31449901 SUPPORT Human Clinical

"Cholesterol, one of the end-products of the mevalonate pathway, is a key component of the extracellular lipid matrix in the stratum corneum, playing an essential role in providing and maintaining skin barrier function."

Establishes the barrier role of the depleted end-product.

PMID:31449901 SUPPORT Human Clinical

"Decreased number of lamellar bodies and disrupted lamellar bilayer architecture have been demonstrated in keratinocytes beneath the cornoid lamella in porokeratosis"

Supplies the lesion-localized ultrastructural correlate of cholesterol depletion.

Mevalonate Pathway Intermediate Accumulation

The substrate arm of the metabolic lesion, and the deliberate complement of the depletion node. Intermediates upstream of the enzymatic block - mevalonate above an MVK block, and the corresponding proximal species for the other enzymes - build up and are potentially toxic and pro-inflammatory. Because inhibiting HMG-CoA reductase with a topical statin shuts off the supply of these intermediates without replacing any end-product, the observation that statin monotherapy is as effective as the cholesterol combination argues that this arm, not the depletion arm, is the dominant driver of the lesion.

Downstream

Perilesional Inflammatory Infiltrate Accumulated mevalonate-pathway intermediates can activate innate immunity and increase cytokine production, one proposed route from the metabolic block to the inflammatory component of the lesion.

Aberrant Keratinocyte Differentiation and Apoptosis Accumulated proximal intermediates are held to be directly toxic to the keratinocyte, but the molecular species and the route to the differentiation and apoptosis phenotype have not been established.

Show evidence (2 references)

PMID:33005717 SUPPORT Human Clinical

"Enzyme deficiency is thought to lead to an insufficiency of the end product of the pathway, cholesterol, and the accumulation of upstream metabolites."

Names accumulation of upstream metabolites as the second arm of the metabolic lesion.

PMID:33005717 SUPPORT Human Clinical

"the results in our patient suggest that the accumulation of intermediates in the mevalonate synthesis pathway, not cholesterol deficiency, is the primary mechanism driving disseminated superficial actinic porokeratosis lesions"

Supports the primacy of this arm; the inference rests on a single patient, hence PARTIAL.

Impaired Protein Prenylation and Geranylgeranylation

Depletion of FPP and GGPP reduces post-translational lipid modification of small GTPases (RAS, RHOA, RHOB, RAC1, CDC42) and of nuclear lamin A. Because these proteins require prenylation for correct membrane or nuclear-envelope localization and act as switches in growth, differentiation and cytoskeletal signalling, their mislocalization is the proximate molecular explanation for the disordered epidermal maturation seen in porokeratosis.

keratinocyte CL:0000312

protein geranylgeranylation GO:0018344 ↓ DECREASED

Downstream

Aberrant Keratinocyte Differentiation and Apoptosis Loss of prenylated small-GTPase and lamin signalling drives the differentiation and apoptosis phenotype; supplying FPP or GGPP rescues both.

Show evidence (1 reference)

PMID:32256770 SUPPORT In Vitro

"MVK interference decreases the expression of differentiation markers, increases apoptosis, and decreases protein prenylation and geranylgeranylation levels in keratinocytes."

Direct experimental demonstration in human keratinocytes that loss of MVK reduces prenylation and geranylgeranylation.

Aberrant Keratinocyte Differentiation and Apoptosis

The biallelically deficient keratinocyte shows reduced expression of terminal differentiation markers (keratin 1, involucrin), premature and dyskeratotic maturation, and increased apoptosis. MVK also normally protects keratinocytes from UVA-induced apoptosis and participates in calcium-induced differentiation, so its loss both disorders maturation and removes a UV-stress safeguard, coupling the cellular defect to the actinic distribution of DSAP.

keratinocyte CL:0000312

keratinocyte differentiation GO:0030216 ⚠ ABNORMAL apoptotic process GO:0006915 ↑ INCREASED cornification GO:0070268 ⚠ ABNORMAL

Downstream

Clonal Expansion of Second-Hit Keratinocytes The abnormal clone behaves as a benign intraepidermal neoplasm and expands centrifugally within the epidermis.

Show evidence (2 references)

PMID:32256770 SUPPORT In Vitro

"MVK interference decreases the expression of differentiation markers, increases apoptosis, and decreases protein prenylation and geranylgeranylation levels in keratinocytes."

Direct in vitro evidence for the differentiation and apoptosis phenotype.

PMID:22983302 SUPPORT In Vitro

"Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation."

Links MVK loss to both the differentiation defect and loss of UVA-apoptosis protection.

Clonal Expansion of Second-Hit Keratinocytes

The single second-hit keratinocyte and its descendants expand laterally within the epidermis. Sampling across an annular DSAP lesion shows that the central epidermis is composed almost entirely of second-hit cells while the peripheral annular ring is a mixture of second-hit and naive (single-mutant) keratinocytes - the spatial signature of an outwardly expanding clone. Kubo and colleagues therefore classify DSAP as a benign intraepidermal neoplasia explicable by Knudson's two-hit hypothesis.

keratinocyte CL:0000312 basal cell of epidermis CL:0002187

skin epidermis UBERON:0001003

Downstream

Cornoid Lamella Formation The boundary between the expanding mutant clone and surrounding naive epidermis is where the parakeratotic column forms.

Central Cutaneous Atrophy The epidermis of the lesion centre, composed almost entirely of second-hit keratinocytes, is atrophic.

Malignant Transformation to Keratinocyte Carcinoma A minority of long-standing lesions progress from benign intraepidermal neoplasia to invasive keratinocyte carcinoma.

Show evidence (3 references)

PMID:31207227 SUPPORT Human Clinical

"In the characteristic annular skin lesions of DSAP, the central epidermis featured mostly second hit keratinocytes, and that of the annular ring featured a mixture of such cells and naïve keratinocytes, implying that each lesion reflects the clonal expansion of single second hit keratinocytes."

The direct spatial evidence for centrifugal clonal expansion modelled by this node.

PMID:31207227 SUPPORT Human Clinical

"DSAP is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson's two-hit hypothesis."

Explicitly frames the lesion as a two-hit clonal neoplasm.

PMID:38653249 SUPPORT Human Clinical

"FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient..."

Independent confirmation of clonal expansion, via the FDFT1 epigenetic route.

Cornoid Lamella Formation

The diagnostic lesion of porokeratosis: a vertical column of parakeratotic (nucleus-retaining) corneocytes rising through the stratum corneum, overlying a diminished or absent granular layer and dyskeratotic, vacuolated keratinocytes. Clinically it corresponds to the raised, ridge-like keratotic border at the advancing edge of the plaque, with the central skin left atrophic. An inflammatory infiltrate typically sits beneath the lamella.

keratinocyte CL:0000312

keratinization GO:0031424 ⚠ ABNORMAL

skin epidermis UBERON:0001003

Downstream

Porokeratotic Annular Plaque with Raised Keratotic Border The cornoid lamella is the histological substrate of the clinically visible raised annular rim.

Hyperkeratosis of the Lesional Rim Retention of nucleated corneocytes in the lamella thickens the stratum corneum at the lesion edge.

Palmoplantar Keratotic Papules In palmoplantar variants each keratotic papule is itself a minute cornoid lamella.

Perilesional Inflammatory Infiltrate The cornoid lamella has been proposed to induce the inflammatory reaction that sits immediately beneath it. This is an explicitly hypothesized relationship, not an established one.

Show evidence (2 references)

PMID:31753123 SUPPORT Other

"Porokeratosis is a phenotypically heterogeneous disorder characterized by the histopathological feature cornoid lamella, which is a vertical column of parakeratosis situated above dyskeratotic cells within the granular layer"

Defines the cornoid lamella exactly as modelled here.

PMID:29722423 SUPPORT Human Clinical

"Porokeratosis comprises heterogeneous keratinization disorders that are characterized by one or more atrophic patches surrounded by a ridge-like cornoid lamella."

Connects the histological column to the clinical ridge-and-atrophic-centre morphology.

Perilesional Inflammatory Infiltrate

A band-like lymphocytic infiltrate sits in the papillary dermis beneath the cornoid lamella and throughout lesional skin. It has been proposed both as a reaction induced by the cornoid lamella and as a constraint limiting further lateral expansion of the mutant clone; the mechanism is not settled. Accumulated mevalonate can activate innate immune responses and increase cytokine production, which is one proposed link between the metabolic block and the inflammatory component, and one reason topical statins may act as anti-inflammatory agents.

inflammatory response GO:0006954 ↑ INCREASED

skin of body UBERON:0002097

Downstream

Pruritus The lesional inflammatory infiltrate underlies the itch reported by a substantial minority of patients, and is most prominent in the eruptive and verrucous/ptychotropic variants where pruritus dominates.

Show evidence (2 references)

PMID:31753123 SUPPORT Other

"since an inflammatory infiltrate was located beneath the cornoid lamella, they suggested that the cornoid lamella might induce the inflammatory reaction"

Documents the infiltrate and marks its causal relationship to the cornoid lamella as hypothesized rather than established.

PMID:33005717 SUPPORT Human Clinical

"Evidence has demonstrated that mevalonate accumulation can result in the activation of the innate immune response and increased cytokine production."

Supplies the proposed metabolic-to-inflammatory link; the authors present it as a suggested rather than demonstrated mechanism in porokeratosis.

Malignant Transformation to Keratinocyte Carcinoma

Porokeratosis is a premalignant condition. In a review of 281 reported cases, 7.5% harboured a malignancy arising within a porokeratotic lesion, most commonly cutaneous squamous cell carcinoma, with basal cell carcinoma next. Large lesions, lesions of long standing and the linear variant carry the greatest risk; in a contemporary genotype-phenotype cohort every patient with porokeratosis plus non-melanoma skin cancer carried an MVD variant. Because transformation can occur decades after onset, long-term surveillance rather than short-term clearance is the central management principle.

keratinocyte CL:0000312

skin of body UBERON:0002097

Downstream

Basal Cell Carcinoma Arising in a Lesion Basal cell carcinoma is the second-commonest malignancy arising within a porokeratotic lesion.

Cutaneous Squamous Cell Carcinoma Arising in a Lesion Squamous cell carcinoma is the commonest malignancy arising by this route.

Show evidence (4 references)

PMID:8624658 SUPPORT Human Clinical

"Twenty-one (7.5%) of 281 cases reported revealed a malignancy arising within porokeratosis. Large lesions, those of long-standing duration, and the linear type were at greatest risk."

Quantifies the malignant risk and identifies the linear variant as highest risk.

PMID:31753123 SUPPORT Other

"Porokeratosis is considered a premalignant condition, and higher rates of skin cancer have been described in linear and large plaques, with the most common malignancy being squamous cell carcinoma"

Independent confirmation that SCC is the dominant malignancy and linear disease the highest-risk variant.

PMID:41240373 SUPPORT Human Clinical

"100% (n = 6/6) of patients with porokeratosis plus nonmelanoma skin cancer and 71% (n = 17/24) of those with linear porokeratosis (LP) harboured MVD variants"

Supports the MVD genotype association with skin cancer and with linear disease.

+ 1 more reference

✶

Histopathology

3

Cornoid Lamella VERY_FREQUENT

The pathognomonic finding. A tightly stacked, vertically oriented column of parakeratotic corneocytes traverses the stratum corneum, angled outward from the lesion centre. It sits in a small epidermal invagination and corresponds exactly to the raised clinical rim. Biopsy must therefore sample the raised border, not the atrophic centre.

Show evidence (2 references)

PMID:31753123 SUPPORT Other

"Porokeratosis is a phenotypically heterogeneous disorder characterized by the histopathological feature cornoid lamella, which is a vertical column of parakeratosis situated above dyskeratotic cells within the granular layer"

Defines the cornoid lamella as a vertical parakeratotic column, the finding coded here.

PMID:38132857 SUPPORT Human Clinical

"Porokeratosis is a heterogeneous group of keratinising disorders characterised by the presence of particular microscopic structural changes, namely the presence of the cornoid lamella."

Establishes the cornoid lamella as the defining microscopic criterion for the whole disease group.

Dyskeratotic Keratinocytes with Diminished Granular Layer

Directly under the cornoid lamella the stratum granulosum is thinned or lost and the underlying keratinocytes are dyskeratotic and vacuolated - the cellular correlate of failed terminal differentiation in the mutant clone. The epidermis of the lesion centre is atrophic.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"which is a vertical column of parakeratosis situated above dyskeratotic cells within the granular layer"

Documents the dyskeratotic granular-layer cells that underlie the lamella.

Subjacent Lymphocytic Inflammatory Infiltrate

A lymphocytic infiltrate is present beneath the cornoid lamella and may extend throughout lesional skin. Its intensity is variable and it is prominent in eruptive and inflammatory variants.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"inflammatory infiltrates, in DSAP as well as in other variants, can be visualized not only beneath the cornoid lamella"

Documents the infiltrate and its distribution beyond the lamella.

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Pathograph

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Phenotypes

8

Integument 6

Hyperkeratosis of the Lesional Rim HP:0000962

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"Porokeratosis is a heterogeneous group of keratinising disorders characterised by the presence of particular microscopic structural changes, namely the presence of the cornoid lamella."

Supports the keratinizing/hyperkeratotic nature of the lesion border.

Central Cutaneous Atrophy Thin skin HP:0000963

Show evidence (1 reference)

PMID:29722423 SUPPORT Human Clinical

"characterized by one or more atrophic patches surrounded by a ridge-like cornoid lamella"

Names the atrophic centre of the lesion.

Pruritus HP:0000989

Show evidence (1 reference)

PMID:41606785 SUPPORT Human Clinical

"Porokeratosis is a chronic disorder of keratinization associated with significant morbidity and no spontaneous resolution."

Supports symptomatic morbidity in porokeratosis; the snippet does not itself name pruritus, so this evidence is PARTIAL.

Palmoplantar Keratotic Papules Palmoplantar keratoderma HP:0000982

Show evidence (1 reference)

PMID:31449901 SUPPORT Human Clinical

"We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2 with linear porokeratosis."

Documents palmoplantar disseminated porokeratosis as a recognized clinical presentation in a genotyped patient series.

Cutaneous Squamous Cell Carcinoma Arising in a Lesion OCCASIONAL HP:0002860

Show evidence (2 references)

PMID:8624658 SUPPORT Human Clinical

"Twenty-one (7.5%) of 281 cases reported revealed a malignancy arising within porokeratosis."

The 7.5% pooled figure falls in the OCCASIONAL band (5-29%); the band is used with the caveat that the denominator is published cases, not a defined cohort.

PMID:31753123 SUPPORT Other

"with the most common malignancy being squamous cell carcinoma"

Identifies SCC as the dominant malignancy.

Basal Cell Carcinoma Arising in a Lesion VERY_RARE HP:0002671

Show evidence (1 reference)

PMID:32401728 SUPPORT Human Clinical

"Many authors consider it to be a premalignant condition because of the potential for malignant transformation to squamous cell or basal cell carcinoma."

Establishes basal cell carcinoma as a recognized transformation outcome; it is reported less often than SCC, supporting the VERY_RARE band.

Other 2

Porokeratotic Annular Plaque with Raised Keratotic Border VERY_FREQUENT Porokeratosis HP:0200044

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29722423 SUPPORT Human Clinical

"Porokeratosis comprises heterogeneous keratinization disorders that are characterized by one or more atrophic patches surrounded by a ridge-like cornoid lamella."

The lesion is definitional for the disease, supporting VERY_FREQUENT and the diagnostic flag.

Photodistribution of Lesions on Sun-Exposed Skin

Deliberately left without an HPO binding. HP:0000992 Cutaneous photosensitivity was considered and rejected: its definition is an increased sensitivity of the skin to light diagnosable by phototesting, whereas what is observed in DSAP is a UV-mutagenesis-driven lesion distribution in patients who are not phototest-abnormal. Binding HP:0000992 would incorrectly cluster porokeratosis with xeroderma pigmentosum, the porphyrias and lupus in HPO-similarity searches.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"the authors show that DSAP lesions result from second-hit somatic mitotic recombination or point mutations with a UV signature, validating the clinical observation that DSAP lesions arise upon sun exposed skin"

Ties the sun-exposed distribution to UV-induced second hits.

🧬

Genetic Associations

5

MVK

Gene: MVK hgnc:7530 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:22983302 SUPPORT Human Clinical

"Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively."

Establishes MVK as a causal DSAP gene and quantifies its contribution.

PMVK

Gene: PMVK hgnc:9141 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:30942823 SUPPORT Human Clinical

"One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin."

Variant-level demonstration of germline-plus-somatic PMVK involvement in linear porokeratosis.

MVD

Gene: MVD hgnc:7529 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30942823 SUPPORT Human Clinical

"In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift)."

Variant-level demonstration of the MVD germline-plus-somatic two-hit configuration.

PMID:41240373 SUPPORT Human Clinical

"100% (n = 6/6) of patients with porokeratosis plus nonmelanoma skin cancer and 71% (n = 17/24) of those with linear porokeratosis (LP) harboured MVD variants"

Supports the MVD genotype-phenotype correlation with skin cancer and linear disease.

FDPS

Gene: FDPS hgnc:3631 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:26202976 SUPPORT Human Clinical

"identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway"

Establishes FDPS as a causal porokeratosis gene.

FDFT1

Gene: FDFT1 hgnc:3629 relationship_type: CAUSATIVE variant_origin: SOMATIC

Show evidence (2 references)

PMID:38653249 SUPPORT Human Clinical

"Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway."

Establishes FDFT1 as a causal gene acting through somatic epigenetic silencing.

PMID:38653249 SUPPORT Human Clinical

"In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes..."

Supports the predisposed epigenetic field described in this gene entry.

💊

Medical Actions

8

Topical Cholesterol Plus Lovastatin

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: lovastatin CHEBI:40303 cholesterol CHEBI:16113

The pathogenesis-directed therapy for porokeratosis, and a direct read-out of the mechanism. Compounded 2% cholesterol plus 2% lovastatin cream applied twice daily simultaneously addresses both arms of the metabolic lesion: lovastatin inhibits HMG-CoA reductase upstream of the enzymatic block, preventing accumulation of potentially toxic mevalonate-pathway intermediates, while cholesterol replaces the missing pathway end-product. In the original case series, cholesterol/lovastatin but not cholesterol alone produced near-complete clearance of DSAP lesions within four weeks, with moderate improvement in PPPD and linear porokeratosis. The strategy is borrowed from CHILD syndrome, another disorder of distal cholesterol metabolism.

Mechanism Target:

INHIBITS Mevalonate Pathway Intermediate Accumulation — The lovastatin component blocks HMG-CoA reductase upstream of the deficient enzyme, shutting off the supply of the intermediates that would otherwise build up behind the block.

Show evidence (1 reference)

PMID:31449901 SUPPORT Human Clinical

"block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis"

States the statin arm of the dual mechanism.

INHIBITS Cholesterol and Non-Sterol Isoprenoid Depletion — The cholesterol component supplies the missing end-product directly to lesional keratinocytes, correcting the depletion arm; topical delivery bypasses hepatic first-pass metabolism and gives keratinocytes direct access to cholesterol.

Show evidence (1 reference)

PMID:31449901 SUPPORT Human Clinical

"We hypothesized that topical therapy that aims to replenish cholesterol, an essential mevalonate pathway end-product, and block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis."

States the end-product replacement arm of the dual mechanism.

Show evidence (4 references)

PMID:31449901 SUPPORT Human Clinical

"Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in near complete clearance of disseminated superficial actinic porokeratosis lesions after 4 weeks of therapy and moderate improvement of porokeratosis palmaris et plantaris disseminata lesions and linear..."

Reports the clinical efficacy of the combination and the negative cholesterol-only control.

PMID:31449901 SUPPORT Human Clinical

"Topical cholesterol/lovastatin is an effective and well-tolerated therapy for porokeratosis that underscores the utility of a pathogenesis-based therapy that replaces deficient end products and prevents accumulation of potentially toxic precursors."

The authors' own statement of the pathogenesis-directed rationale.

PMID:41606785 SUPPORT Human Clinical

"The majority of patients (79%) received compounded topical lovastatin 2% or simvastatin 2%, typically in combination with cholesterol 2%."

Confirms the regimen and concentrations described here across the pooled literature.

+ 1 more reference

Topical Statin Monotherapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: lovastatin CHEBI:40303

Topical lovastatin 2% or simvastatin 2% without added cholesterol. A randomized clinical trial in DSAP found improvement in both the lovastatin-cholesterol and lovastatin-alone arms with only limited additional benefit from cholesterol, implying that blocking accumulation of upstream intermediates, rather than replacing cholesterol, is the dominant mechanism. A pooled systematic review of 95 patients reported clinical improvement in 92%, with response as early as four weeks and mostly mild local adverse events.

Mechanism Target:

INHIBITS Mevalonate Pathway Intermediate Accumulation — Statin inhibition of HMG-CoA reductase prevents build-up of mevalonate and other intermediates upstream of the deficient enzyme, without replacing any end-product - which is why its efficacy argues that this arm dominates.

Show evidence (1 reference)

PMID:33005717 SUPPORT Human Clinical

"We hypothesized that blocking the mevalonate synthesis pathway upstream of the MVD enzyme would be sufficient to alleviate his symptoms by preventing the accumulation of mevalonate pathway metabolites."

States the single-arm mechanism targeted by statin monotherapy.

Show evidence (3 references)

PMID:36947042 SUPPORT Human Clinical

"This randomized clinical trial found improvements in DSAP severity in both treatment groups, without serious AEs, indicating a limited benefit with the addition of cholesterol."

Randomized-trial evidence that statin monotherapy performs comparably to the cholesterol combination.

PMID:36947042 SUPPORT Human Clinical

"These results suggest that lovastatin cream may be a new primary treatment option for patients diagnosed with DSAP."

The trialists' conclusion supporting statin monotherapy as a primary option.

PMID:41606785 SUPPORT Human Clinical

"was observed in 92% of patients (87 of 95), with onset of response reported as early as 4 weeks."

Pooled response rate and time to response across the topical-statin literature.

Photoprotection and Sun Avoidance

Category: Therapeutic Action: photoprotection and sunlight avoidance Ontology label: Preventive Intervention NCIT:C15843

Because DSAP lesions arise from UV-signature somatic second hits, rigorous photoprotection - sun avoidance, protective clothing and broad-spectrum sunscreen - is a mechanistically grounded preventive measure rather than merely symptomatic advice. Unnecessary phototherapy should be avoided in affected individuals.

Mechanism Target:

INHIBITS Somatic Second Hit in Lesional Keratinocytes — Reducing UV exposure reduces the rate of UV-signature C>T second hits that create new lesions.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"The finding that some of the second-hit mutations have UV signatures proves the importance of sun protection as a preventive measure in DSAP."

Directly links photoprotection to prevention of the targeted second-hit node.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"The finding that some of the second-hit mutations have UV signatures proves the importance of sun protection as a preventive measure in DSAP."

Direct statement of the mechanistic rationale for photoprotection.

Surgical Excision of Suspicious or Localized Lesions

Category: Therapeutic Action: surgical excision Ontology label: Surgical Procedure NCIT:C15329

Complete excision provides both definitive local control and histopathology, and is the appropriate response to a lesion showing rapid growth, nodularity, ulceration, bleeding, pain or induration. It is also reasonable for solitary porokeratosis of Mibelli plaques. Destructive alternatives include shave excision, curettage, electrosurgery, cryosurgery and ablative laser.

Mechanism Target:

INHIBITS Malignant Transformation to Keratinocyte Carcinoma — Excising a transformed or suspicious lesion both treats and definitively excludes keratinocyte carcinoma.

Show evidence (1 reference)

PMID:8624658 SUPPORT Human Clinical

"Porokeratosis is a premalignant condition, with certain groups of patients at greatest risk for malignant transformation."

Establishes the premalignant risk that excision of suspicious lesions addresses; the snippet does not report excision outcomes, hence PARTIAL.

Show evidence (1 reference)

PMID:8624658 SUPPORT Human Clinical

"Porokeratosis is a premalignant condition, with certain groups of patients at greatest risk for malignant transformation."

Establishes the premalignant status that justifies excision and surveillance of high-risk lesions; the snippet does not itself report excision outcomes, hence PARTIAL.

Cryosurgery

Category: Therapeutic Action: cryosurgery Ontology label: Cryosurgery NCIT:C15215

Cryosurgery with liquid nitrogen is a widely used destructive option for a limited number of accessible lesions, particularly porokeratosis of Mibelli. Recurrence is common and dyspigmentation or scarring may follow, so it does not remove the need for long-term surveillance.

Show evidence (2 references)

PMID:39485670 SUPPORT Human Clinical

"Multiple management options are available for DSAP, including topical and systemic agents, photodynamic therapy and laser treatments. However, these approaches vary in their balance between efficacy and toxicity."

Systematic review supporting the availability but variable efficacy/toxicity of destructive and physical modalities; cryosurgery is not named in the abstract, hence PARTIAL.

PMID:32401728 SUPPORT Human Clinical

"Therefore, long-term follow-up is a key component of treatment, which is usually complex and often unsatisfactory."

Supports the requirement for continued follow-up after destructive treatment; the snippet does not name cryosurgery, hence PARTIAL.

Photodynamic Therapy

Category: Therapeutic Action: Photodynamic Therapy NCIT:C15300

Topical photosensitizer plus light activation has been used for disseminated disease not amenable to individual lesion destruction. Reported response rates are modest and the procedure can be painful; it is a second-line option now largely superseded by pathway-directed topical statins.

Show evidence (2 references)

PMID:39485670 SUPPORT Human Clinical

"Various treatment modalities were reported, including topical and systemic agents, photodynamic therapy, and laser therapy."

Systematic review naming photodynamic therapy among the reported DSAP management options.

PMID:39485670 SUPPORT Human Clinical

"Currently, there is a paucity of high-quality clinical trial data to guide treatment decisions."

Supports the characterization of this modality as second-line with weak supporting evidence.

Conventional Topical and Systemic Agents

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

The pre-statin therapeutic repertoire, still widely used and still supported only by case reports and small series. Topical options include 5-fluorouracil, imiquimod, retinoids, vitamin D analogues, diclofenac and corticosteroids; systemic acitretin is used for extensive or hyperkeratotic disease but relapses after withdrawal and carries mucocutaneous and metabolic toxicity. A 2025 systematic review of 61 DSAP studies concluded that these options vary widely in their efficacy-toxicity balance and that high-quality trial data are lacking.

Show evidence (3 references)

PMID:39485670 SUPPORT Human Clinical

"Of 923 citations, 61 studies were included, predominantly comprising case reports and retrospective case series."

Characterizes the weak evidence base underlying the conventional agents.

PMID:39485670 SUPPORT Human Clinical

"Various treatment modalities were reported, including topical and systemic agents, photodynamic therapy, and laser therapy."

Supports the topical and systemic agent categories grouped in this entry.

PMID:39485670 SUPPORT Human Clinical

"these approaches vary in their balance between efficacy and toxicity"

Supports the efficacy-toxicity caveat stated in this description.

Genetic Counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Counseling should explain autosomal dominant transmission of the germline variant, the requirement for a somatic second hit (and therefore the incomplete, age-dependent penetrance and variable expressivity), the mosaic basis of linear disease, and the lifelong but generally non-life-limiting course. Molecular diagnosis by an MVK/PMVK/MVD/FDPS panel, with FDFT1 considered, enables cascade testing of relatives.

Show evidence (1 reference)

PMID:41240373 SUPPORT Human Clinical

"In 69 Chinese patients with porokeratosis, 22 pathogenic variants were detected in MVK, PMVK, MVD and FDPS, including 7 novel variants, 4 of which were validated via the 'second-hit' mechanism."

Supports the four-gene diagnostic panel and the second-hit validation step that genetic counseling rests on; the snippet does not itself address counseling practice, cascade testing or penetrance, hence PARTIAL.

🌍

Environmental Factors

2

Ultraviolet radiation exposure

UV is the clearest environmental modifier. DSAP lesions arise preferentially on sun-exposed extensor limbs and often flare in summer; second hits in DSAP lesions carry a UV mutational signature (C>T transitions), so UV is not merely an aggravating factor but a mutagenic cause of the somatic event that creates the lesion. This makes sun protection a mechanistically justified preventive measure.

Show evidence (2 references)

PMID:31753123 SUPPORT Other

"The finding that some of the second-hit mutations have UV signatures proves the importance of sun protection as a preventive measure in DSAP."

Directly links UV mutagenesis to lesion formation and to the preventive recommendation.

PMID:32401728 SUPPORT Human Clinical

"Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and systemic, infectious, and neoplastic diseases."

Independent review-level confirmation of the UV association.

Mechanism Target:

TRIGGERS Somatic Second Hit in Lesional Keratinocytes — The strongest exposure link in this tranche, and unusual in the backfill generally: ultraviolet light is not merely associated with the disease, it is the mutagen that writes the somatic second hit this node holds, and the second hits carry its signature. That makes sun protection a mechanistically justified preventive measure rather than generic advice.

Show evidence (2 references)

PMID:31753123 SUPPORT Other

"The finding that some of the second-hit mutations have UV signatures proves the importance of sun protection as a preventive measure in DSAP."

States that some second-hit mutations carry ultraviolet signatures and draws the sun-protection conclusion from it. The exposure is identified in the mutation itself, which is this node.

PMID:32401728 SUPPORT Human Clinical

"Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and systemic, infectious, and neoplastic diseases."

Review-level confirmation that the disease is associated with ultraviolet radiation. Association only, carried to show the link does not rest on a single study.

Immunosuppression

Left ontologically unbound deliberately. ECTO's only immunosuppression term, ECTO:9001747, is defined as exposure to an immunosuppressive agent (RO:0002309 some CHEBI:35705) -- a drug exposure. This entry describes immunosuppression as a host state with non-drug causes, so that term would assert something the entry's own description rules out. No host-immunosuppression-state exposure term exists.

Iatrogenic or disease-related immunosuppression - solid-organ or haematopoietic stem cell transplantation, HIV infection, haematologic malignancy, immunosuppressive drug therapy - can precipitate eruptive or disseminated porokeratosis and is thought to raise the risk of malignant transformation. Lesions may improve when immunosuppression is reduced.

Show evidence (2 references)

PMID:34418147 SUPPORT Human Clinical

"Porokeratosis is a rare diagnosis in the pediatric population, and eruptive disease has been documented prior in patients with history of stem cell transplantation."

Documents the association between eruptive porokeratosis and post-transplant immunosuppression.

PMID:32401728 SUPPORT Human Clinical

"Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and systemic, infectious, and neoplastic diseases."

Review-level confirmation of the immunosuppression association.

Mechanism Target:

EXACERBATES Clonal Expansion of Second-Hit Keratinocytes — Graded well below the ultraviolet link into this entry, and the difference is real rather than presentational: ultraviolet light creates the mutant clone, whereas immunosuppression appears to let an existing clone expand, which is why this points at the expansion node and not at the second hit. No cited sentence supplies the route, so the intermediates stay unknown.

Show evidence (2 references)

PMID:34418147 SUPPORT Human Clinical

"Porokeratosis is a rare diagnosis in the pediatric population, and eruptive disease has been documented prior in patients with history of stem cell transplantation."

Documents eruptive disease in children after treatment for leukaemia and in prior stem-cell transplant recipients. A clinical association in a small paediatric series.

PMID:32401728 SUPPORT Human Clinical

"Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and systemic, infectious, and neoplastic diseases."

Review listing immunosuppression among the associations of this disease. The same sentence that supports the ultraviolet link, and equally general.

🔬

Diagnosis

4

Skin biopsy of the raised lesional border

The confirmatory test. The biopsy must sample the raised keratotic rim, not the atrophic centre, because the cornoid lamella - the diagnostic structure - sits within the rim; a punch taken from the centre will show only atrophic epidermis and miss the diagnosis. Histology should demonstrate a vertical column of parakeratosis over a diminished or absent granular layer with dyskeratotic keratinocytes beneath. Biopsy is mandatory whenever a lesion becomes nodular, indurated, ulcerated, bleeding or painful, in order to exclude keratinocyte carcinoma arising within it.

skin biopsy NCIT:C51692

Results: A cornoid lamella establishes the diagnosis of porokeratosis; the clinical variant is then assigned on lesion morphology and distribution.

Show evidence (2 references)

PMID:31753123 SUPPORT Other

"Porokeratosis is a phenotypically heterogeneous disorder characterized by the histopathological feature cornoid lamella, which is a vertical column of parakeratosis situated above dyskeratotic cells within the granular layer"

Defines the histological finding that the biopsy is performed to demonstrate.

PMID:29722423 SUPPORT Human Clinical

"Porokeratosis comprises heterogeneous keratinization disorders that are characterized by one or more atrophic patches surrounded by a ridge-like cornoid lamella."

Locates the cornoid lamella in the raised rim rather than the atrophic centre, which is why the rim must be sampled.

Dermoscopy of the lesion border

Non-invasive first-line assessment. Dermoscopy of a porokeratotic lesion shows a sharply defined peripheral white-to-yellow keratotic track running around the lesion, the dermoscopic correlate of the cornoid lamella and often called the "Great Wall" sign. It is the feature that separates porokeratosis from actinic keratosis and other annular dermatoses at the bedside and guides where to place a confirmatory biopsy. Reflectance confocal microscopy and line-field confocal optical coherence tomography can add further non-invasive discrimination, but histopathology remains necessary whenever transformation is suspected.

dermoscopy NCIT:C116478

Results: A peripheral keratotic track corresponding to the cornoid lamella supports the diagnosis and identifies the correct biopsy site.

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"introduces imaging methods facilitating the diagnosis (conventional and ultraviolet-induced fluorescence dermatoscopy, reflectance confocal microscopy and pathology)"

Establishes dermatoscopy and reflectance confocal microscopy as diagnostic imaging methods for porokeratosis; the abstract does not describe the specific dermoscopic pattern, hence PARTIAL.

Mevalonate pathway gene panel

Sequencing of MVK, PMVK, MVD and FDPS, with FDFT1 considered, on peripheral blood. Highest yield in familial, early-onset, disseminated, linear/segmental, mixed or atypical disease. Sequence plus copy-number analysis is preferable, and exome/genome sequencing can be used for panel-negative pedigrees. A negative blood panel does not exclude the diagnosis, because the non-hereditary FDFT1 form and some mosaic presentations carry no germline lesion.

genetic testing NCIT:C15709

Results: A heterozygous loss-of-function variant in MVK, PMVK, MVD or FDPS supports the diagnosis and enables cascade testing of relatives.

Show evidence (2 references)

PMID:41240373 SUPPORT Human Clinical

"In 69 Chinese patients with porokeratosis, 22 pathogenic variants were detected in MVK, PMVK, MVD and FDPS, including 7 novel variants, 4 of which were validated via the 'second-hit' mechanism."

Establishes the four-gene panel and its diagnostic yield in a contemporary cohort.

PMID:41240373 SUPPORT Human Clinical

"These findings enable porokeratosis subtyping guided by genetic testing and provide a foundation for developing molecularly integrated scoring systems to refine risk-stratified management."

Supports the use of the panel for subtyping and risk stratification.

Paired lesional and blood sequencing for the somatic second hit

A research-grade but diagnostically decisive test in mosaic and non-hereditary disease: whole-exome sequencing of microdissected lesional epidermis alongside blood or saliva. It demonstrates the second hit - a copy-neutral loss of heterozygosity, a point mutation in trans, or, for FDFT1, promoter hypermethylation - that is confined to lesional skin. This is the only test that can confirm the two-hit mechanism in an individual patient and the only route to a molecular diagnosis in the germline-negative localized form.

genetic testing NCIT:C15709

Results: A lesion-restricted somatic event on the allele opposite the germline variant, or biallelic somatic FDFT1 promoter hypermethylation in the absence of any germline variant.

Show evidence (2 references)

PMID:30942823 SUPPORT Human Clinical

"Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis."

Describes exactly the paired lesional/blood design this test entry records.

PMID:31207227 SUPPORT Human Clinical

"we showed that each skin lesion of DSAP exhibited an individual second hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis"

Confirms that the somatic event is detectable specifically in lesional epidermis.

📊

Prevalence

1

Worldwide

Point Prevalence Rare

Robust population prevalence estimates per 100,000 are not available. Reviews consistently characterize porokeratosis as an uncommon group of dermatoses; DSAP is the commonest variant and is enriched in fair-skinned populations living in high-ultraviolet settings.

Show evidence (1 reference)

PMID:32401728 SUPPORT Human Clinical

"Porokeratosis comprises a group of heterogeneous and uncommon acquired or congenital skin diseases of unknown origin characterized by a keratinization disorder resulting from abnormal clonal expansion of keratinocytes."

Supports the qualitative rare/uncommon occurrence class in the absence of a quantified population rate.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Porokeratosis:

Actinic keratosis Not Yet Curated MONDO:0005173

Overlapping Features The single most frequent clinical mimic of DSAP: both present as multiple scaly, erythematous macules on chronically sun-exposed extensor limbs and face of older, fair-skinned adults, and both are UV-driven keratinocyte lesions.

Distinguishing Features

Porokeratosis has a sharply demarcated, raised, ridge-like peripheral rim enclosing an atrophic centre; actinic keratosis has adherent rough scale without a discrete annular border.
Histology is decisive - the cornoid lamella (vertical parakeratotic column over a diminished granular layer) is present in porokeratosis and absent in actinic keratosis, which instead shows basal keratinocyte atypia.
Dermoscopy of porokeratosis shows a peripheral white-yellow keratotic track corresponding to the cornoid lamella.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"Porokeratosis is a phenotypically heterogeneous disorder characterized by the histopathological feature cornoid lamella, which is a vertical column of parakeratosis situated above dyskeratotic cells within the granular layer"

Supplies the histological discriminator that separates porokeratosis from actinic keratosis.

Seborrheic keratosis Not Yet Curated MONDO:0008420

Overlapping Features Common benign pigmented keratotic papules and plaques that can be confused with porokeratosis of Mibelli, especially when brown and hyperkeratotic.

Distinguishing Features

Seborrheic keratosis is a stuck-on, waxy, well-demarcated plaque with keratin-filled pseudocysts and comedo-like openings on dermoscopy; it lacks an annular rim and an atrophic centre.
Histology shows acanthosis with horn pseudocysts and no cornoid lamella.
Seborrheic keratoses have no association with the mevalonate pathway and no premalignant potential.

Show evidence (1 reference)

PMID:38132857 SUPPORT Human Clinical

"Porokeratosis is a heterogeneous group of keratinising disorders characterised by the presence of particular microscopic structural changes, namely the presence of the cornoid lamella."

Establishes the required-for-diagnosis microscopic criterion that seborrheic keratosis does not meet; the snippet does not itself discuss seborrheic keratosis, hence PARTIAL.

Bowen disease Not Yet Curated MONDO:0020761

Overlapping Features Squamous cell carcinoma in situ. A well-demarcated erythematous scaly plaque that overlaps clinically with a solitary porokeratosis of Mibelli plaque. The relationship is not purely one of mimicry: SCC in situ can also arise within a long-standing porokeratotic lesion, so the two can coexist.

Distinguishing Features

Bowen disease shows full-thickness keratinocyte atypia on histology, whereas uncomplicated porokeratosis shows a cornoid lamella without full-thickness atypia.
A porokeratotic plaque that becomes nodular, indurated, ulcerated, bleeding or painful should be biopsied to exclude transformation rather than assumed to be simple mimicry.

Show evidence (1 reference)

PMID:8624658 SUPPORT Human Clinical

"Porokeratosis is a premalignant condition, with certain groups of patients at greatest risk for malignant transformation."

Supports the coexistence caveat that distinguishes this differential from simple look-alikes.

Lichen planus Not Yet Curated MONDO:0006572

Overlapping Features An inflammatory, intensely pruritic papulosquamous dermatosis that can resemble the annular or verrucous/ptychotropic porokeratosis variants, particularly in genital and intertriginous sites where annular lichen planus is common.

Distinguishing Features

Lichen planus papules are violaceous, flat-topped and polygonal with Wickham striae; they lack a cornoid lamella.
Histology shows a lichenoid interface dermatitis with basal vacuolar degeneration, hypergranulosis and Civatte bodies - notably hypergranulosis, the opposite of the diminished granular layer beneath a cornoid lamella.
Lichen planus typically responds to topical corticosteroids, which give only transient antipruritic benefit in porokeratosis.

Show evidence (1 reference)

PMID:31753123 SUPPORT Other

"which is a vertical column of parakeratosis situated above dyskeratotic cells within the granular layer"

Provides the granular-layer histological contrast used to separate porokeratosis from the hypergranulosis of lichen planus; the snippet does not discuss lichen planus, hence PARTIAL.

Granuloma annulare Not Yet Curated MONDO:0006554

Overlapping Features Annular skin lesions with a raised border and central clearing, the classic clinical differential for any annular dermatosis and a frequent misdiagnosis of porokeratosis of Mibelli.

Distinguishing Features

The border of granuloma annulare is smooth, firm and dermal (non-scaly); the border of porokeratosis is keratotic and scaly with a palpable ridge and often a visible furrow.
Granuloma annulare is a dermal palisaded granulomatous process with mucin; the epidermis is normal and there is no cornoid lamella.
Granuloma annulare frequently resolves spontaneously, whereas porokeratosis shows no spontaneous resolution.

Show evidence (1 reference)

PMID:41606785 SUPPORT Human Clinical

"Porokeratosis is a chronic disorder of keratinization associated with significant morbidity and no spontaneous resolution."

Supports the no-spontaneous-resolution discriminator against granuloma annulare; the snippet does not itself discuss granuloma annulare, hence PARTIAL.

Mevalonate kinase deficiency MONDO:0017708

Overlapping Features The critical genetic - not clinical - differential, including its mild end, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). MVK variants cause both conditions, but the diseases are unrelated in presentation and must not be conflated. Mevalonate kinase deficiency is a systemic autoinflammatory disorder caused by germline biallelic (homozygous or compound heterozygous) MVK loss-of-function, spanning mevalonic aciduria at the severe end and HIDS at the mild end. Porokeratosis instead requires a germline monoallelic variant plus a somatic second hit restricted to epidermal keratinocytes. A striking and unresolved observation anchors the separation: patients with HIDS carry biallelic MVK loss of function in every cell, including keratinocytes, yet no porokeratosis lesions have been described in them. On a naive two-hit reading they should be the group most at risk, so this is a genuine paradox rather than a demonstration. The usual explanation is that the MVK alleles seen in HIDS are hypomorphic and retain residual enzyme activity, whereas the lesional second hit in porokeratosis produces a true clonal null, but this has not been formally tested.

Distinguishing Features

Mevalonate kinase deficiency presents with recurrent febrile attacks, hepatosplenomegaly, lymphadenopathy, arthralgia, gastrointestinal symptoms and (in mevalonic aciduria) dysmorphism, failure to thrive, visual impairment and psychomotor retardation - none of which occur in porokeratosis.
The rash of mevalonate kinase deficiency is erythematous maculopapular or urticarial, not annular with a cornoid lamella.
Inheritance differs - biallelic germline (autosomal recessive) in mevalonate kinase deficiency versus monoallelic germline plus somatic second hit in porokeratosis.
Mevalonic aciduria shows markedly elevated urinary mevalonic acid; porokeratosis has no systemic biochemical abnormality.

Show evidence (2 references)

PMID:31753123 SUPPORT Other

"with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) representing the severe and mild ends of the clinical and biochemical spectrum of MKD, respectively"

Defines the mevalonate kinase deficiency spectrum that shares MVK with porokeratosis but is a different disease.

PMID:31753123 SUPPORT Other

"no porokeratosis lesions were described in patients with HIDS"

The decisive observation that biallelic germline MVK loss does not produce porokeratosis, keeping the two entities separate.

🔬

Clinical Trials

1

NCT04359823 PHASE_I COMPLETED

Single-blinded randomized comparison of 2% lovastatin plus 2% cholesterol cream versus 2% lovastatin cream alone applied twice daily for 12 weeks in adults with disseminated superficial actinic porokeratosis, at the Medical University of South Carolina. Both arms improved on the DSAP General Assessment Severity Index, with only limited additional benefit from the added cholesterol.

Target Phenotypes: Porokeratosis HP:0200044

Show evidence (1 reference)

clinicaltrials:NCT04359823 SUPPORT Human Clinical

"This study will analyze the effects of topical lovastatin/cholesterol vs topical lovastatin alone in patients with disseminated superficial actinic porokeratosis."

The registered trial testing the pathogenesis-directed regimen in DSAP.

{ }

Source YAML

click to show

name: Porokeratosis
creation_date: "2026-08-01T05:30:00Z"
category: Mendelian
description: >-
  Porokeratosis is a heterogeneous group of disorders of keratinization defined
  histologically by the cornoid lamella, a vertical column of parakeratotic cells
  overlying a diminished granular layer that marks the advancing edge of an
  expanding clone of mutant keratinocytes. Most familial and many sporadic forms
  arise from loss-of-function variants in mevalonate-pathway genes (MVK, PMVK,
  MVD, FDPS). In these hereditary forms a lesion appears only when the germline
  heterozygous variant is joined by a second somatic hit in the wild-type allele
  within lesional epidermis - the classic Knudson two-hit clonal model. A
  non-hereditary localized form reaches the same biallelic state by a different
  route, somatic promoter hypermethylation of FDFT1, with no germline variant at
  all. Because the second hit
  in linear porokeratosis occurs prenatally in a single keratinocyte clone, that
  variant follows the lines of Blaschko as post-zygotic mosaicism, whereas
  disseminated superficial actinic porokeratosis (DSAP) reflects many
  independent, often UV-signature, postnatal second hits. Reduced mevalonate
  flux depletes cholesterol and the non-sterol isoprenoids farnesyl- and
  geranylgeranyl-pyrophosphate while allowing upstream intermediates to
  accumulate, impairing keratinocyte differentiation and protein prenylation and
  increasing apoptosis. This directly motivates topical cholesterol plus
  lovastatin as pathogenesis-directed therapy. Long-standing lesions carry a real
  risk of squamous cell carcinoma, highest in the linear form.
disease_term:
  preferred_term: porokeratosis
  term:
    id: MONDO:0006602
    label: porokeratosis
parents:
- Disorders of keratinization
- hereditary skin disorder

references:
- reference: PMID:38132857
  title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
- reference: PMID:32401728
  title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."

inheritance:
- name: Autosomal dominant inheritance of the germline mevalonate pathway variant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Familial porokeratosis segregates as an autosomal dominant trait, with affected
    individuals carrying a monoallelic germline loss-of-function variant in MVK,
    PMVK, MVD or FDPS. The germline variant alone is not sufficient: clinically
    apparent lesions require an additional somatic event, which explains the
    incomplete, age-dependent penetrance. Expressivity is highly variable even
    within families, and several clinical variants can coexist in one individual.
  evidence:
  - reference: PMID:22983302
    reference_title: "Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly
      inherited epidermal keratinization disorder whose etiology remains unclear.
    explanation: >-
      Establishes the autosomal dominant transmission of the commonest porokeratosis
      variant.
  - reference: PMID:31207227
    reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with disseminated superficial actinic porokeratosis (DSAP) and linear
      porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding
      mevalonate pathway enzymes, such as MVD or MVK.
    explanation: >-
      Confirms the monoallelic germline state that underlies dominant transmission.
- name: Somatic mosaicism of the second hit
  inheritance_term:
    preferred_term: Typified by somatic mosaicism
    term:
      id: HP:0001442
      label: Typified by somatic mosaicism
  description: >-
    Lesional skin is genetically mosaic. In linear porokeratosis a single
    post-zygotic second hit occurring in the embryonic period produces a
    Blaschko-linear clone; in DSAP each lesion carries its own independent
    postnatal second hit. Non-hereditary localized porokeratosis can arise from
    purely somatic biallelic FDFT1 promoter hypermethylation with no germline
    variant at all.
  evidence:
  - reference: PMID:30942823
    reference_title: "Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because linear porokeratosis manifests in the lines of Blaschko representing the
      dorsoventral migration patterns of keratinocyte precursors, it has been suggested
      that postzygotic somatic mutation underlies the disease.
    explanation: >-
      States the mosaic basis of the Blaschko-linear distribution that this inheritance
      block records.
  - reference: PMID:31207227
    reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second hits differed among DSAP lesions but were identical in those of
      congenital LP, suggesting that DSAP is attributable to sporadic postnatal second
      hits and congenital LP to a single second hit in the embryonic period.
    explanation: >-
      Directly distinguishes the mosaic (prenatal, single-clone) mechanism of linear
      porokeratosis from the multi-clone postnatal mechanism of DSAP.

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: RARE
  notes: >-
    Robust population prevalence estimates per 100,000 are not available. Reviews
    consistently characterize porokeratosis as an uncommon group of dermatoses;
    DSAP is the commonest variant and is enriched in fair-skinned populations
    living in high-ultraviolet settings.
  evidence:
  - reference: PMID:32401728
    reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis comprises a group of heterogeneous and uncommon acquired or
      congenital skin diseases of unknown origin characterized by a keratinization
      disorder resulting from abnormal clonal expansion of keratinocytes.
    explanation: >-
      Supports the qualitative rare/uncommon occurrence class in the absence of a
      quantified population rate.

has_subtypes:
- name: DSAP
  display_name: Disseminated superficial actinic porokeratosis
  subtype_term:
    preferred_term: disseminated superficial actinic porokeratosis
    term:
      id: MONDO:0019212
      label: disseminated superficial actinic porokeratosis
  description: >-
    The commonest variant. Multiple small annular macules and papules with a fine
    keratotic rim, distributed symmetrically on sun-exposed extensor limbs, usually
    appearing in the third to fifth decades and often worsening in summer. Each
    lesion carries its own independent postnatal second hit, frequently bearing a
    UV mutational signature, which is why sun protection is a preventive measure.
  genes:
  - preferred_term: MVK
    term:
      id: hgnc:7530
      label: MVK
  - preferred_term: MVD
    term:
      id: hgnc:7529
      label: MVD
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the authors show that DSAP lesions result from second-hit somatic mitotic
      recombination or point mutations with a UV signature, validating the clinical
      observation that DSAP lesions arise upon sun exposed skin
    explanation: >-
      Supports both the actinic distribution and the independent-second-hit basis of
      the DSAP subtype.
- name: Mibelli
  display_name: Porokeratosis of Mibelli
  subtype_term:
    preferred_term: porokeratosis of Mibelli
    term:
      id: MONDO:0019141
      label: porokeratosis of Mibelli
  description: >-
    One or a few slowly enlarging brown annular plaques with a sharply defined,
    prominent keratotic border, often beginning in childhood in hereditary disease.
    Limbs and trunk predominate, but palms, soles, scalp, face, mucosa and genital
    skin can be involved. Because Mibelli plaques are typically large and of long
    standing, they fall into the higher-risk group for malignant transformation
    identified in the pooled case literature.
  evidence:
  - reference: PMID:8624658
    reference_title: "Porokeratosis and cutaneous malignancy. A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Large lesions, those of long-standing duration, and the linear type were at
      greatest risk.
    explanation: >-
      Supports placing large, long-standing Mibelli plaques in the higher-risk group;
      the source does not report a Mibelli-specific rate, hence PARTIAL.
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar
      porokeratosis
    explanation: >-
      Confirms porokeratosis of Mibelli as one of the commonly recognised clinical
      variants of the porokeratosis group.
- name: Linear
  display_name: Linear porokeratosis
  subtype_term:
    preferred_term: linear porokeratosis
    term:
      id: MONDO:0023246
      label: linear porokeratosis
  description: >-
    Congenital or early-onset unilateral streaks of keratotic papules and plaques
    following the lines of Blaschko. It is the mosaic form: a single second hit in
    the embryonic period produces one keratinocyte clone whose descendants trace
    the dorsoventral migration pattern of keratinocyte precursors. Linear
    porokeratosis carries the highest reported risk of malignant transformation.
  genes:
  - preferred_term: PMVK
    term:
      id: hgnc:9141
      label: PMVK
  - preferred_term: MVD
    term:
      id: hgnc:7529
      label: MVD
  evidence:
  - reference: PMID:30942823
    reference_title: "Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that linear porokeratosis is associated with the presence of
      second-hit postzygotic mutations in the genes that encode enzymes within the
      mevalonate biosynthesis pathway
    explanation: >-
      Establishes the mosaic, second-hit genetic basis of the linear subtype and its
      PMVK/MVD gene assignment.
- name: PPPD
  display_name: Porokeratosis palmaris et plantaris disseminata
  subtype_term:
    preferred_term: porokeratosis plantaris palmaris et disseminata
    term:
      id: MONDO:0008291
      label: porokeratosis plantaris palmaris et disseminata
  description: >-
    Small keratotic papules that begin on the palms and soles, typically in
    adolescence or early adult life, and later become generalized to involve
    non-sun-exposed skin. Lesions may be pruritic or painful; nail dystrophy is an
    uncommon complication.
  evidence:
  - reference: PMID:31449901
    reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 with porokeratosis palmaris et plantaris disseminata
    explanation: >-
      Documents PPPD as a distinct, genotyped clinical variant in a porokeratosis
      patient series.
- name: Punctate
  display_name: Punctate porokeratosis (punctate palmoplantar porokeratosis)
  description: >-
    A palmoplantar variant consisting of numerous tiny, seed-like keratotic plugs
    confined to the palms and soles, each of which is a minute cornoid lamella. It
    is grouped with PPPD under palmoplantar porokeratosis. No distinct non-obsolete
    MONDO class was identified for the punctate variant at curation time, so no
    subtype_term is bound.
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      palmoplantar porokeratosis (including porokeratosis palmaris et plantaris
      disseminata and punctate porokeratosis)
    explanation: >-
      Confirms punctate porokeratosis as a recognized palmoplantar variant of the
      porokeratosis group.
- name: DSP
  display_name: Disseminated superficial porokeratosis
  description: >-
    The non-actinic counterpart of DSAP: disseminated lesions involving both
    sun-exposed and covered skin, typically with earlier (often childhood) onset.
    Distinguished from DSAP by distribution rather than by a different mechanism.
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      disseminated superficial actinic porokeratosis, disseminated superficial
      porokeratosis, porokeratosis of Mibelli
    explanation: >-
      Lists disseminated superficial porokeratosis as a recognised variant distinct from
      DSAP.
- name: Verrucous
  display_name: Verrucous porokeratosis (porokeratosis ptychotropica / genitogluteal)
  description: >-
    Verrucous, often intensely pruritic or burning plaques of the genitogluteal,
    perianal and intertriginous skin, expanding centrifugally over years. Histology
    typically shows multiple cornoid lamellae with papillomatosis and psoriasiform
    hyperplasia. It is notably treatment-resistant.
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      verrucous porokeratosis (also known as genitogluteal porokeratosis)
    explanation: >-
      Establishes verrucous/genitogluteal porokeratosis as a recognised clinical variant.
- name: Follicular
  display_name: Follicular porokeratosis
  description: >-
    A rare folliculocentric variant in which the cornoid lamella forms within hair
    follicle infundibula, producing keratotic follicular plugs. Its genetic basis is
    less well characterised than that of the classical variants.
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Commonly recognised variants include disseminated superficial actinic porokeratosis,
      disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar
      porokeratosis (including porokeratosis palmaris et plantaris disseminata and
      punctate porokeratosis), linear porokeratosis, verrucous porokeratosis (also
      known as genitogluteal porokeratosis), follicular porokeratosis and porokeratoma.
    explanation: >-
      Lists follicular porokeratosis among the recognised variants.
- name: Porokeratoma
  display_name: Porokeratoma
  description: >-
    A usually solitary keratotic plaque or nodule that lacks the classic annular rim
    but shows cornoid lamellae histologically, typically presenting in later adult
    life. It is the variant most easily mistaken for a keratinocyte carcinoma
    clinically.
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Commonly recognised variants include disseminated superficial actinic porokeratosis,
      disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar
      porokeratosis (including porokeratosis palmaris et plantaris disseminata and
      punctate porokeratosis), linear porokeratosis, verrucous porokeratosis (also
      known as genitogluteal porokeratosis), follicular porokeratosis and porokeratoma.
    explanation: >-
      Lists porokeratoma among the recognised variants of the porokeratosis group.
- name: Eruptive
  display_name: Eruptive / immunosuppression-associated porokeratosis
  description: >-
    Sudden appearance of numerous inflammatory, often pruritic porokeratotic
    lesions in the setting of iatrogenic or disease-related immunosuppression -
    solid-organ or haematopoietic stem cell transplantation, HIV infection,
    haematologic malignancy, or immunosuppressive drug therapy. Lesions may
    partially regress when the immunosuppressive state is corrected. This is an
    acquired, immunologically gated presentation rather than a distinct genetic
    entity.
  evidence:
  - reference: PMID:34418147
    reference_title: "Localized eruptive porokeratosis in pediatric patients following treatment of acute leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we discuss a single-institution case series of three children who developed
      porokeratosis following hematopoietic stem cell transplantation for acute leukemia,
      and we propose that this presentation be termed localized eruptive porokeratosis (LEP).
    explanation: >-
      Documents eruptive porokeratosis arising after transplant-associated
      immunosuppression.

pathophysiology:
- name: Germline Heterozygous Mevalonate Pathway Variant
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Affected individuals carry a monoallelic germline loss-of-function variant in
    one of four mevalonate-pathway genes - MVK (mevalonate kinase), PMVK
    (phosphomevalonate kinase), MVD (mevalonate diphosphate decarboxylase) or FDPS
    (farnesyl diphosphate synthase). Heterozygosity alone leaves roughly half-normal
    enzyme activity in the epidermis and does not by itself produce a lesion; it
    establishes a field of keratinocytes primed for a second hit. At least one such
    variant was found in 98% of familial and 73% of sporadic index patients in the
    defining cohort.
  genes:
  - preferred_term: MVK
    term:
      id: hgnc:7530
      label: MVK
  - preferred_term: PMVK
    term:
      id: hgnc:9141
      label: PMVK
  - preferred_term: MVD
    term:
      id: hgnc:7529
      label: MVD
  - preferred_term: FDPS
    term:
      id: hgnc:3631
      label: FDPS
  molecular_functions:
  - preferred_term: mevalonate kinase activity
    term:
      id: GO:0004496
      label: mevalonate kinase activity
    modifier: DECREASED
  - preferred_term: phosphomevalonate kinase activity
    term:
      id: GO:0004631
      label: phosphomevalonate kinase activity
    modifier: DECREASED
  - preferred_term: diphosphomevalonate decarboxylase activity
    term:
      id: GO:0004163
      label: diphosphomevalonate decarboxylase activity
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:26202976
    reference_title: "Genomic variations of the mevalonate pathway in porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we performed massively parallel sequencing and exonic CNV screening of 12
      isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and
      identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition
      to MVK in the mevalonate pathway
    explanation: >-
      Establishes the four canonical causal genes named in this node.
  - reference: PMID:26202976
    reference_title: "Genomic variations of the mevalonate pathway in porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At least one mutation in one of the four genes in the mevalonate pathway was found
      in 60 (98%) familial and 53 (73%) sporadic patients
    explanation: >-
      Quantifies the diagnostic yield of the four-gene germline lesion.
  downstream:
  - target: Somatic Second Hit in Lesional Keratinocytes
    causal_link_type: DIRECT
    description: >-
      The germline heterozygous allele is the necessary substrate on which a somatic
      event in the remaining wild-type allele produces biallelic deficiency.
    evidence:
    - reference: PMID:31207227
      reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with disseminated superficial actinic porokeratosis (DSAP) and linear
        porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding
        mevalonate pathway enzymes, such as MVD or MVK.
      explanation: >-
        Places the monoallelic germline lesion upstream of the somatic second hit.

- name: Somatic Second Hit in Lesional Keratinocytes
  biological_scale: MOLECULAR
  role: driver
  description: >-
    A somatic event inactivates the remaining wild-type allele within a single
    epidermal keratinocyte, converting the heterozygous state to biallelic
    deficiency. The two dominant mechanisms are copy-neutral loss of heterozygosity
    from somatic mitotic (homologous) recombination and C>T transition point
    mutations bearing a UV signature. Somatic second hits were detected in 81% of
    patients in a large contemporary cohort, with gene-specific patterns
    (chromosome 12-wide copy-neutral LOH in MVK disease, 16q in MVD disease). Timing
    determines the clinical variant: an embryonic second hit gives a single
    Blaschko-linear clone (linear porokeratosis) whereas many independent postnatal
    second hits give the disseminated lesions of DSAP.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: keratinocyte stem cell
    term:
      id: CL:0002337
      label: keratinocyte stem cell
  biological_processes:
  - preferred_term: response to UV
    term:
      id: GO:0009411
      label: response to UV
  evidence:
  - reference: PMID:31207227
    reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we showed that each skin lesion of DSAP exhibited an individual second hit genetic
      change in the wild-type allele of the corresponding gene specifically in the
      epidermis, indicating that a postnatal second hit triggering biallelic deficiency
      of the gene is required for porokeratosis to develop
    explanation: >-
      The primary evidence that a somatic second hit is required, not merely associated.
  - reference: PMID:31207227
    reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most skin lesions exhibited one of two principal second hits, either somatic
      homologous recombinations rendering the monoallelic mutation biallelic or C>T
      transition mutations in the wild-type allele.
    explanation: >-
      Documents the two mechanisms of the second hit described in this node.
  - reference: PMID:41240373
    reference_title: "Germline and somatic second-hit changes in porokeratosis: comprehensive variant spectrum and genotype-phenotype correlation analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Somatic second-hit changes were identified in 81% (n = 55/68) of patients, mostly
      copy-neutral loss of heterozygosity (CN-LOH) with gene subtype specificity: most
      MVK-related porokeratosis showed chromosome 12-wide CN-LOH, while most MVD-related
      porokeratosis had 16q CN-LOH.
    explanation: >-
      Quantifies second-hit frequency and the gene-specific CN-LOH patterns.
  downstream:
  - target: Biallelic Mevalonate Pathway Enzyme Deficiency
    causal_link_type: DIRECT
    description: >-
      Loss of the wild-type allele leaves the keratinocyte with no functional copy of
      the affected mevalonate-pathway enzyme.
    evidence:
    - reference: PMID:31207227
      reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a postnatal second hit triggering biallelic deficiency of the gene is required for
        porokeratosis to develop
      explanation: >-
        Names biallelic deficiency as the direct consequence of the second hit.
  - target: Photodistribution of Lesions on Sun-Exposed Skin
    causal_link_type: DIRECT
    description: >-
      Because the second hit in DSAP is frequently a UV-signature C>T transition, new
      lesions appear preferentially where UV exposure is greatest.
    evidence:
    - reference: PMID:31753123
      reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the authors show that DSAP lesions result from second-hit somatic mitotic
        recombination or point mutations with a UV signature, validating the clinical
        observation that DSAP lesions arise upon sun exposed skin
      explanation: >-
        Directly ties the UV-signature second hit to the sun-exposed lesion distribution.

- name: Somatic FDFT1 Promoter Hypermethylation
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The alternative, non-hereditary entry point into the same pathway lesion. In
    solitary or linearly arranged localized porokeratosis, FDFT1 (squalene synthase)
    is silenced epigenetically rather than mutationally: lesions carry somatic
    biallelic promoter hypermethylation, or mono-allelic hypermethylation together
    with a somatic genetic alteration on the opposite allele. Gene-specific
    hypermethylation is detectable in morphologically normal epidermis immediately
    adjacent to lesions but not distal to them, indicating an asymptomatic
    epigenetically mosaic field that predisposes particular skin areas.
  genes:
  - preferred_term: FDFT1
    term:
      id: hgnc:3629
      label: FDFT1
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:38653249
    reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we identified non-hereditary porokeratosis associated with epigenetic
      silencing of FDFT1, another gene in the mevalonate pathway.
    explanation: >-
      Establishes epigenetic silencing of FDFT1 as an independent, non-germline cause.
  - reference: PMID:38653249
    reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In some individuals with the localized form, gene-specific promoter
      hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent
      to methylation-related lesions but not distal to these lesions, suggesting that
      asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to
      the disease.
    explanation: >-
      Supports the predisposed epigenetically mosaic field described in this node.
  downstream:
  - target: Biallelic Mevalonate Pathway Enzyme Deficiency
    causal_link_type: DIRECT
    description: >-
      Biallelic promoter hypermethylation abolishes FDFT1 expression in the affected
      clone, producing the same functional pathway block as a biallelic coding lesion.
    evidence:
    - reference: PMID:38653249
      reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        lesions of the solitary or linearly arranged localized form had somatic bi-allelic
        promoter hypermethylation or mono-allelic promoter hypermethylation with somatic
        genetic alterations on opposite alleles in FDFT1, indicating non-hereditary
        porokeratosis
      explanation: >-
        Documents the biallelic silencing configuration that produces the enzyme block.

- name: Biallelic Mevalonate Pathway Enzyme Deficiency
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    The doubly hit keratinocyte has effectively no activity of the affected enzyme,
    so flux through the mevalonate/isoprenoid pathway falls. A parallel,
    non-hereditary route to the same state exists: somatic biallelic (or
    mono-allelic plus somatic variant) promoter hypermethylation of FDFT1, the
    squalene synthase gene immediately downstream of FDPS, silences that enzyme in
    localized porokeratosis with no germline variant.
  genes:
  - preferred_term: FDFT1
    term:
      id: hgnc:3629
      label: FDFT1
  biological_processes:
  - preferred_term: isoprenoid biosynthetic process
    term:
      id: GO:0008299
      label: isoprenoid biosynthetic process
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:38653249
    reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      lesions of the solitary or linearly arranged localized form had somatic bi-allelic
      promoter hypermethylation or mono-allelic promoter hypermethylation with somatic
      genetic alterations on opposite alleles in FDFT1, indicating non-hereditary
      porokeratosis
    explanation: >-
      Establishes the epigenetic route to the same biallelic pathway-enzyme deficiency.
  - reference: PMID:38653249
    reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in
      the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring
      germline and lesion-specific somatic variants on opposite alleles.
    explanation: >-
      Restates the trans (opposite-allele) configuration that defines biallelic deficiency.
  downstream:
  - target: Cholesterol and Non-Sterol Isoprenoid Depletion
    causal_link_type: DIRECT
    description: >-
      Loss of enzyme activity blocks the pathway, starving the clone of cholesterol and
      the non-sterol isoprenoid end-products.
    evidence:
    - reference: PMID:38132857
      reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This structure develops as a consequence of a defective isoprenoid pathway,
        critical for cholesterol synthesis.
      explanation: >-
        Links the pathway defect to the downstream metabolic consequence.
  - target: Mevalonate Pathway Intermediate Accumulation
    causal_link_type: DIRECT
    description: >-
      The same enzymatic block causes substrate and proximal intermediates to build up
      behind it.
    evidence:
    - reference: PMID:33005717
      reference_title: "Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Enzyme deficiency is thought to lead to an insufficiency of the end product of the
        pathway, cholesterol, and the accumulation of upstream metabolites.
      explanation: >-
        States that enzyme deficiency causes upstream metabolite accumulation.

- name: Cholesterol and Non-Sterol Isoprenoid Depletion
  biological_scale: MOLECULAR
  role: mediator
  description: >-
    The end-product arm of the metabolic lesion. Flux through the pathway falls, so
    the clone is starved of cholesterol - an essential membrane constituent and a
    major component of the extracellular lipid matrix of the stratum corneum - and,
    for blocks proximal to the prenyl-donor branch point, of the non-sterol
    isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP).
    Which species are depleted depends on where the block sits: an MVK, PMVK or MVD
    block starves both the sterol and non-sterol branches, whereas an FDFT1 (squalene
    synthase) block lies below the branch point and depletes cholesterol only, with
    FPP spared or increased. Ultrastructurally the cholesterol deficit shows up as a
    reduced number of lamellar bodies and disrupted lamellar bilayer architecture in
    keratinocytes beneath the cornoid lamella. This is the arm that topical
    cholesterol replacement addresses.
  biological_processes:
  - preferred_term: cholesterol biosynthetic process
    term:
      id: GO:0006695
      label: cholesterol biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: cholesterol
    term:
      id: CHEBI:16113
      label: cholesterol
    modifier: DECREASED
  - preferred_term: geranylgeranyl pyrophosphate (GGPP)
    term:
      id: CHEBI:48861
      label: 2-trans,6-trans,10-trans-geranylgeranyl diphosphate
    modifier: DECREASED
  - preferred_term: farnesyl pyrophosphate (FPP)
    term:
      id: CHEBI:50277
      label: farnesyl diphosphate
    modifier: DECREASED
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IPP is the precursor of the sterol isoprenoids (cholesterol and steroid hormones)
      and the nonsterol isoprenoids (FPP, GGPP, dolichols, and ubiquitone (coenzyme Q)).
    explanation: >-
      Identifies the sterol and non-sterol products depleted downstream of the block.
  - reference: PMID:31449901
    reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cholesterol, one of the end-products of the mevalonate pathway, is a key component
      of the extracellular lipid matrix in the stratum corneum, playing an essential role
      in providing and maintaining skin barrier function.
    explanation: >-
      Establishes the barrier role of the depleted end-product.
  - reference: PMID:31449901
    reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Decreased number of lamellar bodies and disrupted lamellar bilayer architecture have
      been demonstrated in keratinocytes beneath the cornoid lamella in porokeratosis
    explanation: >-
      Supplies the lesion-localized ultrastructural correlate of cholesterol depletion.
  notes: >-
    The prenylation edge below applies to blocks proximal to FPP synthesis (MVK, PMVK,
    MVD, FDPS). It does not apply to the FDFT1 route, where the block is downstream of
    the prenyl-donor branch point and prenyl-donor supply is preserved.
  downstream:
  - target: Impaired Protein Prenylation and Geranylgeranylation
    causal_link_type: DIRECT
    description: >-
      FPP and GGPP are the lipid donors for protein prenylation; their depletion
      directly reduces prenylation of small GTPases and nuclear lamins. This edge holds
      for the MVK/PMVK/MVD/FDPS blocks, not for the distal FDFT1 block.
    evidence:
    - reference: PMID:32256770
      reference_title: "Effects of mevalonate kinase interference on cell differentiation, apoptosis, prenylation and geranylgeranylation of human keratinocytes are attenuated by farnesyl pyrophosphate or geranylgeranyl pyrophosphate."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        FPP or GGPP reversed MVK interference-induced decrease in geranylgeranylation
        levels of lamin A, HRAS, KRAS, NRAS, Rho E, Rho B, Rho A, RAC1 and cdc42.
      explanation: >-
        The rescue experiment demonstrates that isoprenoid depletion is what causes the
        prenylation defect.
  - target: Aberrant Keratinocyte Differentiation and Apoptosis
    causal_link_type: DIRECT
    description: >-
      Cholesterol insufficiency perturbs keratinocyte differentiation and lowers the
      threshold for apoptosis.
    evidence:
    - reference: PMID:31449901
      reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Depletion of cholesterol has been reported to result in increased sensitivity of
        keratinocytes to stimuli driving apoptosis.
      explanation: >-
        Directly links the end-product deficit to the apoptosis phenotype.
    - reference: PMID:32256770
      reference_title: "Effects of mevalonate kinase interference on cell differentiation, apoptosis, prenylation and geranylgeranylation of human keratinocytes are attenuated by farnesyl pyrophosphate or geranylgeranyl pyrophosphate."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        MVK interference decreases the expression of differentiation markers, increases
        apoptosis, and decreases protein prenylation and geranylgeranylation levels in
        keratinocytes.
      explanation: >-
        Demonstrates that loss of mevalonate-pathway flux directly produces the
        differentiation and apoptosis phenotype.

- name: Mevalonate Pathway Intermediate Accumulation
  biological_scale: MOLECULAR
  role: mediator
  description: >-
    The substrate arm of the metabolic lesion, and the deliberate complement of the
    depletion node. Intermediates upstream of the enzymatic block - mevalonate above
    an MVK block, and the corresponding proximal species for the other enzymes - build
    up and are potentially toxic and pro-inflammatory. Because inhibiting HMG-CoA
    reductase with a topical statin shuts off the supply of these intermediates
    without replacing any end-product, the observation that statin monotherapy is as
    effective as the cholesterol combination argues that this arm, not the depletion
    arm, is the dominant driver of the lesion.
  chemical_entities:
  - preferred_term: mevalonate
    term:
      id: CHEBI:25350
      label: mevalonate
    modifier: INCREASED
  evidence:
  - reference: PMID:33005717
    reference_title: "Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Enzyme deficiency is thought to lead to an insufficiency of the end product of the
      pathway, cholesterol, and the accumulation of upstream metabolites.
    explanation: >-
      Names accumulation of upstream metabolites as the second arm of the metabolic lesion.
  - reference: PMID:33005717
    reference_title: "Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the results in our patient suggest that the accumulation of intermediates in the
      mevalonate synthesis pathway, not cholesterol deficiency, is the primary mechanism
      driving disseminated superficial actinic porokeratosis lesions
    explanation: >-
      Supports the primacy of this arm; the inference rests on a single patient, hence
      PARTIAL.
  downstream:
  - target: Perilesional Inflammatory Infiltrate
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mevalonate accumulation activating the innate immune response
    - Increased keratinocyte cytokine production
    description: >-
      Accumulated mevalonate-pathway intermediates can activate innate immunity and
      increase cytokine production, one proposed route from the metabolic block to
      the inflammatory component of the lesion.
    evidence:
    - reference: PMID:33005717
      reference_title: "Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Evidence has demonstrated that mevalonate accumulation can result in the activation
        of the innate immune response and increased cytokine production.
      explanation: >-
        The authors present this as a suggested mechanism in porokeratosis rather than a
        demonstrated one, so the edge is PARTIAL.
  - target: Aberrant Keratinocyte Differentiation and Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Accumulated proximal intermediates are held to be directly toxic to the
      keratinocyte, but the molecular species and the route to the differentiation and
      apoptosis phenotype have not been established.
    evidence:
    - reference: PMID:31449901
      reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the porokeratosis phenotype may reflect both the deficiency of metabolic pathway
        end products and the accumulation of toxic metabolites synthesized proximally in
        the pathway
      explanation: >-
        The authors frame the toxic-metabolite contribution as a possibility, hence PARTIAL.

- name: Impaired Protein Prenylation and Geranylgeranylation
  biological_scale: MOLECULAR
  role: mediator
  description: >-
    Depletion of FPP and GGPP reduces post-translational lipid modification of small
    GTPases (RAS, RHOA, RHOB, RAC1, CDC42) and of nuclear lamin A. Because these
    proteins require prenylation for correct membrane or nuclear-envelope
    localization and act as switches in growth, differentiation and cytoskeletal
    signalling, their mislocalization is the proximate molecular explanation for the
    disordered epidermal maturation seen in porokeratosis.
  biological_processes:
  - preferred_term: protein geranylgeranylation
    term:
      id: GO:0018344
      label: protein geranylgeranylation
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:32256770
    reference_title: "Effects of mevalonate kinase interference on cell differentiation, apoptosis, prenylation and geranylgeranylation of human keratinocytes are attenuated by farnesyl pyrophosphate or geranylgeranyl pyrophosphate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MVK interference decreases the expression of differentiation markers, increases
      apoptosis, and decreases protein prenylation and geranylgeranylation levels in
      keratinocytes.
    explanation: >-
      Direct experimental demonstration in human keratinocytes that loss of MVK reduces
      prenylation and geranylgeranylation.
  downstream:
  - target: Aberrant Keratinocyte Differentiation and Apoptosis
    causal_link_type: DIRECT
    description: >-
      Loss of prenylated small-GTPase and lamin signalling drives the differentiation
      and apoptosis phenotype; supplying FPP or GGPP rescues both.
    evidence:
    - reference: PMID:32256770
      reference_title: "Effects of mevalonate kinase interference on cell differentiation, apoptosis, prenylation and geranylgeranylation of human keratinocytes are attenuated by farnesyl pyrophosphate or geranylgeranyl pyrophosphate."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These changes are attenuated by FPP or GGPP.
      explanation: >-
        Rescue by the missing isoprenoids establishes the direction of this causal edge.

- name: Aberrant Keratinocyte Differentiation and Apoptosis
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The biallelically deficient keratinocyte shows reduced expression of terminal
    differentiation markers (keratin 1, involucrin), premature and dyskeratotic
    maturation, and increased apoptosis. MVK also normally protects keratinocytes
    from UVA-induced apoptosis and participates in calcium-induced differentiation,
    so its loss both disorders maturation and removes a UV-stress safeguard,
    coupling the cellular defect to the actinic distribution of DSAP.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: ABNORMAL
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  - preferred_term: cornification
    term:
      id: GO:0070268
      label: cornification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32256770
    reference_title: "Effects of mevalonate kinase interference on cell differentiation, apoptosis, prenylation and geranylgeranylation of human keratinocytes are attenuated by farnesyl pyrophosphate or geranylgeranyl pyrophosphate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MVK interference decreases the expression of differentiation markers, increases
      apoptosis, and decreases protein prenylation and geranylgeranylation levels in
      keratinocytes.
    explanation: >-
      Direct in vitro evidence for the differentiation and apoptosis phenotype.
  - reference: PMID:22983302
    reference_title: "Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our functional studies in cultured primary keratinocytes suggest that MVK has a role
      in regulating calcium-induced keratinocyte differentiation and could protect
      keratinocytes from apoptosis induced by type A ultraviolet radiation.
    explanation: >-
      Links MVK loss to both the differentiation defect and loss of UVA-apoptosis
      protection.
  downstream:
  - target: Clonal Expansion of Second-Hit Keratinocytes
    causal_link_type: DIRECT
    description: >-
      The abnormal clone behaves as a benign intraepidermal neoplasm and expands
      centrifugally within the epidermis.
    evidence:
    - reference: PMID:31207227
      reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        DSAP is therefore a benign intraepidermal neoplasia, which can be included in the
        genetic tumor disorders explicable by Knudson's two-hit hypothesis.
      explanation: >-
        Frames the metabolically abnormal clone as a proliferating benign intraepidermal
        neoplasm.

- name: Clonal Expansion of Second-Hit Keratinocytes
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    The single second-hit keratinocyte and its descendants expand laterally within
    the epidermis. Sampling across an annular DSAP lesion shows that the central
    epidermis is composed almost entirely of second-hit cells while the peripheral
    annular ring is a mixture of second-hit and naive (single-mutant) keratinocytes -
    the spatial signature of an outwardly expanding clone. Kubo and colleagues
    therefore classify DSAP as a benign intraepidermal neoplasia explicable by
    Knudson's two-hit hypothesis.
  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
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:31207227
    reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the characteristic annular skin lesions of DSAP, the central epidermis featured
      mostly second hit keratinocytes, and that of the annular ring featured a mixture of
      such cells and naïve keratinocytes, implying that each lesion reflects the clonal
      expansion of single second hit keratinocytes.
    explanation: >-
      The direct spatial evidence for centrifugal clonal expansion modelled by this node.
  - reference: PMID:31207227
    reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DSAP is therefore a benign intraepidermal neoplasia, which can be included in the
      genetic tumor disorders explicable by Knudson's two-hit hypothesis.
    explanation: >-
      Explicitly frames the lesion as a two-hit clonal neoplasm.
  - reference: PMID:38653249
    reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FDFT1 localization was uniformly diminished within the lesions, and lesion-derived
      keratinocytes showed cholesterol dependence for cell growth and altered expression
      of genes related to cell-cycle and epidermal development, confirming that lesions
      form by clonal expansion of FDFT1-deficient keratinocytes.
    explanation: >-
      Independent confirmation of clonal expansion, via the FDFT1 epigenetic route.
  downstream:
  - target: Cornoid Lamella Formation
    causal_link_type: DIRECT
    description: >-
      The boundary between the expanding mutant clone and surrounding naive epidermis
      is where the parakeratotic column forms.
    evidence:
    - reference: PMID:31753123
      reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        They hypothesized that a cornoid lamella forms due to the mixture of naïve and
        second-hit cells
      explanation: >-
        The clone-boundary origin of the cornoid lamella is an explicitly stated
        hypothesis requiring experimental validation, so this edge is PARTIAL.
  - target: Central Cutaneous Atrophy
    causal_link_type: DIRECT
    description: >-
      The epidermis of the lesion centre, composed almost entirely of second-hit
      keratinocytes, is atrophic.
    evidence:
    - reference: PMID:31207227
      reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the central epidermis featured mostly second hit keratinocytes
      explanation: >-
        Establishes that the atrophic lesion centre is composed of the second-hit clone.
  - target: Malignant Transformation to Keratinocyte Carcinoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Continued ultraviolet mutagenesis within the already-clonal keratinocyte field
    - Accumulation of additional oncogenic driver events over years to decades
    - Reduced immune surveillance in immunosuppressed patients
    description: >-
      A minority of long-standing lesions progress from benign intraepidermal
      neoplasia to invasive keratinocyte carcinoma.
    evidence:
    - reference: PMID:8624658
      reference_title: "Porokeratosis and cutaneous malignancy. A review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Large lesions, those of long-standing duration, and the linear type were at
        greatest risk.
      explanation: >-
        Identifies lesion size and duration - i.e. extent of clonal expansion - as the
        determinants of transformation risk.

- name: Cornoid Lamella Formation
  biological_scale: TISSUE
  role: consequence
  description: >-
    The diagnostic lesion of porokeratosis: a vertical column of parakeratotic
    (nucleus-retaining) corneocytes rising through the stratum corneum, overlying a
    diminished or absent granular layer and dyskeratotic, vacuolated keratinocytes.
    Clinically it corresponds to the raised, ridge-like keratotic border at the
    advancing edge of the plaque, with the central skin left atrophic. An
    inflammatory infiltrate typically sits beneath the lamella.
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Porokeratosis is a phenotypically heterogeneous disorder characterized by the
      histopathological feature cornoid lamella, which is a vertical column of parakeratosis
      situated above dyskeratotic cells within the granular layer
    explanation: >-
      Defines the cornoid lamella exactly as modelled here.
  - reference: PMID:29722423
    reference_title: "Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis comprises heterogeneous keratinization disorders that are characterized
      by one or more atrophic patches surrounded by a ridge-like cornoid lamella.
    explanation: >-
      Connects the histological column to the clinical ridge-and-atrophic-centre
      morphology.
  downstream:
  - target: Porokeratotic Annular Plaque with Raised Keratotic Border
    causal_link_type: DIRECT
    description: >-
      The cornoid lamella is the histological substrate of the clinically visible
      raised annular rim.
    evidence:
    - reference: PMID:29722423
      reference_title: "Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        one or more atrophic patches surrounded by a ridge-like cornoid lamella
      explanation: >-
        Explicitly equates the clinical ridge with the cornoid lamella.
  - target: Hyperkeratosis of the Lesional Rim
    causal_link_type: DIRECT
    description: >-
      Retention of nucleated corneocytes in the lamella thickens the stratum corneum
      at the lesion edge.
    evidence:
    - reference: PMID:29722423
      reference_title: "Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        one or more atrophic patches surrounded by a ridge-like cornoid lamella
      explanation: >-
        The lamella is described as a keratotic ridge, i.e. the hyperkeratotic rim.
  - target: Palmoplantar Keratotic Papules
    causal_link_type: DIRECT
    description: >-
      In palmoplantar variants each keratotic papule is itself a minute cornoid
      lamella.
    evidence:
    - reference: PMID:38132857
      reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        palmoplantar porokeratosis (including porokeratosis palmaris et plantaris
        disseminata and punctate porokeratosis)
      explanation: >-
        Establishes the palmoplantar variants as members of the cornoid-lamella-defined
        group; the snippet does not describe the per-papule lamella, hence PARTIAL.
  - target: Perilesional Inflammatory Infiltrate
    causal_link_type: DIRECT
    description: >-
      The cornoid lamella has been proposed to induce the inflammatory reaction that
      sits immediately beneath it. This is an explicitly hypothesized relationship, not
      an established one.
    evidence:
    - reference: PMID:31753123
      reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        since an inflammatory infiltrate was located beneath the cornoid lamella, they
        suggested that the cornoid lamella might induce the inflammatory reaction
      explanation: >-
        The commentary states this as a suggestion requiring validation, hence PARTIAL.

- name: Perilesional Inflammatory Infiltrate
  biological_scale: TISSUE
  role: consequence
  description: >-
    A band-like lymphocytic infiltrate sits in the papillary dermis beneath the
    cornoid lamella and throughout lesional skin. It has been proposed both as a
    reaction induced by the cornoid lamella and as a constraint limiting further
    lateral expansion of the mutant clone; the mechanism is not settled. Accumulated
    mevalonate can activate innate immune responses and increase cytokine production,
    which is one proposed link between the metabolic block and the inflammatory
    component, and one reason topical statins may act as anti-inflammatory agents.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      since an inflammatory infiltrate was located beneath the cornoid lamella, they
      suggested that the cornoid lamella might induce the inflammatory reaction
    explanation: >-
      Documents the infiltrate and marks its causal relationship to the cornoid lamella
      as hypothesized rather than established.
  - reference: PMID:33005717
    reference_title: "Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Evidence has demonstrated that mevalonate accumulation can result in the activation
      of the innate immune response and increased cytokine production.
    explanation: >-
      Supplies the proposed metabolic-to-inflammatory link; the authors present it as a
      suggested rather than demonstrated mechanism in porokeratosis.
  downstream:
  - target: Pruritus
    causal_link_type: DIRECT
    description: >-
      The lesional inflammatory infiltrate underlies the itch reported by a substantial
      minority of patients, and is most prominent in the eruptive and
      verrucous/ptychotropic variants where pruritus dominates.
    evidence:
    - reference: PMID:41606785
      reference_title: "Topical statins in the treatment of porokeratosis: a systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Porokeratosis is a chronic disorder of keratinization associated with significant
        morbidity and no spontaneous resolution.
      explanation: >-
        Supports persistent symptomatic morbidity; the inflammatory origin of pruritus is
        inferred rather than directly quoted, hence PARTIAL.

- name: Malignant Transformation to Keratinocyte Carcinoma
  biological_scale: TISSUE
  role: outcome
  description: >-
    Porokeratosis is a premalignant condition. In a review of 281 reported cases,
    7.5% harboured a malignancy arising within a porokeratotic lesion, most commonly
    cutaneous squamous cell carcinoma, with basal cell carcinoma next. Large lesions,
    lesions of long standing and the linear variant carry the greatest risk; in a
    contemporary genotype-phenotype cohort every patient with porokeratosis plus
    non-melanoma skin cancer carried an MVD variant. Because transformation can occur
    decades after onset, long-term surveillance rather than short-term clearance is
    the central management principle.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: PMID:8624658
    reference_title: "Porokeratosis and cutaneous malignancy. A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-one (7.5%) of 281 cases reported revealed a malignancy arising within
      porokeratosis. Large lesions, those of long-standing duration, and the linear type
      were at greatest risk.
    explanation: >-
      Quantifies the malignant risk and identifies the linear variant as highest risk.
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Porokeratosis is considered a premalignant condition, and higher rates of skin cancer
      have been described in linear and large plaques, with the most common malignancy being
      squamous cell carcinoma
    explanation: >-
      Independent confirmation that SCC is the dominant malignancy and linear disease the
      highest-risk variant.
  - reference: PMID:41240373
    reference_title: "Germline and somatic second-hit changes in porokeratosis: comprehensive variant spectrum and genotype-phenotype correlation analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      100% (n = 6/6) of patients with porokeratosis plus nonmelanoma skin cancer and 71%
      (n = 17/24) of those with linear porokeratosis (LP) harboured MVD variants
    explanation: >-
      Supports the MVD genotype association with skin cancer and with linear disease.
  - reference: PMID:32401728
    reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many authors consider it to be a premalignant condition because of the potential
      for malignant transformation to squamous cell or basal cell carcinoma.
    explanation: >-
      Sources both tumour types named in this node, including basal cell carcinoma.
  downstream:
  - target: Basal Cell Carcinoma Arising in a Lesion
    causal_link_type: DIRECT
    description: >-
      Basal cell carcinoma is the second-commonest malignancy arising within a
      porokeratotic lesion.
    evidence:
    - reference: PMID:32401728
      reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the potential for malignant transformation to squamous cell or basal cell
        carcinoma
      explanation: >-
        Names basal cell carcinoma as a transformation outcome.
  - target: Cutaneous Squamous Cell Carcinoma Arising in a Lesion
    causal_link_type: DIRECT
    description: >-
      Squamous cell carcinoma is the commonest malignancy arising by this route.
    evidence:
    - reference: PMID:31753123
      reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        with the most common malignancy being squamous cell carcinoma
      explanation: >-
        Names SCC as the dominant transformation outcome.

phenotypes:
- category: Cutaneous
  name: Porokeratotic Annular Plaque with Raised Keratotic Border
  description: >-
    The defining clinical lesion: one or more atrophic patches surrounded by a
    sharply demarcated, ridge-like hyperkeratotic border that corresponds to the
    cornoid lamella. Lesions expand centrifugally over years.
  phenotype_term:
    preferred_term: Porokeratosis
    term:
      id: HP:0200044
      label: Porokeratosis
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:29722423
    reference_title: "Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis comprises heterogeneous keratinization disorders that are characterized
      by one or more atrophic patches surrounded by a ridge-like cornoid lamella.
    explanation: >-
      The lesion is definitional for the disease, supporting VERY_FREQUENT and the
      diagnostic flag.

- category: Cutaneous
  name: Hyperkeratosis of the Lesional Rim
  description: >-
    Thickening of the stratum corneum forming the palpable keratotic ridge at the
    advancing lesion edge; parakeratotic within the cornoid lamella itself.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a heterogeneous group of keratinising disorders characterised by the
      presence of particular microscopic structural changes, namely the presence of the
      cornoid lamella.
    explanation: >-
      Supports the keratinizing/hyperkeratotic nature of the lesion border.

- category: Cutaneous
  name: Central Cutaneous Atrophy
  description: >-
    The skin enclosed by the advancing keratotic ring is thinned and atrophic,
    sometimes anhidrotic and hairless, reflecting the abnormal epidermis of the
    expanded mutant clone.
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:29722423
    reference_title: "Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by one or more atrophic patches surrounded by a ridge-like cornoid
      lamella
    explanation: >-
      Names the atrophic centre of the lesion.

- category: Cutaneous
  name: Photodistribution of Lesions on Sun-Exposed Skin
  description: >-
    In DSAP, lesions are concentrated on sun-exposed extensor surfaces of the arms
    and legs and often flare in summer, reflecting UV-signature second hits and the
    loss of MVK-mediated protection from UVA-induced keratinocyte apoptosis.
  subtype: DSAP
  notes: >-
    Deliberately left without an HPO binding. HP:0000992 Cutaneous photosensitivity was
    considered and rejected: its definition is an increased sensitivity of the skin to
    light diagnosable by phototesting, whereas what is observed in DSAP is a
    UV-mutagenesis-driven lesion distribution in patients who are not phototest-abnormal.
    Binding HP:0000992 would incorrectly cluster porokeratosis with xeroderma
    pigmentosum, the porphyrias and lupus in HPO-similarity searches.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the authors show that DSAP lesions result from second-hit somatic mitotic
      recombination or point mutations with a UV signature, validating the clinical
      observation that DSAP lesions arise upon sun exposed skin
    explanation: >-
      Ties the sun-exposed distribution to UV-induced second hits.

- category: Cutaneous
  name: Pruritus
  description: >-
    Itch affects a substantial minority of patients, particularly in DSAP and in the
    verrucous/ptychotropic and eruptive variants, where it can be the dominant
    symptom.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:41606785
    reference_title: "Topical statins in the treatment of porokeratosis: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a chronic disorder of keratinization associated with significant
      morbidity and no spontaneous resolution.
    explanation: >-
      Supports symptomatic morbidity in porokeratosis; the snippet does not itself name
      pruritus, so this evidence is PARTIAL.

- category: Cutaneous
  name: Palmoplantar Keratotic Papules
  description: >-
    Small keratotic papules on the palms and soles, each representing a minute
    cornoid lamella. Characteristic of the palmoplantar variants (PPPD and punctate
    porokeratosis), which typically begin in adolescence and may later generalize.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  subtype: PPPD
  evidence:
  - reference: PMID:31449901
    reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial
      actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2
      with linear porokeratosis.
    explanation: >-
      Documents palmoplantar disseminated porokeratosis as a recognized clinical
      presentation in a genotyped patient series.

- category: Neoplastic
  name: Cutaneous Squamous Cell Carcinoma Arising in a Lesion
  description: >-
    Invasive squamous cell carcinoma developing within a long-standing porokeratotic
    plaque. It is the commonest malignancy complicating porokeratosis and is most
    frequent in large, long-standing and linear lesions. The most-cited figure - 21 of
    281 (7.5%) - comes from a narrative review of published cases, so the denominator
    is reported cases rather than a defined cohort and the estimate is subject to
    ascertainment and publication bias; the source itself states that the true risk
    remains unknown.
  phenotype_term:
    preferred_term: Squamous cell carcinoma
    term:
      id: HP:0002860
      label: Squamous cell carcinoma
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:8624658
    reference_title: "Porokeratosis and cutaneous malignancy. A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-one (7.5%) of 281 cases reported revealed a malignancy arising within
      porokeratosis.
    explanation: >-
      The 7.5% pooled figure falls in the OCCASIONAL band (5-29%); the band is used with
      the caveat that the denominator is published cases, not a defined cohort.
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with the most common malignancy being squamous cell carcinoma
    explanation: >-
      Identifies SCC as the dominant malignancy.

- category: Neoplastic
  name: Basal Cell Carcinoma Arising in a Lesion
  description: >-
    Basal cell carcinoma developing within a porokeratotic lesion. It is the
    second-commonest malignancy complicating porokeratosis, after squamous cell
    carcinoma.
  phenotype_term:
    preferred_term: Basal cell carcinoma
    term:
      id: HP:0002671
      label: Basal cell carcinoma
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32401728
    reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many authors consider it to be a premalignant condition because of the potential
      for malignant transformation to squamous cell or basal cell carcinoma.
    explanation: >-
      Establishes basal cell carcinoma as a recognized transformation outcome; it is
      reported less often than SCC, supporting the VERY_RARE band.

histopathology:
- name: Cornoid Lamella
  finding_term:
    preferred_term: Cornoid lamella (vertical parakeratotic column)
    term:
      id: NCIT:C34892
      label: Parakeratosis
  description: >-
    The pathognomonic finding. A tightly stacked, vertically oriented column of
    parakeratotic corneocytes traverses the stratum corneum, angled outward from the
    lesion centre. It sits in a small epidermal invagination and corresponds exactly
    to the raised clinical rim. Biopsy must therefore sample the raised border, not
    the atrophic centre.
  diagnostic: true
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Porokeratosis is a phenotypically heterogeneous disorder characterized by the
      histopathological feature cornoid lamella, which is a vertical column of parakeratosis
      situated above dyskeratotic cells within the granular layer
    explanation: >-
      Defines the cornoid lamella as a vertical parakeratotic column, the finding coded
      here.
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a heterogeneous group of keratinising disorders characterised by the
      presence of particular microscopic structural changes, namely the presence of the
      cornoid lamella.
    explanation: >-
      Establishes the cornoid lamella as the defining microscopic criterion for the whole
      disease group.
  notes: >-
    NCIT has no dedicated cornoid-lamella class; the closest reachable
    histopathology-branch term is Parakeratosis (NCIT:C34892), the specific keratinizing
    abnormality the lamella is composed of, so preferred_term carries the more specific
    clinical name. Multiple cornoid lamellae in a single specimen are common in linear
    and verrucous porokeratosis, and the number varies between samples even within one
    variant.

- name: Dyskeratotic Keratinocytes with Diminished Granular Layer
  finding_term:
    preferred_term: Dyskeratosis
    term:
      id: NCIT:C62570
      label: Dyskeratosis
  description: >-
    Directly under the cornoid lamella the stratum granulosum is thinned or lost and
    the underlying keratinocytes are dyskeratotic and vacuolated - the cellular
    correlate of failed terminal differentiation in the mutant clone. The epidermis
    of the lesion centre is atrophic.
  diagnostic: true
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      which is a vertical column of parakeratosis situated above dyskeratotic cells within
      the granular layer
    explanation: >-
      Documents the dyskeratotic granular-layer cells that underlie the lamella.

- name: Subjacent Lymphocytic Inflammatory Infiltrate
  finding_term:
    preferred_term: Lymphocytic infiltrate
    term:
      id: NCIT:C35983
      label: Lymphocytic Infiltrate
  description: >-
    A lymphocytic infiltrate is present beneath the cornoid lamella and may extend
    throughout lesional skin. Its intensity is variable and it is prominent in
    eruptive and inflammatory variants.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      inflammatory infiltrates, in DSAP as well as in other variants, can be visualized not
      only beneath the cornoid lamella
    explanation: >-
      Documents the infiltrate and its distribution beyond the lamella.

genetic:
- name: MVK
  gene_term:
    preferred_term: MVK
    term:
      id: hgnc:7530
      label: MVK
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Mevalonate kinase, the first enzyme after HMG-CoA reductase, phosphorylating
    mevalonate to 5-phosphomevalonate. The founding porokeratosis gene, identified by
    exome sequencing in DSAP families. Germline heterozygous loss-of-function
    variants were found in 33% of familial and 16% of sporadic DSAP cases. MVK
    lesional second hits characteristically take the form of chromosome 12-wide
    copy-neutral loss of heterozygosity. Note that biallelic germline MVK loss causes
    mevalonate kinase deficiency, a different disease (see differential_diagnoses).
  evidence:
  - reference: PMID:22983302
    reference_title: "Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with
      sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases),
      respectively.
    explanation: >-
      Establishes MVK as a causal DSAP gene and quantifies its contribution.
  case_fractions:
  - population: Chinese familial DSAP cohort
    case_fraction_percent: 33.0
    cohort_size: 57
    notes: Familial DSAP index cases with an identified MVK variant.
    evidence:
    - reference: PMID:22983302
      reference_title: "Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with
        sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases),
        respectively.
      explanation: Direct quantification of the familial MVK case fraction.
  - population: Chinese sporadic DSAP cohort
    case_fraction_percent: 16.0
    cohort_size: 25
    notes: Sporadic DSAP index cases with an identified MVK variant.
    evidence:
    - reference: PMID:22983302
      reference_title: "Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with
        sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases),
        respectively.
      explanation: Direct quantification of the sporadic MVK case fraction.

- name: PMVK
  gene_term:
    preferred_term: PMVK
    term:
      id: hgnc:9141
      label: PMVK
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Phosphomevalonate kinase. Germline heterozygous loss-of-function variants cause
    disseminated superficial and linear porokeratosis. PMVK was one of the three
    genes added to MVK by targeted sequencing of the isoprenoid pathway, and paired
    lesional/blood exome sequencing in linear porokeratosis demonstrated germline
    PMVK variants with a second somatic PMVK event (or copy-neutral LOH) confined to
    lesional skin.
  evidence:
  - reference: PMID:30942823
    reference_title: "Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic
      copy-neutral loss of heterozygosity confined to the lesional skin, while a second had
      a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation
      in the lesional skin.
    explanation: >-
      Variant-level demonstration of germline-plus-somatic PMVK involvement in linear
      porokeratosis.

- name: MVD
  gene_term:
    preferred_term: MVD
    term:
      id: hgnc:7529
      label: MVD
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Mevalonate diphosphate decarboxylase. Causal in DSAP, linear porokeratosis and
    PPPD. MVD carries the strongest genotype-phenotype signal in the group: it was
    found in every patient with porokeratosis plus non-melanoma skin cancer and in
    71% of linear porokeratosis cases in a large genotype-phenotype analysis, and its
    lesional second hit is characteristically 16q copy-neutral loss of heterozygosity.
  evidence:
  - reference: PMID:30942823
    reference_title: "Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A)
      and a somatic deletion in MVD causing frameshift and premature codon termination
      within the lesional skin (c.811_815del, p.F271Afs*33 frameshift).
    explanation: >-
      Variant-level demonstration of the MVD germline-plus-somatic two-hit configuration.
  - reference: PMID:41240373
    reference_title: "Germline and somatic second-hit changes in porokeratosis: comprehensive variant spectrum and genotype-phenotype correlation analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      100% (n = 6/6) of patients with porokeratosis plus nonmelanoma skin cancer and 71%
      (n = 17/24) of those with linear porokeratosis (LP) harboured MVD variants
    explanation: >-
      Supports the MVD genotype-phenotype correlation with skin cancer and linear disease.

- name: FDPS
  gene_term:
    preferred_term: FDPS
    term:
      id: hgnc:3631
      label: FDPS
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Farnesyl diphosphate synthase, which condenses isopentenyl pyrophosphate to
    farnesyl pyrophosphate at the branch point supplying both cholesterol and the
    non-sterol prenyl donors. Loss-of-function variants are the least common of the
    four canonical porokeratosis genes but follow the same germline-plus-somatic
    logic.
  evidence:
  - reference: PMID:26202976
    reference_title: "Genomic variations of the mevalonate pathway in porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition
      to MVK in the mevalonate pathway
    explanation: >-
      Establishes FDPS as a causal porokeratosis gene.

- name: FDFT1
  gene_term:
    preferred_term: FDFT1
    term:
      id: hgnc:3629
      label: FDFT1
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: SOMATIC
  notes: >-
    Squalene synthase, the first committed step of sterol-specific cholesterol
    synthesis downstream of FDPS. A fifth mevalonate-pathway gene, added in 2024,
    that reaches biallelic inactivation by a distinct route: somatic promoter
    hypermethylation. Localized, non-hereditary porokeratosis can be caused by
    somatic biallelic FDFT1 promoter hypermethylation, or mono-allelic
    hypermethylation plus a somatic variant in trans, with no germline lesion.
    Gene-specific hypermethylation detectable in adjacent normal-appearing epidermis
    suggests an asymptomatic epigenetically mosaic field that predisposes to lesions.
    A germline-plus-somatic FDFT1 hereditary form was also identified.
  evidence:
  - reference: PMID:38653249
    reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we identified non-hereditary porokeratosis associated with epigenetic silencing
      of FDFT1, another gene in the mevalonate pathway.
    explanation: >-
      Establishes FDFT1 as a causal gene acting through somatic epigenetic silencing.
  - reference: PMID:38653249
    reference_title: "Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In some individuals with the localized form, gene-specific promoter hypermethylation
      of FDFT1 was detected in morphologically normal epidermis adjacent to
      methylation-related lesions but not distal to these lesions, suggesting that
      asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to
      the disease.
    explanation: >-
      Supports the predisposed epigenetic field described in this gene entry.

environmental:
- name: Ultraviolet radiation exposure
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  influences_mechanisms:
  - target: Somatic Second Hit in Lesional Keratinocytes
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The strongest exposure link in this tranche, and unusual in the backfill
      generally: ultraviolet light is not merely associated with the disease,
      it is the mutagen that writes the somatic second hit this node holds,
      and the second hits carry its signature. That makes sun protection a
      mechanistically justified preventive measure rather than generic advice.
    evidence:
    - reference: PMID:31753123
      reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The finding that some of the second-hit mutations have UV signatures proves the importance of sun protection as a preventive measure in DSAP."
      explanation: >-
        States that some second-hit mutations carry ultraviolet signatures and
        draws the sun-protection conclusion from it. The exposure is
        identified in the mutation itself, which is this node.
    - reference: PMID:32401728
      reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and systemic, infectious, and neoplastic diseases."
      explanation: >-
        Review-level confirmation that the disease is associated with
        ultraviolet radiation. Association only, carried to show the link does
        not rest on a single study.
  description: >-
    UV is the clearest environmental modifier. DSAP lesions arise preferentially on
    sun-exposed extensor limbs and often flare in summer; second hits in DSAP lesions
    carry a UV mutational signature (C>T transitions), so UV is not merely an
    aggravating factor but a mutagenic cause of the somatic event that creates the
    lesion. This makes sun protection a mechanistically justified preventive measure.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The finding that some of the second-hit mutations have UV signatures proves the
      importance of sun protection as a preventive measure in DSAP.
    explanation: >-
      Directly links UV mutagenesis to lesion formation and to the preventive
      recommendation.
  - reference: PMID:32401728
    reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and
      systemic, infectious, and neoplastic diseases.
    explanation: >-
      Independent review-level confirmation of the UV association.

- name: Immunosuppression
  notes: >-
    Left ontologically unbound deliberately. ECTO's only immunosuppression
    term, ECTO:9001747, is defined as exposure to an immunosuppressive
    agent (RO:0002309 some CHEBI:35705) -- a drug exposure. This entry
    describes immunosuppression as a host state with non-drug causes, so
    that term would assert something the entry's own description rules
    out. No host-immunosuppression-state exposure term exists.
  influences_mechanisms:
  - target: Clonal Expansion of Second-Hit Keratinocytes
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Graded well below the ultraviolet link into this entry, and the
      difference is real rather than presentational: ultraviolet light creates
      the mutant clone, whereas immunosuppression appears to let an existing
      clone expand, which is why this points at the expansion node and not at
      the second hit. No cited sentence supplies the route, so the
      intermediates stay unknown.
    evidence:
    - reference: PMID:34418147
      reference_title: "Localized eruptive porokeratosis in pediatric patients following treatment of acute leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Porokeratosis is a rare diagnosis in the pediatric population, and eruptive disease has been documented prior in patients with history of stem cell transplantation."
      explanation: >-
        Documents eruptive disease in children after treatment for leukaemia
        and in prior stem-cell transplant recipients. A clinical association
        in a small paediatric series.
    - reference: PMID:32401728
      reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and systemic, infectious, and neoplastic diseases."
      explanation: >-
        Review listing immunosuppression among the associations of this
        disease. The same sentence that supports the ultraviolet link, and
        equally general.
  description: >-
    Iatrogenic or disease-related immunosuppression - solid-organ or haematopoietic
    stem cell transplantation, HIV infection, haematologic malignancy, immunosuppressive
    drug therapy - can precipitate eruptive or disseminated porokeratosis and is
    thought to raise the risk of malignant transformation. Lesions may improve when
    immunosuppression is reduced.
  evidence:
  - reference: PMID:34418147
    reference_title: "Localized eruptive porokeratosis in pediatric patients following treatment of acute leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a rare diagnosis in the pediatric population, and eruptive disease
      has been documented prior in patients with history of stem cell transplantation.
    explanation: >-
      Documents the association between eruptive porokeratosis and post-transplant
      immunosuppression.
  - reference: PMID:32401728
    reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis has been associated with immunosuppression, ultraviolet radiation, and
      systemic, infectious, and neoplastic diseases.
    explanation: >-
      Review-level confirmation of the immunosuppression association.

treatments:
- name: Topical Cholesterol Plus Lovastatin
  description: >-
    The pathogenesis-directed therapy for porokeratosis, and a direct read-out of the
    mechanism. Compounded 2% cholesterol plus 2% lovastatin cream applied twice daily
    simultaneously addresses both arms of the metabolic lesion: lovastatin inhibits
    HMG-CoA reductase upstream of the enzymatic block, preventing accumulation of
    potentially toxic mevalonate-pathway intermediates, while cholesterol replaces the
    missing pathway end-product. In the original case series, cholesterol/lovastatin
    but not cholesterol alone produced near-complete clearance of DSAP lesions within
    four weeks, with moderate improvement in PPPD and linear porokeratosis. The
    strategy is borrowed from CHILD syndrome, another disorder of distal cholesterol
    metabolism.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lovastatin
      term:
        id: CHEBI:40303
        label: lovastatin
    - preferred_term: cholesterol
      term:
        id: CHEBI:16113
        label: cholesterol
  target_mechanisms:
  - target: Mevalonate Pathway Intermediate Accumulation
    treatment_effect: INHIBITS
    description: >-
      The lovastatin component blocks HMG-CoA reductase upstream of the deficient
      enzyme, shutting off the supply of the intermediates that would otherwise build
      up behind the block.
    evidence:
    - reference: PMID:31449901
      reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        block the accumulation of mevalonate pathway toxic metabolites could alleviate
        porokeratosis
      explanation: >-
        States the statin arm of the dual mechanism.
  - target: Cholesterol and Non-Sterol Isoprenoid Depletion
    treatment_effect: INHIBITS
    description: >-
      The cholesterol component supplies the missing end-product directly to lesional
      keratinocytes, correcting the depletion arm; topical delivery bypasses hepatic
      first-pass metabolism and gives keratinocytes direct access to cholesterol.
    evidence:
    - reference: PMID:31449901
      reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We hypothesized that topical therapy that aims to replenish cholesterol, an
        essential mevalonate pathway end-product, and block the accumulation of mevalonate
        pathway toxic metabolites could alleviate porokeratosis.
      explanation: >-
        States the end-product replacement arm of the dual mechanism.
  evidence:
  - reference: PMID:31449901
    reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in
      near complete clearance of disseminated superficial actinic porokeratosis lesions
      after 4 weeks of therapy and moderate improvement of porokeratosis palmaris et
      plantaris disseminata lesions and linear porokeratosis lesions.
    explanation: >-
      Reports the clinical efficacy of the combination and the negative cholesterol-only
      control.
  - reference: PMID:31449901
    reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Topical cholesterol/lovastatin is an effective and well-tolerated therapy for
      porokeratosis that underscores the utility of a pathogenesis-based therapy that
      replaces deficient end products and prevents accumulation of potentially toxic
      precursors.
    explanation: >-
      The authors' own statement of the pathogenesis-directed rationale.
  - reference: PMID:41606785
    reference_title: "Topical statins in the treatment of porokeratosis: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients (79%) received compounded topical lovastatin 2% or
      simvastatin 2%, typically in combination with cholesterol 2%.
    explanation: >-
      Confirms the regimen and concentrations described here across the pooled literature.
  - reference: PMID:31449901
    reference_title: "Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A therapeutic approach preventing the accumulation of toxic metabolites while
      replenishing essential end-products has been successfully utilized in CHILD
      syndrome, an X-linked dominant disorder of distal cholesterol metabolism.
    explanation: >-
      Sources the CHILD syndrome precedent named in this treatment description.
  notes: >-
    There is no FDA-approved therapy for porokeratosis; these are off-label compounded
    formulations with attendant variability in quality and potency.

- name: Topical Statin Monotherapy
  description: >-
    Topical lovastatin 2% or simvastatin 2% without added cholesterol. A randomized
    clinical trial in DSAP found improvement in both the lovastatin-cholesterol and
    lovastatin-alone arms with only limited additional benefit from cholesterol,
    implying that blocking accumulation of upstream intermediates, rather than
    replacing cholesterol, is the dominant mechanism. A pooled systematic review of 95
    patients reported clinical improvement in 92%, with response as early as four
    weeks and mostly mild local adverse events.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lovastatin
      term:
        id: CHEBI:40303
        label: lovastatin
  target_mechanisms:
  - target: Mevalonate Pathway Intermediate Accumulation
    treatment_effect: INHIBITS
    description: >-
      Statin inhibition of HMG-CoA reductase prevents build-up of mevalonate and other
      intermediates upstream of the deficient enzyme, without replacing any
      end-product - which is why its efficacy argues that this arm dominates.
    evidence:
    - reference: PMID:33005717
      reference_title: "Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We hypothesized that blocking the mevalonate synthesis pathway upstream of the MVD
        enzyme would be sufficient to alleviate his symptoms by preventing the accumulation
        of mevalonate pathway metabolites.
      explanation: >-
        States the single-arm mechanism targeted by statin monotherapy.
  evidence:
  - reference: PMID:36947042
    reference_title: "Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone for the Treatment of Disseminated Superficial Actinic Porokeratosis: A Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This randomized clinical trial found improvements in DSAP severity in both treatment
      groups, without serious AEs, indicating a limited benefit with the addition of
      cholesterol.
    explanation: >-
      Randomized-trial evidence that statin monotherapy performs comparably to the
      cholesterol combination.
  - reference: PMID:36947042
    reference_title: "Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone for the Treatment of Disseminated Superficial Actinic Porokeratosis: A Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that lovastatin cream may be a new primary treatment option for
      patients diagnosed with DSAP.
    explanation: >-
      The trialists' conclusion supporting statin monotherapy as a primary option.
  - reference: PMID:41606785
    reference_title: "Topical statins in the treatment of porokeratosis: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was observed in 92% of patients (87 of 95), with onset of response reported as early
      as 4 weeks.
    explanation: >-
      Pooled response rate and time to response across the topical-statin literature.
  notes: >-
    The systematic review notes that off-label compounded formulations introduce
    variability in efficacy and safety, and that adverse events occurred in 15% of
    patients, mostly mild localized dermatological reactions.

- name: Photoprotection and Sun Avoidance
  description: >-
    Because DSAP lesions arise from UV-signature somatic second hits, rigorous
    photoprotection - sun avoidance, protective clothing and broad-spectrum sunscreen -
    is a mechanistically grounded preventive measure rather than merely symptomatic
    advice. Unnecessary phototherapy should be avoided in affected individuals.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: photoprotection and sunlight avoidance
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  target_mechanisms:
  - target: Somatic Second Hit in Lesional Keratinocytes
    treatment_effect: INHIBITS
    description: >-
      Reducing UV exposure reduces the rate of UV-signature C>T second hits that create
      new lesions.
    evidence:
    - reference: PMID:31753123
      reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The finding that some of the second-hit mutations have UV signatures proves the
        importance of sun protection as a preventive measure in DSAP.
      explanation: >-
        Directly links photoprotection to prevention of the targeted second-hit node.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The finding that some of the second-hit mutations have UV signatures proves the
      importance of sun protection as a preventive measure in DSAP.
    explanation: >-
      Direct statement of the mechanistic rationale for photoprotection.

- name: Surgical Excision of Suspicious or Localized Lesions
  description: >-
    Complete excision provides both definitive local control and histopathology, and
    is the appropriate response to a lesion showing rapid growth, nodularity,
    ulceration, bleeding, pain or induration. It is also reasonable for solitary
    porokeratosis of Mibelli plaques. Destructive alternatives include shave excision,
    curettage, electrosurgery, cryosurgery and ablative laser.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical excision
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Malignant Transformation to Keratinocyte Carcinoma
    treatment_effect: INHIBITS
    description: >-
      Excising a transformed or suspicious lesion both treats and definitively excludes
      keratinocyte carcinoma.
    evidence:
    - reference: PMID:8624658
      reference_title: "Porokeratosis and cutaneous malignancy. A review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Porokeratosis is a premalignant condition, with certain groups of patients at
        greatest risk for malignant transformation.
      explanation: >-
        Establishes the premalignant risk that excision of suspicious lesions addresses;
        the snippet does not report excision outcomes, hence PARTIAL.
  evidence:
  - reference: PMID:8624658
    reference_title: "Porokeratosis and cutaneous malignancy. A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a premalignant condition, with certain groups of patients at
      greatest risk for malignant transformation.
    explanation: >-
      Establishes the premalignant status that justifies excision and surveillance of
      high-risk lesions; the snippet does not itself report excision outcomes, hence
      PARTIAL.

- name: Cryosurgery
  description: >-
    Cryosurgery with liquid nitrogen is a widely used destructive option for a limited
    number of accessible lesions, particularly porokeratosis of Mibelli. Recurrence is
    common and dyspigmentation or scarring may follow, so it does not remove the need
    for long-term surveillance.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cryosurgery
    term:
      id: NCIT:C15215
      label: Cryosurgery
  evidence:
  - reference: PMID:39485670
    reference_title: "Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multiple management options are available for DSAP, including topical and systemic
      agents, photodynamic therapy and laser treatments. However, these approaches vary
      in their balance between efficacy and toxicity.
    explanation: >-
      Systematic review supporting the availability but variable efficacy/toxicity of
      destructive and physical modalities; cryosurgery is not named in the abstract,
      hence PARTIAL.
  - reference: PMID:32401728
    reference_title: "Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, long-term follow-up is a key component of treatment, which is usually
      complex and often unsatisfactory.
    explanation: >-
      Supports the requirement for continued follow-up after destructive treatment;
      the snippet does not name cryosurgery, hence PARTIAL.

- name: Photodynamic Therapy
  description: >-
    Topical photosensitizer plus light activation has been used for disseminated
    disease not amenable to individual lesion destruction. Reported response rates are
    modest and the procedure can be painful; it is a second-line option now largely
    superseded by pathway-directed topical statins.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Photodynamic Therapy
    term:
      id: NCIT:C15300
      label: Photodynamic Therapy
  evidence:
  - reference: PMID:39485670
    reference_title: "Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Various treatment modalities were reported, including topical and systemic agents,
      photodynamic therapy, and laser therapy.
    explanation: >-
      Systematic review naming photodynamic therapy among the reported DSAP management
      options.
  - reference: PMID:39485670
    reference_title: "Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, there is a paucity of high-quality clinical trial data to guide treatment
      decisions.
    explanation: >-
      Supports the characterization of this modality as second-line with weak supporting
      evidence.

- name: Conventional Topical and Systemic Agents
  description: >-
    The pre-statin therapeutic repertoire, still widely used and still supported only
    by case reports and small series. Topical options include 5-fluorouracil,
    imiquimod, retinoids, vitamin D analogues, diclofenac and corticosteroids;
    systemic acitretin is used for extensive or hyperkeratotic disease but relapses
    after withdrawal and carries mucocutaneous and metabolic toxicity. A 2025
    systematic review of 61 DSAP studies concluded that these options vary widely in
    their efficacy-toxicity balance and that high-quality trial data are lacking.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:39485670
    reference_title: "Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 923 citations, 61 studies were included, predominantly comprising case reports
      and retrospective case series.
    explanation: >-
      Characterizes the weak evidence base underlying the conventional agents.
  - reference: PMID:39485670
    reference_title: "Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Various treatment modalities were reported, including topical and systemic agents,
      photodynamic therapy, and laser therapy.
    explanation: >-
      Supports the topical and systemic agent categories grouped in this entry.
  - reference: PMID:39485670
    reference_title: "Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these approaches vary in their balance between efficacy and toxicity
    explanation: >-
      Supports the efficacy-toxicity caveat stated in this description.
  notes: >-
    The individual agent names (5-fluorouracil, imiquimod, acitretin, diclofenac,
    vitamin D analogues) are drawn from the deep-research synthesis and standard
    dermatologic practice; the cited systematic review abstract groups them as
    "topical and systemic agents" without naming each, so no agent-level
    therapeutic_agent bindings are asserted here.

- name: Genetic Counseling
  description: >-
    Counseling should explain autosomal dominant transmission of the germline variant,
    the requirement for a somatic second hit (and therefore the incomplete,
    age-dependent penetrance and variable expressivity), the mosaic basis of linear
    disease, and the lifelong but generally non-life-limiting course. Molecular
    diagnosis by an MVK/PMVK/MVD/FDPS panel, with FDFT1 considered, enables cascade
    testing of relatives.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41240373
    reference_title: "Germline and somatic second-hit changes in porokeratosis: comprehensive variant spectrum and genotype-phenotype correlation analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 69 Chinese patients with porokeratosis, 22 pathogenic variants were detected in
      MVK, PMVK, MVD and FDPS, including 7 novel variants, 4 of which were validated via the
      'second-hit' mechanism.
    explanation: >-
      Supports the four-gene diagnostic panel and the second-hit validation step that
      genetic counseling rests on; the snippet does not itself address counseling
      practice, cascade testing or penetrance, hence PARTIAL.

clinical_trials:
- name: NCT04359823
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Single-blinded randomized comparison of 2% lovastatin plus 2% cholesterol cream
    versus 2% lovastatin cream alone applied twice daily for 12 weeks in adults with
    disseminated superficial actinic porokeratosis, at the Medical University of South
    Carolina. Both arms improved on the DSAP General Assessment Severity Index, with
    only limited additional benefit from the added cholesterol.
  target_phenotypes:
  - preferred_term: Porokeratosis
    term:
      id: HP:0200044
      label: Porokeratosis
  evidence:
  - reference: clinicaltrials:NCT04359823
    reference_title: "Topical Treatment for Superficial Disseminated Actinic Porokeratosis: A Single-Blinded Comparison Between Lovastatin/Cholesterol and Lovastatin"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study will analyze the effects of topical lovastatin/cholesterol vs topical
      lovastatin alone in patients with disseminated superficial actinic porokeratosis.
    explanation: >-
      The registered trial testing the pathogenesis-directed regimen in DSAP.

diagnosis:
- name: Skin biopsy of the raised lesional border
  description: >-
    The confirmatory test. The biopsy must sample the raised keratotic rim, not the
    atrophic centre, because the cornoid lamella - the diagnostic structure - sits
    within the rim; a punch taken from the centre will show only atrophic epidermis
    and miss the diagnosis. Histology should demonstrate a vertical column of
    parakeratosis over a diminished or absent granular layer with dyskeratotic
    keratinocytes beneath. Biopsy is mandatory whenever a lesion becomes nodular,
    indurated, ulcerated, bleeding or painful, in order to exclude keratinocyte
    carcinoma arising within it.
  diagnosis_term:
    preferred_term: skin biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  results: >-
    A cornoid lamella establishes the diagnosis of porokeratosis; the clinical variant
    is then assigned on lesion morphology and distribution.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Porokeratosis is a phenotypically heterogeneous disorder characterized by the
      histopathological feature cornoid lamella, which is a vertical column of parakeratosis
      situated above dyskeratotic cells within the granular layer
    explanation: >-
      Defines the histological finding that the biopsy is performed to demonstrate.
  - reference: PMID:29722423
    reference_title: "Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis comprises heterogeneous keratinization disorders that are characterized
      by one or more atrophic patches surrounded by a ridge-like cornoid lamella.
    explanation: >-
      Locates the cornoid lamella in the raised rim rather than the atrophic centre, which
      is why the rim must be sampled.

- name: Dermoscopy of the lesion border
  description: >-
    Non-invasive first-line assessment. Dermoscopy of a porokeratotic lesion shows a
    sharply defined peripheral white-to-yellow keratotic track running around the
    lesion, the dermoscopic correlate of the cornoid lamella and often called the
    "Great Wall" sign. It is the feature that separates porokeratosis from actinic
    keratosis and other annular dermatoses at the bedside and guides where to place a
    confirmatory biopsy. Reflectance confocal microscopy and line-field confocal
    optical coherence tomography can add further non-invasive discrimination, but
    histopathology remains necessary whenever transformation is suspected.
  diagnosis_term:
    preferred_term: dermoscopy
    term:
      id: NCIT:C116478
      label: Dermoscopy
  results: >-
    A peripheral keratotic track corresponding to the cornoid lamella supports the
    diagnosis and identifies the correct biopsy site.
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      introduces imaging methods facilitating the diagnosis (conventional and
      ultraviolet-induced fluorescence dermatoscopy, reflectance confocal microscopy and
      pathology)
    explanation: >-
      Establishes dermatoscopy and reflectance confocal microscopy as diagnostic imaging
      methods for porokeratosis; the abstract does not describe the specific dermoscopic
      pattern, hence PARTIAL.

- name: Mevalonate pathway gene panel
  description: >-
    Sequencing of MVK, PMVK, MVD and FDPS, with FDFT1 considered, on peripheral blood.
    Highest yield in familial, early-onset, disseminated, linear/segmental, mixed or
    atypical disease. Sequence plus copy-number analysis is preferable, and
    exome/genome sequencing can be used for panel-negative pedigrees. A negative blood
    panel does not exclude the diagnosis, because the non-hereditary FDFT1 form and
    some mosaic presentations carry no germline lesion.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A heterozygous loss-of-function variant in MVK, PMVK, MVD or FDPS supports the
    diagnosis and enables cascade testing of relatives.
  evidence:
  - reference: PMID:41240373
    reference_title: "Germline and somatic second-hit changes in porokeratosis: comprehensive variant spectrum and genotype-phenotype correlation analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 69 Chinese patients with porokeratosis, 22 pathogenic variants were detected in
      MVK, PMVK, MVD and FDPS, including 7 novel variants, 4 of which were validated via the
      'second-hit' mechanism.
    explanation: >-
      Establishes the four-gene panel and its diagnostic yield in a contemporary cohort.
  - reference: PMID:41240373
    reference_title: "Germline and somatic second-hit changes in porokeratosis: comprehensive variant spectrum and genotype-phenotype correlation analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings enable porokeratosis subtyping guided by genetic testing and provide a
      foundation for developing molecularly integrated scoring systems to refine
      risk-stratified management.
    explanation: >-
      Supports the use of the panel for subtyping and risk stratification.

- name: Paired lesional and blood sequencing for the somatic second hit
  description: >-
    A research-grade but diagnostically decisive test in mosaic and non-hereditary
    disease: whole-exome sequencing of microdissected lesional epidermis alongside
    blood or saliva. It demonstrates the second hit - a copy-neutral loss of
    heterozygosity, a point mutation in trans, or, for FDFT1, promoter
    hypermethylation - that is confined to lesional skin. This is the only test that
    can confirm the two-hit mechanism in an individual patient and the only route to
    a molecular diagnosis in the germline-negative localized form.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A lesion-restricted somatic event on the allele opposite the germline variant, or
    biallelic somatic FDFT1 promoter hypermethylation in the absence of any germline
    variant.
  evidence:
  - reference: PMID:30942823
    reference_title: "Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paired whole-exome sequencing of affected skin and blood/saliva samples from 3
      participants from 3 academic medical centers with clinical and histologic diagnoses
      of linear porokeratosis.
    explanation: >-
      Describes exactly the paired lesional/blood design this test entry records.
  - reference: PMID:31207227
    reference_title: "Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we showed that each skin lesion of DSAP exhibited an individual second hit genetic
      change in the wild-type allele of the corresponding gene specifically in the
      epidermis
    explanation: >-
      Confirms that the somatic event is detectable specifically in lesional epidermis.

differential_diagnoses:
- name: Actinic keratosis
  disease_term:
    preferred_term: actinic keratosis
    term:
      id: MONDO:0005173
      label: actinic keratosis
  description: >-
    The single most frequent clinical mimic of DSAP: both present as multiple
    scaly, erythematous macules on chronically sun-exposed extensor limbs and face of
    older, fair-skinned adults, and both are UV-driven keratinocyte lesions.
  distinguishing_features:
  - Porokeratosis has a sharply demarcated, raised, ridge-like peripheral rim enclosing an atrophic centre; actinic keratosis has adherent rough scale without a discrete annular border.
  - Histology is decisive - the cornoid lamella (vertical parakeratotic column over a diminished granular layer) is present in porokeratosis and absent in actinic keratosis, which instead shows basal keratinocyte atypia.
  - Dermoscopy of porokeratosis shows a peripheral white-yellow keratotic track corresponding to the cornoid lamella.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Porokeratosis is a phenotypically heterogeneous disorder characterized by the
      histopathological feature cornoid lamella, which is a vertical column of parakeratosis
      situated above dyskeratotic cells within the granular layer
    explanation: >-
      Supplies the histological discriminator that separates porokeratosis from actinic
      keratosis.

- name: Seborrheic keratosis
  disease_term:
    preferred_term: seborrheic keratosis
    term:
      id: MONDO:0008420
      label: seborrheic keratosis
  description: >-
    Common benign pigmented keratotic papules and plaques that can be confused with
    porokeratosis of Mibelli, especially when brown and hyperkeratotic.
  distinguishing_features:
  - Seborrheic keratosis is a stuck-on, waxy, well-demarcated plaque with keratin-filled pseudocysts and comedo-like openings on dermoscopy; it lacks an annular rim and an atrophic centre.
  - Histology shows acanthosis with horn pseudocysts and no cornoid lamella.
  - Seborrheic keratoses have no association with the mevalonate pathway and no premalignant potential.
  evidence:
  - reference: PMID:38132857
    reference_title: "Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a heterogeneous group of keratinising disorders characterised by the
      presence of particular microscopic structural changes, namely the presence of the
      cornoid lamella.
    explanation: >-
      Establishes the required-for-diagnosis microscopic criterion that seborrheic keratosis
      does not meet; the snippet does not itself discuss seborrheic keratosis, hence PARTIAL.

- name: Bowen disease
  disease_term:
    preferred_term: Bowen disease of the skin
    term:
      id: MONDO:0020761
      label: Bowen disease of the skin
  description: >-
    Squamous cell carcinoma in situ. A well-demarcated erythematous scaly plaque that
    overlaps clinically with a solitary porokeratosis of Mibelli plaque. The
    relationship is not purely one of mimicry: SCC in situ can also arise within a
    long-standing porokeratotic lesion, so the two can coexist.
  distinguishing_features:
  - Bowen disease shows full-thickness keratinocyte atypia on histology, whereas uncomplicated porokeratosis shows a cornoid lamella without full-thickness atypia.
  - A porokeratotic plaque that becomes nodular, indurated, ulcerated, bleeding or painful should be biopsied to exclude transformation rather than assumed to be simple mimicry.
  evidence:
  - reference: PMID:8624658
    reference_title: "Porokeratosis and cutaneous malignancy. A review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a premalignant condition, with certain groups of patients at
      greatest risk for malignant transformation.
    explanation: >-
      Supports the coexistence caveat that distinguishes this differential from simple
      look-alikes.

- name: Lichen planus
  disease_term:
    preferred_term: lichen planus
    term:
      id: MONDO:0006572
      label: lichen planus
  description: >-
    An inflammatory, intensely pruritic papulosquamous dermatosis that can resemble
    the annular or verrucous/ptychotropic porokeratosis variants, particularly in
    genital and intertriginous sites where annular lichen planus is common.
  distinguishing_features:
  - Lichen planus papules are violaceous, flat-topped and polygonal with Wickham striae; they lack a cornoid lamella.
  - Histology shows a lichenoid interface dermatitis with basal vacuolar degeneration, hypergranulosis and Civatte bodies - notably hypergranulosis, the opposite of the diminished granular layer beneath a cornoid lamella.
  - Lichen planus typically responds to topical corticosteroids, which give only transient antipruritic benefit in porokeratosis.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      which is a vertical column of parakeratosis situated above dyskeratotic cells within
      the granular layer
    explanation: >-
      Provides the granular-layer histological contrast used to separate porokeratosis from
      the hypergranulosis of lichen planus; the snippet does not discuss lichen planus,
      hence PARTIAL.

- name: Granuloma annulare
  disease_term:
    preferred_term: granuloma annulare
    term:
      id: MONDO:0006554
      label: granuloma annulare
  description: >-
    Annular skin lesions with a raised border and central clearing, the classic
    clinical differential for any annular dermatosis and a frequent misdiagnosis of
    porokeratosis of Mibelli.
  distinguishing_features:
  - The border of granuloma annulare is smooth, firm and dermal (non-scaly); the border of porokeratosis is keratotic and scaly with a palpable ridge and often a visible furrow.
  - Granuloma annulare is a dermal palisaded granulomatous process with mucin; the epidermis is normal and there is no cornoid lamella.
  - Granuloma annulare frequently resolves spontaneously, whereas porokeratosis shows no spontaneous resolution.
  evidence:
  - reference: PMID:41606785
    reference_title: "Topical statins in the treatment of porokeratosis: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Porokeratosis is a chronic disorder of keratinization associated with significant
      morbidity and no spontaneous resolution.
    explanation: >-
      Supports the no-spontaneous-resolution discriminator against granuloma annulare;
      the snippet does not itself discuss granuloma annulare, hence PARTIAL.

- name: Mevalonate kinase deficiency
  disease_term:
    preferred_term: mevalonate kinase deficiency
    term:
      id: MONDO:0017708
      label: mevalonate kinase deficiency
  description: >-
    The critical genetic - not clinical - differential, including its mild end,
    hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). MVK variants cause
    both conditions, but the diseases are unrelated in presentation and must not be
    conflated. Mevalonate kinase deficiency is a systemic autoinflammatory disorder
    caused by germline biallelic (homozygous or compound heterozygous) MVK
    loss-of-function, spanning mevalonic aciduria at the severe end and HIDS at the
    mild end. Porokeratosis instead requires a germline monoallelic variant plus a
    somatic second hit restricted to epidermal keratinocytes. A striking and
    unresolved observation anchors the separation: patients with HIDS carry biallelic
    MVK loss of function in every cell, including keratinocytes, yet no porokeratosis
    lesions have been described in them. On a naive two-hit reading they should be the
    group most at risk, so this is a genuine paradox rather than a demonstration. The
    usual explanation is that the MVK alleles seen in HIDS are hypomorphic and retain
    residual enzyme activity, whereas the lesional second hit in porokeratosis produces
    a true clonal null, but this has not been formally tested.
  distinguishing_features:
  - Mevalonate kinase deficiency presents with recurrent febrile attacks, hepatosplenomegaly, lymphadenopathy, arthralgia, gastrointestinal symptoms and (in mevalonic aciduria) dysmorphism, failure to thrive, visual impairment and psychomotor retardation - none of which occur in porokeratosis.
  - The rash of mevalonate kinase deficiency is erythematous maculopapular or urticarial, not annular with a cornoid lamella.
  - Inheritance differs - biallelic germline (autosomal recessive) in mevalonate kinase deficiency versus monoallelic germline plus somatic second hit in porokeratosis.
  - Mevalonic aciduria shows markedly elevated urinary mevalonic acid; porokeratosis has no systemic biochemical abnormality.
  evidence:
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with mevalonic aciduria and hyperimmunoglobulinemia D with periodic fever syndrome
      (HIDS) representing the severe and mild ends of the clinical and biochemical spectrum
      of MKD, respectively
    explanation: >-
      Defines the mevalonate kinase deficiency spectrum that shares MVK with porokeratosis
      but is a different disease.
  - reference: PMID:31753123
    reference_title: "Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      no porokeratosis lesions were described in patients with HIDS
    explanation: >-
      The decisive observation that biallelic germline MVK loss does not produce
      porokeratosis, keeping the two entities separate.
  notes: >-
    This differential is recorded because MVK, MVD, PMVK and FDPS are shared between
    the two disease groups and literature searches for these genes readily retrieve
    mevalonate kinase deficiency material. Nothing from the mevalonate kinase
    deficiency / HIDS autoinflammatory literature should be imported into this entry.

📚

References & Deep Research

References

2

PMID:38132857

Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants.

No top-level findings curated for this source.

PMID:32401728

Porokeratosis: A Review of Its Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 10 citations 2026-08-01T05:12:02.397096

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Porokeratosis
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Porokeratosis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Porokeratosis: comprehensive disease-characteristics report

Executive summary

Porokeratosis is a heterogeneous group of inherited or acquired epidermal keratinization disorders. Its defining clinicopathologic feature is an expanding clone of abnormal keratinocytes that produces a raised keratotic border and, histologically, a cornoid lamella. The principal modern disease model is loss of mevalonate/isoprenoid-pathway function—most firmly involving MVK, PMVK, MVD, and FDPS—combined in many lesions with a somatic “second hit,” ultraviolet (UV) exposure, immunosuppression, or another local trigger. Disease is usually cutaneous and chronic rather than life-limiting, but it carries a clinically important risk of keratinocyte carcinoma, especially squamous-cell carcinoma (SCC). A 2023 review estimated overall keratinocyte-cancer risk at approximately 6.8–11.6%, with substantial variation by subtype. (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, vargasmora2020porokeratosisareview pages 1-2, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)

The most important recent therapeutic development is pathway-directed topical statin therapy. A completed 31-person randomized trial, NCT04359823, compared 2% lovastatin/2% cholesterol with 2% lovastatin alone for 12 weeks; its peer-reviewed report appeared in JAMA Dermatology in 2023 (PMID 36947042). Evidence remains limited, however, and no treatment is uniformly curative. (NCT04359823 chunk 1, NCT04359823 chunk 2, pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47)

The following structured table is suitable for knowledge-base ingestion.

domain	entity/finding	evidence-ready interpretation	suggested ontology IDs/terms
disease identifier	Porokeratosis	Heterogeneous group of keratinization disorders defined histologically by the cornoid lamella; evidence is aggregated from disease-level reviews plus primary variant-specific studies (vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 2-4, pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5)	MONDO: verify exact class; MeSH: Porokeratosis; ICD-10: verify specific coding used locally
synonym/nomenclature	Porokeratoses	Preferred umbrella term when referring to the disease spectrum rather than a single clinicopathologic variant (vargasmora2020porokeratosisareview pages 1-2, pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7)	MeSH term mapping to Porokeratosis; disease synonym: porokeratoses
variant	Disseminated superficial actinic porokeratosis (DSAP)	Most common clinical variant in reviewed series; multiple small annular atrophic/keratotic macules-papules on sun-exposed skin, often adult onset, female-predominant in reviews (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)	HPO: Actinic keratosis-like lesion; Abnormality of the skin; Multiple skin lesions; UBERON: skin of upper limb, skin of lower limb
variant	Disseminated superficial porokeratosis (DSP)	Disseminated non-actinic form, often childhood onset, involving sun-exposed and non-exposed areas (vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)	HPO: Generalized skin lesions; Childhood onset; UBERON: trunk skin
variant	Porokeratosis of Mibelli (PM)	Often begins in childhood; enlarging annular plaques with raised keratotic border, commonly limbs/trunk; higher malignant potential than DSAP (pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)	HPO: Plaque; Hyperkeratotic papule; Childhood onset; UBERON: limb skin
variant	Linear porokeratosis (LP)	Usually congenital/early onset, linear or Blaschkoid distribution; among the highest malignant-transformation risks in reviews (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, vargasmora2020porokeratosisareview pages 4-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 52-54)	HPO: Linear skin lesion; Blaschkoid distribution; Congenital onset
variant	Verrucous porokeratosis / porokeratosis ptychotropica	Pruritic or burning verrucous plaques, often anogenital/intertriginous, diagnostically difficult, prolonged course (pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31, pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33)	HPO: Pruritus; Burning sensation; Verrucous lesion; UBERON: perianal skin, genital skin
variant	Punctate palmoplantar porokeratosis / PPPD spectrum	Punctate keratotic lesions of palms/soles; low but non-zero premalignant concern in reviews (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, pietkiewicz2023porokeratoses—acomprehensivereview pages 52-54)	HPO: Palmoplantar hyperkeratosis; Punctate keratosis; UBERON: skin of palm, skin of sole
variant	Porokeratoma	Solitary well-demarcated porokeratotic plaque/nodule, usually sporadic; PMVK implicated in a minority of studied index cases (pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36)	HPO: Solitary skin nodule; Hyperkeratotic plaque
gene	MVK	Core causal gene in porokeratosis spectrum; mevalonate-pathway enzyme; AD inheritance with incomplete penetrance in familial disease; implicated strongly in DSAP and other variants (pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, pietkiewicz2023porokeratoses—acomprehensivereview pages 43-44, aersilan2022microrna874targetsphosphomevalonate pages 17-17)	HGNC: MVK; GO: mevalonate pathway, cholesterol biosynthetic process
gene	PMVK	Core causal gene; loss-of-function variants reported in AD porokeratosis; also found in sporadic porokeratoma subset (pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47, pietkiewicz2023porokeratoses—acomprehensivereview pages 43-44, pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36)	HGNC: PMVK; GO: phosphomevalonate kinase activity, isoprenoid biosynthetic process
gene	MVD	Core causal gene in porokeratosis; part of mevalonate/isoprenoid biosynthesis and implicated in second-hit models (pietkiewicz2023porokeratoses—acomprehensivereview pages 43-44, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)	HGNC: MVD; GO: diphosphomevalonate decarboxylase activity
gene	FDPS	Core causal gene in porokeratosis reviews; supports mevalonate-pathway disease model (pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7)	HGNC: FDPS; GO: farnesyl diphosphate biosynthetic process
gene, emerging	FDFT1	Emerging 2024 mechanism: gene-specific somatic epigenetic mosaicism reported for a non-hereditary localized form; important but should be labeled emerging until independently consolidated across cohorts (pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7)	HGNC: FDFT1; label as emerging/candidate mechanistic gene
gene, candidate/emerging	SLC17A9	Candidate/legacy DSAP-associated gene/locus in some pedigrees; not part of the canonical mevalonate-pathway core and should be labeled candidate/emerging (pietkiewicz2023porokeratoses—acomprehensivereview pages 43-44, vargasmora2020porokeratosisareview pages 1-2)	HGNC: SLC17A9; label as candidate susceptibility/causal gene pending broader consensus
inheritance	Autosomal dominant with incomplete penetrance	Best-supported familial inheritance pattern across common inherited forms; one review cites ~22% penetrance for DSAP (pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 2-4)	HP: Autosomal dominant inheritance; HP: Reduced penetrance
molecular mechanism	Mevalonate/isoprenoid pathway dysfunction	Unifying current model: deficiency of enzymes in cholesterol/isoprenoid biosynthesis perturbs keratinocyte differentiation, apoptosis control, and local epidermal homeostasis (pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, aersilan2022microrna874targetsphosphomevalonate pages 17-17)	GO: cholesterol biosynthetic process; isoprenoid biosynthetic process; regulation of keratinocyte differentiation
molecular mechanism	Second-hit / mosaic clonal expansion	Localized lesions can reflect postzygotic or somatic second-hit events driving clonal lesional epidermis over a germline background (pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43, vargasmora2020porokeratosisareview pages 1-2)	GO: somatic mutation; clonal cell proliferation
molecular mechanism	Premature keratinocyte apoptosis beneath cornoid lamella	Classic downstream histopathologic process with granular layer loss and abnormal terminal differentiation (vargasmora2020porokeratosisareview pages 2-4, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)	GO: apoptotic process; keratinocyte differentiation; epidermis development
cell/anatomy	Keratinocyte	Principal implicated cell type in pathogenesis and malignant transformation models (vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 2-4, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)	CL: keratinocyte
cell/anatomy	Epidermis / spinous-granular layers	Primary tissue compartment showing cornoid lamella, granular layer attenuation, dyskeratosis, and abnormal keratinization (pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19, pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33, vargasmora2020porokeratosisareview pages 2-4)	UBERON: epidermis; GO CC: cornified envelope
phenotype	Annular keratotic plaque/papule with raised rim	Core clinical morphology across variants (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)	HPO: Annular skin lesion; Hyperkeratotic papule; Plaque
phenotype	Atrophic center	Common central lesional feature, especially in DSAP and PM-type lesions (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36)	HPO: Cutaneous atrophy
phenotype	Pruritus	Common but variable symptom; up to one-third in DSAP review data and prominent in ptychotropic/verrucous forms (vargasmora2020porokeratosisareview pages 4-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31)	HPO: Pruritus
phenotype	Burning sensation	Reported particularly in verrucous/ptychotropic disease (pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31)	HPO: Burning sensation
phenotype	Symmetric photo-distributed lesions	Characteristic DSAP distribution on extensor extremities and back/shoulders (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)	HPO: Photosensitivity-related skin finding; UBERON: skin of upper limb, skin of lower limb, back skin
diagnostic hallmark	Cornoid lamella	Histopathologic hallmark and defining diagnostic feature of porokeratosis spectrum (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 2-4)	SNOMED/pathology concept: cornoid lamella; GO/UBERON not directly applicable
diagnostic method	Dermoscopy	Often shows a peripheral keratotic rim corresponding to the cornoid lamella; helpful for clinical diagnosis and monitoring suspicious change (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)	NCIT: Dermoscopy
trigger/risk factor	Ultraviolet radiation / sun exposure	Major trigger and exacerbating factor, especially for DSAP; seasonal worsening and predilection for sun-exposed sites support gene-environment interaction (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 2-4)	CHEBI/Exposome: ultraviolet radiation exposure
trigger/risk factor	Immunosuppression	Important acquired trigger/risk state, including organ transplantation and immunosuppressive therapy (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, vargasmora2020porokeratosisareview pages 2-4, pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19)	NCIT: Immunosuppression
trigger/risk factor	Mechanical trauma / friction / scratching	Reported aggravating factors, especially in intertriginous/verrucous forms (pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31, pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, vargasmora2020porokeratosisareview pages 2-4)	Exposome term: skin trauma; friction exposure
trigger/risk factor	Medication-associated porokeratosis	Reported with several drugs in review literature; evidence is largely case-based (vargasmora2020porokeratosisareview pages 2-4)	NCIT: Drug exposure
trigger/risk factor	Infection-associated cases	Case-level associations reported for HPV, HSV, HCV, leishmania; causality uncertain (vargasmora2020porokeratosisareview pages 2-4)	NCBI Taxonomy terms as appropriate; label as reported trigger association
cancer complication	Keratinocyte carcinoma, especially squamous cell carcinoma	Main serious complication; overall malignant transformation estimated about 6.8-11.6% in one review, with higher risk in LP and PM than DSAP (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, vargasmora2020porokeratosisareview pages 2-4)	NCIT: Squamous Cell Carcinoma of the Skin; Basal Cell Carcinoma
prognostic factor	Large, long-standing, non-sun-exposed or acral lesions; older age; prior irradiation; immunosuppression	Factors associated with increased malignant risk in reviews (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, vargasmora2020porokeratosisareview pages 2-4)	NCIT: Risk factor
intervention	Topical lovastatin plus cholesterol	Pathogenesis-directed therapy based on mevalonate-pathway defect; studied prospectively in DSAP and now a principal modern intervention of interest (pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47, NCT04359823 chunk 1, NCT04359823 chunk 2)	NCIT: Lovastatin; CHEBI: cholesterol; NCIT: Topical Cream Dosage Form
intervention	Topical lovastatin monotherapy	Randomized DSAP trial suggests benefit may not require added cholesterol in all patients, though comparative evidence is still limited (NCT04359823 chunk 2, pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47)	NCIT: Lovastatin
intervention	Surgical excision / shave-curettage	Best suited to localized lesions and suspicious or transformed lesions; several case-based reports show good local control (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, vargasmora2020porokeratosisareview pages 12-13)	NCIT: Surgical Excision; Curettage
intervention	Cryotherapy	Common local destructive therapy with variable efficacy and recurrence risk (pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33, vargasmora2020porokeratosisareview pages 12-13)	NCIT: Cryotherapy
intervention	Topical 5-fluorouracil	Traditional topical option; some complete responses reported but evidence mainly case based (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, vargasmora2020porokeratosisareview pages 12-13)	NCIT: Fluorouracil
intervention	Topical imiquimod	Used especially in PM and some localized variants; response inconsistent (pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33, vargasmora2020porokeratosisareview pages 12-13)	NCIT: Imiquimod
intervention	Topical/systemic retinoids including acitretin	Frequently used for disseminated or hyperkeratotic disease; outcomes variable and relapse common (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, vargasmora2020porokeratosisareview pages 12-13)	NCIT: Acitretin; Retinoid Therapy
intervention	Photodynamic therapy / laser-based treatments	Employed in DSAP and localized lesions with modest or variable response and procedure-related adverse effects (pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47, vargasmora2020porokeratosisareview pages 12-13)	NCIT: Photodynamic Therapy; Carbon Dioxide Laser Therapy
prevention/surveillance	Sun protection and long-term skin cancer surveillance	Supported by the disease’s photo-triggering and premalignant potential; biopsy is recommended for suspicious change (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 2-4, vargasmora2020porokeratosisareview pages 12-13)	NCIT: Sunscreen/Sun Protection Counseling; Skin Examination
evidence caveat	Population prevalence/incidence	Robust population-based incidence and prevalence are not well established in retrieved sources; avoid over-precise epidemiologic coding without registry confirmation (vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 4-5)	annotation note: evidence gap
evidence caveat	Protective factors	No validated genetic protective factors were identified in the retrieved evidence base (pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, vargasmora2020porokeratosisareview pages 1-2)	annotation note: none established
evidence caveat	Model organisms / other species	No disease-faithful animal model or robust natural veterinary counterpart was validated in the retrieved materials; current evidence is mainly human clinical/lesional tissue based (pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43, vargasmora2020porokeratosisareview pages 1-2)	annotation note: evidence gap

Table: This table summarizes ontology-ready disease, gene, phenotype, mechanism, trigger, complication, and intervention annotations for porokeratosis. It is designed to support knowledge-base population while clearly labeling candidate or emerging findings and evidence gaps.

1. Disease information

Definition and terminology

Porokeratosis is an umbrella diagnosis encompassing multiple clinical variants of an epidermal keratinization disorder. Typical lesions are annular papules or plaques with an atrophic center and sharply raised, ridge-like peripheral scale. The histologic cornoid lamella is a column of parakeratotic cells overlying reduced or absent granular layer and abnormal underlying keratinocytes. The term porokeratoses appropriately emphasizes that this is a spectrum rather than one uniform phenotype. (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 2-4)

A directly relevant 2023 review abstract states: “Porokeratosis is a heterogeneous group of keratinising disorders characterised by … the presence of the cornoid lamella.” It further attributes this structure to a defective isoprenoid pathway critical to cholesterol synthesis. Publication: Pietkiewicz et al., Metabolites, 30 November 2023; DOI/URL: https://doi.org/10.3390/metabo13121176. (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7)

Identifiers

MONDO: an exact umbrella-class MONDO identifier was not reliably established in the retrieved sources and should be verified directly against the current MONDO release before ingestion.
MeSH: Porokeratosis.
ICD-10-CM: L56.5, disseminated superficial actinic porokeratosis. Other forms may be coded under broader local skin-disorder categories; coding should remain subtype- and jurisdiction-specific.
OMIM phenotype entries commonly used: disseminated superficial actinic porokeratosis (175800), porokeratosis of Mibelli (175900), and porokeratosis palmaris et plantaris disseminata (175850); these should be release-verified because porokeratosis is genetically heterogeneous.
Common synonyms: porokeratoses; disseminated superficial actinic porokeratosis (DSAP); disseminated superficial porokeratosis (DSP); porokeratosis of Mibelli (PM); linear porokeratosis (LP); porokeratosis palmaris et plantaris disseminata (PPPD); punctate porokeratosis; verrucous porokeratosis; porokeratosis ptychotropica; follicular porokeratosis; porokeratoma.

Most information in this report is aggregated disease-level evidence from reviews, cohorts, pedigrees, and trials—not individual EHR data. Case reports and lesional sequencing studies constitute patient-level evidence where explicitly noted.

2. Etiology and risk or protective factors

Causal and susceptibility factors

The strongest causal genes encode enzymes in the mevalonate/isoprenoid pathway:

MVK—mevalonate kinase;
PMVK—phosphomevalonate kinase;
MVD—mevalonate diphosphate decarboxylase;
FDPS—farnesyl diphosphate synthase.

Familial disease is usually autosomal dominant with incomplete and age-dependent penetrance. One synthesis reported approximately 22% penetrance for DSAP, although this figure should not be generalized to every genotype or subtype. Historical linked regions include 12q24.1–24.2, 15q25.1–26.1, 1p31.3–p31.1, and 16q24.1–24.3. SLC17A9, SSH1, and SART3 have been reported in older pedigree/candidate-gene literature, but their status is less secure than that of the four canonical pathway genes. (pietkiewicz2023porokeratoses—acomprehensivereview pages 43-44, pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, vargasmora2020porokeratosisareview pages 1-2)

Localized and linear lesions may result from postzygotic mosaicism or a second somatic event in epidermis. Human lesional studies have reported second hits or loss of heterozygosity involving mevalonate-pathway genes, including UV-signature C>T substitutions, supporting clonal expansion of biallelically impaired keratinocytes. (pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)

A major 2024 development was the report of gene-specific somatic epigenetic mosaicism of FDFT1 in nonhereditary localized porokeratosis (Saito et al., American Journal of Human Genetics, May 2024; DOI: https://doi.org/10.1016/j.ajhg.2024.03.017). This expands the disease model from sequence-level defects to focal epigenetic silencing of another cholesterol-biosynthesis gene, but independent replication and estimates of population contribution are still needed.

Environmental and acquired risk factors

UV radiation: the clearest environmental interaction, especially in DSAP. Lesions favor sun-exposed extensor limbs, often worsen in summer, and may be induced or aggravated by phototherapy. MVK also participates in keratinocyte differentiation and protection from UVA-induced apoptosis, providing a plausible gene–environment link. (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, vargasmora2020porokeratosisareview pages 4-5)
Immunosuppression: organ or bone-marrow transplantation, AIDS, hematologic disease, and immunosuppressive medication can precipitate or disseminate disease and increase malignant risk. An older review reported porokeratosis in approximately 10% of kidney-transplant recipients, generally 4–14 years after transplantation, but this estimate requires contemporary registry validation. (pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19, pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, vargasmora2020porokeratosisareview pages 2-4)
Trauma/friction: scratching, clothing friction, and local injury can aggravate lesions, particularly intertriginous verrucous/ptychotropic disease. (pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31, pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39)
Medication-associated cases: reports involve hydroxyurea, thiazide and loop diuretics, suramin, gentamicin, exemestane, selected biologics, trastuzumab, and antibiotics. Evidence is mostly case-based and does not establish comparable causal risk across drugs. (vargasmora2020porokeratosisareview pages 2-4)
Infections: HPV, HSV, HCV, and leishmaniasis have been reported in association with lesions, but none is established as a necessary infectious cause. Porokeratosis is neither contagious nor known to be zoonotic. (vargasmora2020porokeratosisareview pages 2-4)

No reproducible protective allele, diet, supplement, smoking/alcohol effect, or exercise association has been established. Practical environmental protection consists principally of reducing UV exposure and avoiding lesion trauma.

3. Phenotypes

Major clinicopathologic variants

DSAP: multiple pink-to-brown annular macules/papules, usually under 1 cm, symmetrically affecting sun-exposed arms and legs. Sporadic onset is commonly in the third–fifth decades; familial disease often appears in the third–fourth decades. It is usually asymptomatic, but pruritus occurs in up to one-third. Reviews describe female predominance, approximately 1.8:1, and DSAP as 42–56% of clinical series. Suggested HPO concepts: annular skin lesion, multiple skin lesions, hyperkeratotic papule, cutaneous atrophy, pruritus, adult onset. (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)
DSP: disseminated lesions on both exposed and covered skin, often beginning at ages 5–10 years. Suggested HPO: generalized skin lesions, childhood onset, hyperkeratosis. (vargasmora2020porokeratosisareview pages 4-5)
PM: one or several slowly enlarging plaques, often beginning in childhood in hereditary disease and later in sporadic disease; limbs and trunk predominate, but palms, soles, scalp, face, mucosa, and genital skin can be involved. Suggested HPO: plaque, annular skin lesion, childhood onset, pruritus. (pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19, vargasmora2020porokeratosisareview pages 4-5)
LP: congenital or early-onset lesions following Blaschko lines; often unilateral or segmental and slowly progressive. Suggested HPO: linear skin lesion, Blaschkoid distribution, congenital onset. (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, vargasmora2020porokeratosisareview pages 4-5)
PPPD/punctate disease: punctate or disseminated palmoplantar keratotic lesions; nail dystrophy and pseudoainhum are uncommon complications. Suggested HPO: palmoplantar hyperkeratosis, punctate keratosis, nail dystrophy. (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, pietkiewicz2023porokeratoses—acomprehensivereview pages 52-54)
Verrucous porokeratosis/ptychotropica: intensely pruritic or burning verrucous plaques, usually genitogluteal, perianal, or intertriginous. Lesions may spread centrifugally for 5–10 years. Male predominance and onset in the third–fifth decades are typical. Suggested HPO: verrucous lesion, pruritus, burning sensation. (pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31, pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33)
Follicular porokeratosis: folliculocentric keratotic lesions with plugs; the genetic basis remains uncertain. (pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36)
Porokeratoma: usually a solitary plaque or nodule lacking the classic annular rim; pooled cases had a male:female ratio of 19:4 and mean onset of 55 years (range 13–78). (pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36)
Eruptive pruritic papular porokeratosis: sudden inflammatory, itchy lesions; occasionally associated with malignancy or immunologic change and may regress when the associated disorder is treated. (pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47, vargasmora2020porokeratosisareview pages 4-5)

Quality of life

Formal EQ-5D/SF-36 data are sparse. Most burden derives from visible chronic lesions, pruritus, burning, treatment inconvenience, pigmentary change or scarring, and anxiety concerning malignancy. NCT04359823 therefore included the Dermatology Life Quality Index, appearance, color, size, pain, and itch as patient-centered outcomes. (NCT04359823 chunk 1, NCT04359823 chunk 2)

4. Genetic and molecular information

Pathogenic variants reported across the canonical genes include missense, nonsense, frameshift, splice-altering, and loss-of-function alleles. The aggregate mechanism is reduced enzymatic function rather than a well-established gain-of-function or dominant-negative effect. A 2016 study specifically identified loss-of-function PMVK variants causing autosomal-dominant disseminated superficial porokeratosis. PMVK variants were also detected in 5 of 134 index cases in one series containing porokeratoma, illustrating genetic heterogeneity rather than a universal subtype-specific mutation. (pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47, pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36)

Variant-level ACMG classification and allele frequencies must be assigned individually from the current ClinVar and gnomAD releases. It is unsafe to attach one classification or population frequency to a gene as a whole. Familial variants are germline; lesional second hits are somatic. Large recurrent chromosomal abnormalities, aneuploidy, repeat expansions, mitochondrial variants, and a routine role for karyotyping/FISH are not established. Chromosome 3p12–14 instability and lesional polyploidy have been described as tumor-associated findings, not as the usual inherited cause. (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39)

No clinically validated modifier gene or pharmacogenomic rule is available. The 2024 FDFT1 finding is the principal disease-specific epigenetic development; broader methylome, histone, single-cell, spatial-transcriptomic, proteomic, and metabolomic signatures remain insufficiently validated for diagnosis.

5. Environmental information

The disease is best regarded as a genetic or mosaic keratinocyte disorder whose expression is modified by UV exposure, immune surveillance, trauma/friction, and selected medications. There is no established toxin, pollution, occupation, diet, alcohol, tobacco, or exercise exposure with quantified causal effect. Warm climate and friction may worsen ptychotropic disease, while UV exposure is particularly relevant to DSAP. Infectious associations are triggers or coincident findings, not transmissible causes. (pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31, vargasmora2020porokeratosisareview pages 1-2, vargasmora2020porokeratosisareview pages 2-4)

6. Mechanism and pathophysiology

Causal chain

Upstream defect: germline or postzygotic impairment of MVK/PMVK/MVD/FDPS—or emerging focal FDFT1 epigenetic silencing—reduces normal mevalonate/isoprenoid-pathway flux.
Metabolic consequences: altered sterol/cholesterol synthesis and shortage of nonsterol isoprenoids disturb membrane biology and protein prenylation.
Cellular dysfunction: epidermal keratinocytes show abnormal differentiation, reduced granular layer, altered filaggrin/loricrin expression, dyskeratosis, and premature apoptosis.
Clonal localization: a somatic second hit, UV-induced mutation, or epigenetic event gives a local keratinocyte clone a distinctive lesional phenotype.
Tissue manifestation: centrifugally expanding abnormal epidermis creates the peripheral cornoid lamella and central atrophy.
Downstream inflammation and cancer risk: chronic injury, immune alteration, UV, and clonal genomic instability promote inflammatory symptoms and, in a minority, SCC/BCC or melanoma. (aersilan2022microrna874targetsphosphomevalonate pages 17-17, pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, vargasmora2020porokeratosisareview pages 2-4, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)

Relevant GO suggestions include cholesterol biosynthetic process; isoprenoid biosynthetic process; protein prenylation; keratinocyte differentiation; epidermis development; cornification; apoptotic process; cell-cycle regulation; and response to UV. The principal Cell Ontology term is keratinocyte; follicular stem/progenitor keratinocytes may participate in follicular disease. Lesional studies report p53, p63, p16^INK4a, survivin, and hTERT abnormalities, but these are downstream markers of stress, senescence, or neoplastic potential rather than validated diagnostic biomarkers. (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39)

7. Anatomy

The primary organ is the skin, specifically epidermis and epidermal appendages. Relevant anatomical mappings are epidermis; skin of upper limb; skin of lower limb; trunk/back skin; facial/scalp skin; palm; sole; genital skin; and perianal skin. Mucosal and nail involvement is uncommon but documented. The affected cellular compartment extends from basal/spinous keratinocytes to the granular and cornified layers; the most conspicuous structure is the parakeratotic cornoid lamella. No consistent internal-organ disease is intrinsic to ordinary porokeratosis. (pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19, pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33, vargasmora2020porokeratosisareview pages 2-4)

8. Temporal development

Onset ranges from congenital LP to childhood PM/DSP and adult DSAP or ptychotropica. Most lesions emerge insidiously and expand slowly over years. Disease is generally chronic or lifelong, with variable activity and occasional inflammatory eruptions. Spontaneous durable remission is uncommon; recurrence after treatment is frequent. Malignant transformation may occur decades after onset—one review reports intervals as long as 36 years—making long-term surveillance more important than short-term clearance alone. (pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)

9. Inheritance and population

The predominant familial pattern is autosomal dominant with incomplete, variable, and age-dependent penetrance. Expressivity is highly variable even within families. Segmental disease may reflect postzygotic mosaicism or type-2 segmental manifestation. Germline mosaicism, anticipation, founder effects, consanguinity effects, and carrier frequency are not well quantified. (pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, vargasmora2020porokeratosisareview pages 1-2, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)

Robust population prevalence and incidence per 100,000 are unavailable. Porokeratosis is conventionally described as rare, although recent registry work suggests it may be among the more frequent genodermatoses. DSAP is enriched in fair-skinned populations living in high-UV settings; no exclusive ethnicity is affected. Sex ratios vary by subtype: DSAP and LP show female predominance in reviews, whereas PM, PPPD, ptychotropica, and porokeratoma tend toward male predominance. (pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 1-2)

10. Diagnostics

Clinical and pathology workflow

Recognize the peripheral ridge or “Great Wall” morphology and subtype-specific distribution.
Perform dermoscopy: a sharply defined peripheral keratotic track corresponding to the cornoid lamella is characteristic. The furrow-ink test may accentuate the ridge.
Biopsy the raised border, not merely the atrophic center, when morphology is uncertain or malignancy is suspected.
Histology should identify a cornoid lamella, diminished/absent granular layer, dyskeratotic or vacuolated keratinocytes, and variable underlying inflammation. Multiple cornoid lamellae, papillomatosis, and psoriasiform hyperplasia favor verrucous disease. (pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19, pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33)

Reflectance confocal microscopy, conventional or UV-fluorescence dermoscopy, and emerging line-field confocal optical coherence tomography can improve noninvasive discrimination, but histopathology remains necessary for suspicious transformation. Routine blood chemistry, imaging, electrophysiology, or circulating biomarkers are not diagnostic.

Genetic testing

Testing is most useful in familial, early-onset, disseminated, linear/segmental, mixed, or atypical disease. A practical panel should include MVK, PMVK, MVD, and FDPS, with consideration of FDFT1 and research-level candidate genes depending on phenotype and laboratory validation. Sequence plus copy-number analysis is preferable. WES/WGS may help panel-negative pedigrees and mosaic cases; paired lesional and blood sequencing can detect somatic second hits. Standard CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing have low expected yield unless another syndrome is suspected. (pietkiewicz2023porokeratoses—acomprehensivereview pages 43-44, pietkiewicz2023porokeratoses—acomprehensivereview pages 5-7, pietkiewicz2023porokeratoses—acomprehensivereview pages 41-43)

Differential diagnosis

Actinic keratosis, SCC in situ/invasive SCC, superficial BCC, psoriasis, tinea corporis, lichen planus, pityriasis, seborrheic keratosis, epidermal nevus, viral warts, cutaneous T-cell lymphoma, and inflammatory genital dermatoses should be considered. Rapid growth, ulceration, pain, bleeding, marked induration, or a new nodule warrants biopsy. (pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36, pietkiewicz2023porokeratoses—acomprehensivereview pages 2-5, pietkiewicz2023porokeratoses—acomprehensivereview pages 16-19)

There is no population or newborn screening program. Cascade clinical examination and targeted familial-variant testing are reasonable after a molecular diagnosis.

11. Outcome and prognosis

Life expectancy is ordinarily normal, and disease-specific mortality statistics are unavailable. Morbidity is predominantly dermatologic, cosmetic, pruritic, and treatment-related. The major prognostic issue is malignancy. Reviews estimate overall keratinocyte-cancer transformation at approximately 6.8–11.6% or 7.5–11%. Subtype estimates include DSAP 3.4%, PM 7.6–8%, and LP 11–19%; these figures derive from heterogeneous series and are vulnerable to referral and publication bias. SCC is the dominant tumor, followed by BCC; melanoma has also been reported. (pietkiewicz2023porokeratoses—acomprehensivereview pages 37-39, pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, vargasmora2020porokeratosisareview pages 4-5, vargasmora2020porokeratosisareview pages 2-4)

Higher-risk features include large, long-standing, linear, acral or non-sun-exposed lesions, older age, previous irradiation, and immunosuppression. Porokeratoma has no reported malignant transformation in the summarized literature, whereas linear disease carries the highest consistently cited risk. (pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36, pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37)

12. Treatment

No universally accepted guideline or curative algorithm exists. Choice depends on lesion number, site, thickness, symptoms, cosmetic burden, immunosuppression, and cancer suspicion.

Pathway-directed topical statins

The strongest recent translational advance is topical statin therapy. By inhibiting upstream HMG-CoA reductase, topical lovastatin is intended to limit accumulation of potentially toxic intermediates; added cholesterol was intended to replace deficient end product. In NCT04359823, 31 adults were randomized and single-blinded to 2% lovastatin/2% cholesterol or 2% lovastatin alone, applied twice daily with occlusion for 12 weeks. Outcomes included DSAP-GASI, dermoscopic cornoid lamellae, lesion appearance/color/size, itch/pain, and DLQI. The study ran from 24 August 2020 through 23 April 2021. (NCT04359823 chunk 1, NCT04359823 chunk 2)

The publication is Santa Lucia et al., “Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone…,” JAMA Dermatology 159, 488–495, published March 2023; PMID 36947042; DOI: https://doi.org/10.1001/jamadermatol.2023.0205. Both regimens produced clinical improvement, and the trial did not establish that added cholesterol was necessary; small sample size, short follow-up, compounded formulations, and DSAP-only enrollment limit generalization. Earlier evidence included a 2021 split-body simvastatin/cholesterol study and a seven-person 2022 lovastatin/cholesterol series. (NCT04359823 chunk 2, pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47)

Suggested NCIt mappings: Lovastatin; Cholesterol; Topical Drug Administration; Cream Dosage Form.

Other therapies

Localized or suspicious lesions: complete excision provides pathology and definitive local control; shave/curettage, electrosurgery, cryotherapy, and ablative laser are alternatives. Excision yielded no relapse in 10 of 12 summarized cases, although this is uncontrolled evidence. (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, vargasmora2020porokeratosisareview pages 12-13)
Topical agents: 5-fluorouracil, imiquimod, retinoids, vitamin-D analogues, diclofenac, and corticosteroids have variable efficacy. One 17-person DSAP study found 3% diclofenac over 3–6 months prevented progression in more than 50%, not necessarily complete clearance. (vargasmora2020porokeratosisareview pages 12-13)
Systemic retinoids: acitretin may help extensive or hyperkeratotic disease but relapse and mucocutaneous/metabolic adverse effects limit long-term use. (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37)
Procedures: photodynamic therapy produced approximately 31–35% response in older studies but can be painful; CO₂, erbium, Q-switched ruby, and other lasers have inconsistent clearance and recurrence. (pietkiewicz2023porokeratoses—acomprehensivereview pages 46-47, vargasmora2020porokeratosisareview pages 12-13)
Ptychotropica: particularly treatment-resistant. In summarized reports, topical corticosteroids largely supplied only transient antipruritic benefit; imiquimod was fully effective in 1, partly effective in 1, and ineffective in 8 cases. CO₂ laser and surgery can clear limited disease, but recurrence occurs. (pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33)

There is no approved gene, cell, RNA, or immunotherapy and no established pharmacogenomic dosing rule. Treatment of SCC arising in porokeratosis follows skin-cancer standards.

13. Prevention

Primary: rigorous sun protection—protective clothing, shade, and broad-spectrum sunscreen—especially in DSAP or genetically susceptible relatives; minimize unnecessary phototherapy and repeated lesion trauma.
Secondary: regular self-examination and periodic clinician examination. Biopsy lesions showing rapid growth, nodularity, ulceration, bleeding, pain, or induration. Immunosuppressed patients and those with LP, large PM, or prior radiation merit closer review.
Tertiary: treat symptomatic or repeatedly traumatized lesions, optimize immunosuppression when medically feasible, and excise confirmed malignant transformation.
Genetic counseling: explain autosomal-dominant inheritance, incomplete penetrance, variable expression, and mosaic disease. If a familial pathogenic variant is known, cascade, prenatal, or preimplantation testing is technically possible, but proportionality should be considered because isolated porokeratosis is usually compatible with normal lifespan.

No vaccine, chemoprophylaxis, newborn screening, or validated preventive systemic medication exists. (pietkiewicz2023porokeratoses—acomprehensivereview pages 36-37, vargasmora2020porokeratosisareview pages 2-4, vargasmora2020porokeratosisareview pages 12-13)

14. Other species and natural disease

The retrieved evidence did not establish a well-characterized naturally occurring veterinary counterpart with a conserved causal genotype, breed association, or OMIA entry. Histologic cornoid-lamella-like lesions may be described in veterinary pathology, but they should not automatically be equated with human Mendelian porokeratosis. There is no zoonotic transmission. Orthologues of MVK, PMVK, MVD, FDPS, and FDFT1 are broadly conserved, supporting comparative biochemical studies, but not establishing homologous natural disease.

15. Model organisms and experimental systems

No disease-faithful mouse, rat, zebrafish, fly, or worm model emerged as a validated standard. Current mechanistic evidence rests mainly on:

human pedigrees and germline sequencing;
paired lesional/nonlesional skin sequencing for second hits;
human histopathology and immunohistochemistry;
cultured keratinocyte experiments addressing mevalonate flux, apoptosis, differentiation, and rescue by pathway metabolites.

A useful future model would conditionally reduce a pathway gene in sparse epidermal keratinocytes, permitting clonal mosaic expansion and controlled UV exposure. Global biallelic disruption may model severe systemic mevalonate disorders rather than cutaneous porokeratosis, which is an important limitation. Patient-derived keratinocyte organoids or reconstructed epidermis, CRISPR-corrected isogenic controls, single-cell RNA/ATAC sequencing, and spatial metabolomics are high-priority platforms but are not yet validated clinical tools.

Evidence limitations and interpretation

The evidence base is dominated by case reports, small series, retrospective cohorts, and heterogeneous clinical definitions. Variant frequencies and cancer-risk percentages should therefore be stored with provenance and confidence metadata, not treated as universal population estimates. Exact abstract quotations were limited to retrieved source text; the principal quoted 2023 review is secondary evidence. Variant-specific pathogenicity, HGNC IDs, gnomAD frequencies, and MONDO/ontology numeric identifiers should be release-checked before production ingestion. The best-supported current conclusions are the cornoid-lamella phenotype, mevalonate-pathway genetic architecture, germline-plus-somatic/mosaic disease model, UV and immunosuppression interactions, malignant potential, and early clinical efficacy of topical lovastatin-based therapy.

References

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(pietkiewicz2023porokeratoses—acomprehensivereview pages 29-31): P. Pietkiewicz, Katarzyna Korecka, Natalia Salwowska, Ihor Kohut, Adarsha Adhikari, M. Bowszyc‑Dmochowska, A. Pogorzelska-Antkowiak, and C. Navarrete-Dechent. Porokeratoses—a comprehensive review on the genetics and metabolomics, imaging methods and management of common clinical variants. Metabolites, Nov 2023. URL: https://doi.org/10.3390/metabo13121176, doi:10.3390/metabo13121176. This article has 42 citations.
(pietkiewicz2023porokeratoses—acomprehensivereview pages 31-33): P. Pietkiewicz, Katarzyna Korecka, Natalia Salwowska, Ihor Kohut, Adarsha Adhikari, M. Bowszyc‑Dmochowska, A. Pogorzelska-Antkowiak, and C. Navarrete-Dechent. Porokeratoses—a comprehensive review on the genetics and metabolomics, imaging methods and management of common clinical variants. Metabolites, Nov 2023. URL: https://doi.org/10.3390/metabo13121176, doi:10.3390/metabo13121176. This article has 42 citations.
(pietkiewicz2023porokeratoses—acomprehensivereview pages 34-36): P. Pietkiewicz, Katarzyna Korecka, Natalia Salwowska, Ihor Kohut, Adarsha Adhikari, M. Bowszyc‑Dmochowska, A. Pogorzelska-Antkowiak, and C. Navarrete-Dechent. Porokeratoses—a comprehensive review on the genetics and metabolomics, imaging methods and management of common clinical variants. Metabolites, Nov 2023. URL: https://doi.org/10.3390/metabo13121176, doi:10.3390/metabo13121176. This article has 42 citations.
(pietkiewicz2023porokeratoses—acomprehensivereview pages 43-44): P. Pietkiewicz, Katarzyna Korecka, Natalia Salwowska, Ihor Kohut, Adarsha Adhikari, M. Bowszyc‑Dmochowska, A. Pogorzelska-Antkowiak, and C. Navarrete-Dechent. Porokeratoses—a comprehensive review on the genetics and metabolomics, imaging methods and management of common clinical variants. Metabolites, Nov 2023. URL: https://doi.org/10.3390/metabo13121176, doi:10.3390/metabo13121176. This article has 42 citations.
(aersilan2022microrna874targetsphosphomevalonate pages 17-17): Alimasi Aersilan, Naoko Hashimoto, Kazuyuki Yamagata, Masataka Yokoyama, Akitoshi Nakayama, Xiaoyan Shi, Hidekazu Nagano, Ikki Sakuma, Nijiro Nohata, Takashi Kinoshita, Naohiko Seki, Bahityar Rahmutulla, Atsushi Kaneda, Siti Nurul Zhahara, Yingbo Gong, Motoi Nishimura, Shoichiro Kawauchi, Eiryo Kawakami, and Tomoaki Tanaka. Microrna-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway. Scientific Reports, Nov 2022. URL: https://doi.org/10.1038/s41598-022-23205-w, doi:10.1038/s41598-022-23205-w. This article has 17 citations and is from a peer-reviewed journal.
(vargasmora2020porokeratosisareview pages 12-13): P. Vargas-Mora, D. Morgado-Carrasco, and X. Fustà-Novell. Porokeratosis: a review of its pathophysiology, clinical manifestations, diagnosis, and treatment. Sep 2020. URL: https://doi.org/10.1016/j.adengl.2020.08.005, doi:10.1016/j.adengl.2020.08.005. This article has 107 citations.

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Inheritance

Subtypes

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Prevalence

Differential Diagnoses

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

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Output Format

Porokeratosis: comprehensive disease-characteristics report

Executive summary

1. Disease information

Definition and terminology

Identifiers

2. Etiology and risk or protective factors

Causal and susceptibility factors

Environmental and acquired risk factors

3. Phenotypes

Major clinicopathologic variants

Quality of life

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

7. Anatomy

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and pathology workflow

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Pathway-directed topical statins

Other therapies

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Evidence limitations and interpretation

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